David Baltimore, Biologist, Nobelist, President Emeritus

Over the past seventy years, David Baltimore has been witness to, and a central participant in, every major scientific and administrative development in molecular biology from its inception in the 1950s to biotechnology and the world of health science today. Baltimore's recollections and perspective constitute a treasure trove for the history of science, and for understanding how universities, government agencies, and private enterprise work together to translate fundamental discoveries in biology to human betterment. In the discussions below - transcribed from fourteen interview sessions totaling over thirty hours of audio - readers will follow Baltimore's perspective and storytelling on biology, science and society, higher education, and national policy, among others.

Born in 1938 in New York, David Baltimore gravitated early toward biology, intuiting that the field was ripe for revolutionary advances that would transform the study of life. As he tells it, Watson's and Crick's discovery in 1953 of the double helix model of DNA - arguably the most important scientific advance in biology in the twentieth century - barely registered at the time, because the world was simply not ready to grasp its implications for understanding life at the molecular level. After a formative experience in high school at the Jackson Lab in Bar Harbor, Maine, where he first experienced cutting-edge laboratory work, Baltimore enrolled at Swarthmore College, eschewing larger schools such as Harvard and Yale in favor of a more intimate academic environment offering greater access to professors. By the late 1950s, when the import of the DNA discovery had reverberated and was advancing the field of molecular biology, Baltimore conducted research at Cold Spring Harbor Laboratory, where he met luminaries including Salvador Luria and Cyrus Levinthal. These meetings cemented Baltimore's decision to pursue graduate work at MIT, where he shifted his initial focus on phage genetics to animal virology.

In the first of many bold decisions in his career, Baltimore then determined his best move was to transfer to Rockefeller University, where Richard Franklin's lab was pursuing field-leading work in virology and RNA studies. Baltimore completed his PhD in three years, and returned immediately to MIT for a postdoc with Jim Darnell before moving to Jerry Hurwitz's lab at the Einstein School of Medicine in New York. By this point, Baltimore was considered the leading expert in poliovirus, and his research held promise for breakthrough understanding of the mechanisms and interplay of RNA and DNA. As he emphasizes, his own ambitions - and those in biology as a whole - were completely rooted in fundamental research. Although one could be imaginative about the potential benefits of this work toward some future progress in human health science, the notion of translating basic science to clinical benefit in the 1960s was fantastical. As Baltimore reflects, there was simply too much to understand about the basic operative functions of molecules before one could think about therapies and medicines.

In 1965 Baltimore joined the Salk Institute in La Jolla California to work with Renato Delbucco, where he continued his poliovirus research. Earlier in his life, California seemed too removed from the classic New Yorker's perspective that puts the East Coast at the center of the universe, but as an independent investigator with his own lab, Baltimore felt ready for an adventure. These years also provided his first interface with Caltech, which he recognized from undergraduate days as one of the leading centers of genetics. His return to MIT in 1968 as an assistant professor put him on the path to the discovery of reverse transcriptase. In partnership with the biologist Alice Huang, whom he met at Salk and would later marry, Baltimore worked on vesicular stomatitis virus and RNA tumor viruses. In a case of multiple independent discovery alongside Howard Temin, Baltimore showed that genetic information was exchanged between RNA and DNA as a two-way street. In comparing the field's reaction to this discovery to what Watson and Crick had achieved in 1953, Baltimore provides key perspective on how discovery begets discovery in science. Whereas no one was prepared to understand the import of the DNA model because biology was in "the dark ages" when Baltimore was a college student, by the time he was an MIT professor, the revolutionary advances primed the field to grasp the profound implications for Baltimore's and Temin's discovery as a foundation point for immunology, virology, and cancer research. The "buzz" around the Nobel Prize began immediately, and Baltimore reflects poignantly on the impact of this experience.

The level of recognition of this singular honor changes the career and life direction of every Nobel Prize winner. For Baltimore, it offered an opportunity for departure and renewal. On the former, he determined the time was right to leave active laboratory experiments to his graduate students and postdocs (as he muses, the last experiment he did himself was in 1975) and to focus on institute building and national policy. In 1973 he spearheaded the effort to create the MIT Cancer Institute at a time when federal support of basic biological research massively increased in the hopes that recent discoveries would ultimately lead to curing diseases. In the mid-1970s, Baltimore was also a key player in the development of the Asilomar Conference and the creation ultimately of a biosecurity regime, which recognized that advances in recombinant DNA research required highly regulated precautions to prevent nightmarish scenarios of virulent outbreaks.

In the 1980s Baltimore had built up his MIT laboratory as a large and thriving organization with dozens of graduate students and postdoctoral scholars conducting leading work in genetics, virology and cancer research. As he quips, and in taking a page out of the hands-off style of his mentors, Baltimore's students did their best work when he was engaged in other matters. Two major endeavors occupied Baltimore's attention during this time. In 1982 Baltimore began the launch of the Whitehead Institute for Biomedical Research with a donation from the businessman Jack Whitehead, and in the mid-1980s, he became a leading advocate for a more robust government response to the HIV/AIDS epidemic. It was also during this time that the so-called "Baltimore Case" metastasized from confusion over note taking in Baltimore's laboratory into a full-blown Washington scandal about supposed scientific malfeasance and misuse of NIH funding. This case, which garnered headline media attention, has been examined exhaustively elsewhere, but Baltimore's firsthand account below adds valuable detail to the historical record.

On the mistaken assumption that the scandal was behind him, in 1990 Baltimore became president of Rockefeller University. As an alumnus, and as one of the most accomplished and well-regarded biologists of the time, Baltimore came in with a mandate to change Rockefeller's research culture which was geared exclusively for the benefit of senior faculty, toward one that provided greater support and promotion opportunities for junior faculty. With the scandal in Washington reigniting and a faculty rebellion against Baltimore's mandate, he ended his presidency abruptly and eventually returned to MIT, where he faced an uncertain future. When the final report of the "Baltimore Case" fully vindicated Baltimore and his associates from charges of wrongdoing, he met the moment with elation and relief, and lessons learned regarding the importance of meticulousness for laboratory note taking to ease experimental reproducibility. But the question lingered: was the harm done to Baltimore's reputation beyond repair?

It is a testament to Caltech's values and its laser-focus on excellence in research and leadership that its presidential search committee looked beyond the distractions of the "Baltimore Case" when it recruited Baltimore to succeed Tom Everhart as Institute president. From his initial conversations in Pasadena, Baltimore determined that he needed several months to immerse himself in Caltech's unique culture and to understand in particular the importance of Caltech's management of JPL. During his tenure as Caltech president from 1997-2006, Baltimore led the Institute's Biology Initiative to expand and modernize biological research across campus, he secured the historic $650 million gift from alumnus and Intel cofounder Gordon Moore, he oversaw JPL's successful launch of the Mars rover and exploration program, and he spearheaded efforts to make campus more diverse, with particular emphasis on encouraging more opportunities for women students and faculty members. As he reflects on the scientific accomplishments of his mother and his wife, promoting women in science always seemed natural to Baltimore; as Caltech president he was provided a unique platform to transform this sentiment into real and positive change.

Crucially, as a condition of his acceptance to become president, Baltimore insisted that he would maintain an active lab. By the turn of the century, he was convinced that technological advances and experimental breakthroughs would finally translate into large scale successes in drug delivery and therapies in the biotech sector. His partnership with the Gates Foundation advanced prophylactic strategies for protection against HIV infection (absent the elusive quest to create an HIV vaccine) and his focus on gene expression has led to promising new directions in cancer therapies. After closing his lab in 2018, Baltimore is fully engaged in biotechnology startups, he has served in an advisory capacity for the scientific response to the Covid pandemic crisis, and his long term goal is to establish Los Angeles as a "hub" of biotechnology innovation for decades to come.

In all, Baltimore's narration of his life and surrounding events underscore that science is a fundamentally human endeavor, filled with Shakespearian-level drama that cannot, and should not, be cloistered away from the broader challenges in society. In committing himself to leadership beyond the lab, Baltimore's contributions have changed not only the way we understand the molecular basis of life, but the way we understand how to harness science for the benefit of humankind. Perhaps the fundamental secret of Baltimore's success is that he has never let go of the notion that he is, and always has been, a student willing to learn from mistakes and to build on the strengths of others.

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, December 22nd, 2021. I am delighted to be here with Professor David Baltimore. David, thank you so much for joining me today.

DAVID BALTIMORE: Pleasure.

ZIERLER: To start, would you please tell me your current title and institutional affiliation at Caltech?

BALTIMORE: I am President, Emeritus; Professor of Biology; and I hold a chair, which was the Millikan Chair, and then was changed, because of the association of Millikan with eugenics, to the Judge Shirley Hufstedler Chair. Shirley Hufstedler was a woman I knew and was a member of the board of Caltech. I guess she was the first female secretary of the United States.

ZIERLER: Of Education.

BALTIMORE: Secretary of Education, and just a wonderful, liberal icon.

Giving up the Millikan Chair

ZIERLER: Having been named in Millikan's honor, having held that chair for so long, was it difficult for you to give that up, to feel compelled to give it up, or what was the thought process?

BALTIMORE: I was on the committee that decided to change the name of anything associated with Millikan. We decided some other things, too. It was hard. It was hard because first of all, Millikan represented some wonderful things. He was a great scientist. He was a great developer of scientific institutions. I was proud to keep that name.

ZIERLER: In some ways it was considered the highest honor at Caltech.

BALTIMORE: Yeah, it was an honorary chair that was given by the president. I can't remember who had it previously.

ZIERLER: But you took that on after you stepped down as president?

BALTIMORE: Yes. When I was president, I was just president. The president now has a named chair, but in the time when I was president, there was no named chair for the president.

ZIERLER: There's a generational divide, of course, in the Caltech community, about taking Millikan's name down, where a lot of people on the more senior side are upset about the issue.

BALTIMORE: Yeah.

ZIERLER: I wonder, for you, who's of that senior generation but being part of the renaming committee, how you balanced those considerations.

BALTIMORE: I had to look in my own heart and recognize that what Millikan had done was to violate the principles of science, because he accepted the notion of eugenics and honored it, believed in it, when in fact there was already such strong evidence against it and in favor of a sort of commonality of inheritance, that he should have known better.

ZIERLER: You're saying it's important to judge him by the historical standards of his own time?

BALTIMORE: That's right. If I really believed that he had acted in full good faith, I would have been much less comfortable with changing the name, ridding Caltech, really, of the name. Because he's at the heart of the history of Caltech.

ZIERLER: As a Jewish person, did that influence your views at all?

BALTIMORE: If I started taking umbrage as a Jewish person, I couldn't have anything to do with Caltech at all, because anti-Semitism was so strong in this area among the supporters of Caltech, the board members of Caltech. But the same thing is true throughout America. I grew up in New York City, which is sort of an island of acceptance of Jews, because so many Jews did make their lives there and became very prominent members of the society. I never actually felt anti-Semitism as I grew up. But the history is very plain, and Caltech, this area of California was just rabidly anti-Semitic.

ZIERLER: When you came to Caltech, were you aware of Millikan's association with the eugenics movement?

BALTIMORE: No, I was not. Well, no, wait a minute; that's not completely true, because—maybe when I came here, I wasn't aware of it, but by the time I got the chair, I was aware that he and other members of the Board—

ZIERLER: Munro, Robinson, people like that?

BALTIMORE: —right—had been members of the eugenics movement, had been officials in the eugenics movement. He wasn't just a member of an organization without any involvement; he was a member of the board.

ZIERLER: He was active?

BALTIMORE: He was active. He wasn't as active as some other people, but he was active.

ZIERLER: Even if you had a faint understanding of this connection, did you have any misgivings in taking on the name?

BALTIMORE: I did. I recognized, in fact I commented to people, that you have to accept a certain amount of unpleasantness along with a named chair for somebody who comes out of the history of Caltech, or probably of many different institutions. But I said the importance of Millikan to Caltech and his importance to science, the very brilliant work he had done, to my mind overweighted the history. But as the history became more and more a concern of students, of other faculty, of the general public, my own feeling about which way it was weighted changed.

ZIERLER: As president, prior to being named in honor of Millikan, were there opportunities to offset those concerns in earlier iterations of what we now call diversity and inclusivity initiatives?

BALTIMORE: During the time I was president, the focus was so much on gender that those concerns were—not exactly swept under the rug, but not prominent. What was prominent was the very strong gender imbalance which had been a part of Caltech's history. Caltech was a men's school. We found lots of evidence of that in looking into Millikan and the other members of the board, because they were totally accepting of the notion that women were unfit to be professors. Millikan was a physicist, and the idea of a woman physicist was inconceivable to him. That was true throughout the history of Caltech up until really almost up to my presidency. Certainly, the couple of presidents before me were conscious of that, I'm sure, and were generally reasonably liberal people, at least. Who was the president—? Not before me; that was Tom Everhart.

ZIERLER: Harold Brown?

BALTIMORE: Harold Brown, right.

ZIERLER: The first Jewish president of Caltech.

BALTIMORE: Right, right.

ZIERLER: Although he was not very out front with his identity, I don't believe.

BALTIMORE: That was, as far as I know, not a part of his thinking.

ZIERLER: Do you see the events leading to the creation of the renaming committee, of course taken in the context of a very difficult 2020 with the murder of George Floyd and so many other tragedies, as a quickly developing event, or one that was more of a slow burn that reached a crescendo in 2020?

BALTIMORE: Oh, no, that was a quickly developing perspective that we had. Until the murder of George Floyd, that was not a prominent concern of any sort.

ZIERLER: For all the years that you were Millikan Professor, there weren't particularly among the younger generation—students, graduate students—misgivings that were voiced about Millikan and his views?

BALTIMORE: Not to me, and not that I ever heard about, but I think there weren't. I really think that people were simply not aware of the pervasiveness of the eugenics movement and of the meaning of it, the association with Nazis, the association with World War II, the Holocaust. I think all of that was just not a concern.

ZIERLER: Is it better that Caltech institutionally was reactive rather than proactive in coming to grips with this legacy?

BALTIMORE: It would not have ever happened proactively.

ZIERLER: Too much of a headache? Too difficult?

BALTIMORE: Yeah, and we had more immediate concerns. As I said, gender was the dominant one. When I came here, there were about, I don't know, 20% women, something like that, and we now have about 50% women.

ZIERLER: That's a tremendous advance. For a brief time, before being named in honor of Hufstedler, you were simply, I believe, Distinguished Professor.

BALTIMORE: Yeah, that was something we came up with, because I didn't want it to look like they hadn't honored me at all at the university. Actually, many places took that name—"distinguished"—and used it in place of names that they were getting rid of, or certainly looking into.

ZIERLER: Did you choose Hufstedler, or how did that work?

BALTIMORE: No, it was chosen by the board. I was perfectly comfortable with Distinguished Professor, actually. [laughs] But I was very glad of it, because I had known her pretty well, and really admired her.

ZIERLER: She was a trustee?

BALTIMORE: She was an active trustee. She really came from a time when to be a liberal thinker as she was, a strong Democrat, in Southern California, was to really be a pioneer. I had every reason to admire her as a person. When you're president, you come across legal issues that your own background is not really able to handle, just things you haven't ever run into, so I had a special appreciation for the people on the board who had legal training and would turn to them in sticky situations and get some advice about which way to move. She was one of those people.

ZIERLER: I wonder if your interest in promoting women to rebalance the imbalance among the genders as president, being named in her honor, I wonder if that was particularly meaningful for you?

BALTIMORE: I was very glad that that happened. In the naming committee, when we considered alternatives—we didn't have a mandate to name names, but we were asked to consider what would be appropriate names, so we looked very hard for women. As I remember, her name didn't come up, and one way or another, I hadn't thought of her. Somebody on the board, and I can even guess almost who, was a particular admirer of Shirley and suggested her.

ZIERLER: Different topic—sad news this week—we lost Bob Grubbs.

BALTIMORE: Yes, I wasn't very aware that he was that ill.

ZIERLER: I wonder if you'd like to take the opportunity to reflect on his legacy, what he meant for Caltech, if you knew him well.

BALTIMORE: I knew him somewhat. I didn't know him well. He was in a different division. He did a very different kind of science from what I was aware of. When I came here, I was actually not aware of his prominence, but by the time he received the Nobel Prize, it was clear to me that he was deserving of it. He was sort of a gentle giant, a big guy, and also a trout fisherman, as I am, so we talked fishing occasionally. He was representative of the best of Caltech, in not being particularly demonstrative, in being involved deeply in his own work, in his own scientific considerations. He actually reflected a position that was representative of some of the older faculty, even though he wasn't that old, in that he didn't take it as a goal to develop the commercial side of his activities. He was really interested in the scientific side and what kinds of reactions he could catalyze. He recognized that the reactions he had developed were very useful in a practical sense, and so he did develop Materia, the company through which he funneled a lot of his translational work.

ZIERLER: Was he on the earlier side of that broader historical development of startup culture at Caltech, for which people like Lee Hood, for example, thought was not developed enough?

BALTIMORE: Right. I think he was sort of halfway in between. He recognized that developing the commercial side of the metathesis reactions was a positive thing for society, and presumably positive for him and his family, but he didn't then sort of devote his later years, as some people have—somebody like Lee Hood did—very much, to forming companies. But he was interested in it, and he had a good balance.

Covid Becomes Endemic

ZIERLER: Another current question. We're heading into an omicron wave right now.

BALTIMORE: Oy! We sure are.

ZIERLER: Are we at a point in the pandemic where no end is really in sight at this point?

BALTIMORE: We've been there for a while, almost from the beginning. I think most infectious disease people have said, "This is going to become endemic."

ZIERLER: What will that look like, and what's the difference?

BALTIMORE: It will look like every other virus. In fact, the movement towards a more infectious, less pathogenic virus, which omicron seems to be, is exactly what you expect, because if viruses are too lethal, they are selected against, very strongly. Particularly for a respiratory virus, the equilibrium position is to be mildly pathogenic, non-lethal—generally—and to spread around humans, ultimately becoming so focused on human infection that it doesn't infect anything else. Viruses like mumps, measles, chicken pox, are all of that sort. They had enough disease causation and enough lethality that we've developed vaccines against them, so that they're not the plagues they were years ago—polio, in particular, in my childhood was a scourge. Polio only infects humans and certain monkeys, but it doesn't even spread among monkeys. It only spreads in humans. So we could create a vaccine against it, and prevent its spreading in humans, and then there should be no other source of it. In this way we've virtually eliminated polio from the world. We have eliminated smallpox from the world. Also another virus, rinderpest, which doesn't affect humans, but it affects cattle. Coronavirus could evolve to become quite human-specific, at which point we might be able to get rid of it.

ZIERLER: If omicron has suggested that the virus is on the way to becoming endemic, does that mean in the broad scale of things, that's good news? What's the other option?

BALTIMORE: It is good news, because if it's true that omicron is significantly less pathogenic, and that's what it's looking like.

ZIERLER: Fewer hospital rates, fewer ICU admissions?

BALTIMORE: That's right, and those things are indicative of a virus which is causing less severe illness.

ZIERLER: The control is among the unvaccinated, I would assume?

BALTIMORE: The control is first of all the delta virus, which causes really severe disease. That's sort of unstable in a society, and particularly when we have a vaccine to fight against it. We could have brought down delta, I think. Particularly if we can get people to take the vaccine, we could bring it down to very low levels. But with omicron, it might get to the point where it is just a cold virus again. That's what we don't know. At least I can't suss out from the reporting—we're really dependent on journalistic reporting—whether it might be so benign that it begins to approach or becomes the equivalent of a common cold.

ZIERLER: There's a lot more on the Greek alphabet to go through first, though.

BALTIMORE: Maybe, maybe not. I mean, it's really strange that it came out with 50 mutations as if it incubated itself somewhere. People say maybe in a person who was immunocompromised, and you can get an aggregation of lots and lots of mutations over time.

ZIERLER: Why would an immunocompromised person be a host for something that could mutate so much? What does that tell us?

BALTIMORE: It just means that the virus keeps growing and mutating in one person and so can evolve over long genetic distances to the point of being a wholly new kind of entity, which it really is, amazingly so. I've never paid a whole lot of attention to the evolution of viruses as they spread in the population. I've been interested in the evolution of viruses on longer time scales. But I've never seen evidence that we understood the rates of mutation as well as we do for the coronavirus for any other virus. The idea that a virus can change wholesale was to me new. I just had never seen it before. Most of my work, early work particularly, was on poliovirus. Poliovirus is an incredibly stable virus. There are three kinds—type 1, type 2, type 3—and they maintain their identity. They can recombine with each other, but they don't, not much anyway. You occasionally do see evidence of a recombination, but you don't see any evidence of wholesale change, wholesale mutation. In particular, we've never had to change the nature of the vaccine from the earliest days of the generation of the vaccine. That's true for all of these viruses. It's true for mumps and measles and chickenpox and whatever. We don't ever make new vaccine variants. We just don't see this kind of mutation, and it's fascinating to see it. It's an experiment in natural history.

ZIERLER: It's also terrible for PR, for all the people who are suspicious of the vaccines.

BALTIMORE: Oh, yeah.

ZIERLER: It only strengthens their suspicion to see that we're in this arms race, vaccine versus a constantly changing virus.

BALTIMORE: [laughs] I've been saying this now to people—I think we have to think carefully about the way we talk to the general community. We very much said, and in fact this was a mantra through the terrible Trump times, that it's important to believe in science, that you have to accept the changing understanding that science brings us, of whatever, of a virus.

ZIERLER: Scientists are not omniscient. They can't be prophets. They can't see what's going on ahead of their time.

BALTIMORE: Well, but they also are readily accepting of changed perspective. Things that we believe in our core, we change overnight. Plate tectonics is a good example of that. For years, people said it was just nonsense, and then with the right piece of evidence, it was common wisdom.

ZIERLER: Dogma is for religion, is what you're saying.

BALTIMORE: Yeah. [laughs]

ZIERLER: A policy question: at the most basic level, do you believe that the Chinese government itself knows for sure where COVID-19 originated?

BALTIMORE: I just don't know. I do know that they are being very much less than transparent about things that they should have knowledge of, but whether they're doing that as a reflex reaction, or they're doing it because they know something that they don't want to admit to, I can't tell, because those two things look alike. I know that they have a reflex reaction of hiding anything which is unpleasant, controversial, anti-Communist dogma of the moment. I don't know if they know something they're not telling us. I wish I did.

ZIERLER: It really could go either way with the reflex reaction. It could have come out of the Wuhan Institute, or it could have come out of the wet market. If they're not being transparent, it doesn't tell us anything one way or the other?

BALTIMORE: Right. Now, their reaction to clean up the wet market and to not, at least as far as I know, save samples that could be helpful, makes it very hard to go back and look at how that evolved. There's enough suggestion that there were people infected in Wuhan before the first indication of the virus, of sick people, people who had maybe less severe illness, so that it may not have evolved in the wet market. It may have actually evolved somewhere else, somehow else, and made its way into the wet market, because the virus does infect lots of different animals.

ZIERLER: Again, unlike so many other viruses.

BALTIMORE: Right, domestic pets and—because it hasn't had a chance to evolve into a human virus. It's still in the process of making that adaptation.

ZIERLER: Has your thinking on the so-called "lab leak" theory changed over the past two years?

BALTIMORE: Yeah. I have become more aware of the diversity of strains of virus that exist, and the many, many isolates that have different kinds of structure around the cleavage site, and so there is certainly a larger pool of evolved cleavage mechanism than I knew about. Coronaviruses were a footnote when I first taught virology. I hardly mentioned them. I hadn't ever become knowledgeable on the literature about coronaviruses, so I had a lot of learning to do.

ZIERLER: Does the "lab leak" theory strike you now as more plausible than when this first started?

BALTIMORE: Not more. In fact, maybe less, just because there are so many other ways it could have happened, all of which are of low but significant probability.

ZIERLER: Were you in touch with the NIH or anyone in the CDC when all of this was happening?

BALTIMORE: No.

ZIERLER: From a public health perspective, what are some of the missed opportunities that government officials missed in the early days of the pandemic?

BALTIMORE: In the very early days, the lack of recognition in Wuhan of what was going on, and the lack of a public health culture that would have saved lots of samples, is unfortunate.

ZIERLER: For history, or for the next pandemic?

BALTIMORE: For both. For allowing us to reconstruct what happened, and as a warning into the future.

ZIERLER: What about the World Health Organization? Where have you seen their strengths and weaknesses?

BALTIMORE: They're so political, and underfunded. They make an effort to be the international spokesmen, but I don't see them as particularly sophisticated, how they deal with a new challenge like this.

Biology and Political Freedom

ZIERLER: Totally different topic, going back in time. It was wonderful to hear Alex Varshavsky narrate the course of events that got him to the United States, and he emphasized with such gratitude your central role in this process. It would be wonderful to hear your narration of it. We could start first from that phone call you got when he was in diplomatic limbo in Germany. Do you remember that phone call?

BALTIMORE: Yeah, I do remember getting it.

ZIERLER: Do you remember where you first met him? Did you go to a conference in Russia?

BALTIMORE: When I arrived at Caltech, Alex gave me this (handing David Z a picture that ordinarily hangs on a wall in our house.). This is a picture taken in the auditorium of a physics research laboratory in Kiev where there was a joint meeting of biological scientists from the US and Soviet Russia. This group of American scientists had come to Russia, and there was a symposium that was held in Kiev, and the Russians came here from Moscow and elsewhere, and we came from various parts of the United States. That's me. That's Wally Gilbert. This is John Abelson and his then-girlfriend. He married her, later.

ZIERLER: You're wearing headphones; it's being translated?

BALTIMORE: Yes, right. This was Goldfarb, who was a very great Russian scientist. The Russians don't have earphones, but some Americans don't either.

ZIERLER: Varshavsky is not in this photo, but he was at the conference?

BALTIMORE: He was at the conference. This is Spirin, who was a great Russian scientist. That's Varshavsky right there.

ZIERLER: Oh! Look at that! [laughs]

BALTIMORE: And I think his father was also there. It's a great picture.

ZIERLER: To have attracted you, there must have been some cutting-edge research that was going on there.

BALTIMORE: Oh, no, anything would have attracted any of us, just because none of us had ever been to Russia.

ZIERLER: [laughs]

BALTIMORE: To have the diplomatic cover of the National Academy of Sciences meant that we had a lot of freedom, so I went and visited the refuseniks at that time. So did Wally.

ZIERLER: You met Alex at this conference?

BALTIMORE: Right.

ZIERLER: Did he make any particular impression on you?

BALTIMORE: Yes, he was already well known, as one of the few Soviet scientists who were making contributions to international science. He was widely recognized as a major intellect in DNA science.

ZIERLER: This is before ubiquitin?

BALTIMORE: Oh, yeah, long before.

ZIERLER: When that call came in, you were at MIT, you were just in your office?

BALTIMORE: I don't remember where I—for some reason, I think it was at home. But the reason—he was with a guy—he must have told you his name; I forgot his name—from Mass General. He did the sleuthing to find out where I was.

ZIERLER: You had won the Nobel Prize at this point? 1977.

BALTIMORE: Right, 1977, yes. I won it in 1975.

ZIERLER: You must have just been a prominent scientist that might be able to make a phone call?

BALTIMORE: Why did he call me as opposed to anybody else? There is a reason.

ZIERLER: Fellow Jew?

BALTIMORE: I don't think Alex really thought that way. Russian Jews were not particularly Jewish.

ZIERLER: [laughs]

BALTIMORE: Let me see if I can get my wife to—

ZIERLER: Oh, wonderful.

BALTIMORE: Have you met her?

ZIERLER: No.

BALTIMORE: Alice? [pause; refers to Alice Huang, biologist, and Baltimore's wife] Alice is involved in her own things, but she thinks that it was because of that meeting that he thought of me.

ZIERLER: You must have established a nice rapport.

BALTIMORE: We went out drinking some while we were there, and tried as best we could to be colleagues, when the Russians were just terrified of there being microphones everywhere. They just assumed there were microphones everywhere. We were living in a dormitory of this physics institute in Kiev, and if we wanted to talk with the Russians, we'd go outside and walk around.

ZIERLER: He gave no indication that he was thinking about this, at that point?

BALTIMORE: No, no.

ZIERLER: It might not have even occurred to him at that point.

BALTIMORE: I think not. He knew, they all knew, that they were living in a hell that absolutely limited what they could do scientifically, but limited even having personal relations with anybody else. But there is a warmth that comes through from Russians in particular, and particularly at that time, because they were so suppressed and spied upon. There was a great Russian polio virologist—there was one—and I met with him in Moscow and we talked about virology. His name is Vadim Agol. He was perfectly able to say anything that he wanted about his work. But the only time we talked about the repressive regimes that he was living under as in his apartment, where he did feel comfortable, and he invited me for a meal there. I'm just remembering this. He recently got in touch with me. He's still alive. He's about my age. He'd be an international superstar if he had lived anywhere else. He refused to leave. He was a Jewish scientist. He had a father who was a physicist, I think. The Russians didn't want to leave their families and the government did not trust him to travel outside of the Soviet bloc.

ZIERLER: Fast forward two years, you get this call. What did he ask of you?

BALTIMORE: "Is there anything you can do so I don't have to spend two years in a camp in Vienna?" Which is what they were doing with people who had defected. There was an established procedure, but it involved being in a camp for a couple of years. I understood that. I didn't for a moment say, "Well, just put up with it." He was a young scientist, very much in the middle of his career. He had taken a huge step, and he wanted to get into a scientific community and continue doing what he loved to do. That's why he had left, in order to get the freedom and the resources to be able to do science in a different way.

ZIERLER: What did you tell him?

BALTIMORE: I said I would see what I could do. I said I'd call the State Department. I started calling around. The important thing was I could vouch for him, and the fact that I had a Nobel Prize meant that people would listen to me, and it worked.

ZIERLER: Who did you think to call first? International affairs is simply not your world.

BALTIMORE: No. [laughs]

ZIERLER: Did you bring this to the attention of the dean at MIT or anybody else who might have a connection at State?

BALTIMORE: Yes, I did go through some connection, and I don't remember what.

ZIERLER: Ultimately this gets to Frank Press.

BALTIMORE: That's right, I went through the National Academy. Frank was the head of the National Academy at that time. I was able to make a connection to someone in the State Department, and I can't remember why there was somebody I knew. I can imagine the people I might have gone through. One is Walter Rosenblith, who was provost at MIT and very much involved in international affairs. He may have even been the foreign secretary of the National Academy.

ZIERLER: Clearly Frank Press's involvement fast-tracked the visa. It must have. I can't imagine just going through the bureaucracy of the State Department would have—because as Alex narrates the story, he was immediately called back to the consulate, and the consul general provided him with papers and a first-class ticket to New York. That doesn't happen just from the State Department. The White House must have been involved at some level.

BALTIMORE: No, I don't think the White House was involved.

ZIERLER: Press was science advisor to Jimmy Carter at that point, though, I think.

BALTIMORE: Was he? No. Well, I don't remember, but somehow, I was able to hopscotch over the bureaucracy and get to the people who could make a difference.

ZIERLER: Were you in contact with Alex again before he got to the United States? Did you tell him you had good news? Did you know the good news yourself? Did anybody assure you that they would make this happen?

BALTIMORE: I just don't remember. I'm afraid that what memory I have of that has dulled over the years, and I've never written down all the details.

ZIERLER: Do you have a memory of reuniting with Alex at MIT?

BALTIMORE: Oh, yeah. I do.

ZIERLER: Or maybe Mass General, first?

BALTIMORE: No, he came right to MIT. He didn't spend any time at Mass General that I remember. We invited him to give a seminar at MIT, and he gave a seminar on the work he had done and what he was thinking about. As I was walking out of that seminar, I was with Salvador Luria, who was sort of my mentor. Luria said it was like listening to Max. Max Delbrück.

ZIERLER: His mastery of the subject?

BALTIMORE: No, just the way his mind worked. It was the highest compliment that Luria could give to the seminar.

ZIERLER: Your efforts to get him here was not just a human rights issue; it was a win for science, it was a win for MIT?

BALTIMORE: Absolutely. And [laughs] my advice to him was that he should go somewhere where he wasn't going to have to deal with the bureaucracy of a university and getting grants and all the things that we all knew how to do.

ZIERLER: He had no idea about any of that.

BALTIMORE: No, he didn't. But I misunderstood his dream. His dream was to be on the MIT faculty, and that overrode any concerns of what he'd have to get used to, and what he'd have to learn how to do. He just wanted to be on the MIT faculty. He said to me once that, "I sat in Moscow in my apartment and dreamed of what it would be like to be on the MIT faculty."

ZIERLER: Did he associate that with you? Was that his connection?

BALTIMORE: Yeah, I was the one person he knew there, from the time when he was in Russia, because in that group, there was just one other person from MIT, Alex Rich. And Alex, I believe, was helpful to Alex Varshavsky too. When we said we'll offer him a position, that was it. He had gotten what he wanted most in life. He accepted it and actually in the end, he very easily adapted to the exigencies of American academic life.

ZIERLER: He figured out how to write a grant proposal.

BALTIMORE: Exactly. I thought maybe he should go to Cold Spring Harbor, because they could sort of watch over him, but it was unnecessary. I was wrong. He very rapidly became one of the stars at MIT.

ZIERLER: Then of course your paths crossed again at Caltech.

BALTIMORE: Yeah, surprisingly. Very surprising. He had left MIT and come to Caltech because of his wife, really. He's such a loner, also, that it sort of didn't matter where he was. But when he left MIT, I never thought I'd come to Caltech.

ZIERLER: If I remember him narrating this, did you occupy his lab for a bit of time when you came?

BALTIMORE: Yes. Oddly enough—you mean here?

ZIERLER: No, I mean at MIT.

BALTIMORE: Oh, at MIT?

ZIERLER: In the interregnum period?

BALTIMORE: Right, right. I had left to go to Rockefeller, and then I came back to MIT, and when I came back to MIT, there was a new building that had just been finished. In that building, they had designed a lab for Alex, but Alex had gone to Caltech, so there was space sitting there, which they offered to me in the new building, and which I used for a few years.

ZIERLER: To pick up the narrative again, to create a transition from your oral history with Sarah Lippincott in 2009, that discussion ended with this idea that there was that lame duck period where you announce your intentions to step down as president to go back to the regular faculty. When you accepted the presidency at Caltech, did you appreciate that you were at a young enough stage in life where this would not be a capstone position for you, that it would be a set amount of time and there would be a scientific career waiting for you on the other side?

BALTIMORE: I guess the answer to that is yes, I did imagine that. I had a moment—I think it was literally maybe a day or two—when I thought about closing my lab and ending my career in experimental science, which I had maintained through the directorship of Whitehead and through the presidency of Rockefeller. I didn't know if I'd have enough time to give to it, and particularly in a new environment, an environment I didn't know anything about.

Maintaining a Lab as Caltech President

ZIERLER: Were the terms of your acceptance of the presidency at Caltech, did you want to ensure that you could have a scientific life if you wanted it, or if you had the bandwidth?

BALTIMORE: Yes.

ZIERLER: Which entailed what? What kind of support, what kind of lab work, what kind of access to students? What did that look like?

BALTIMORE: I wanted a tenured professorship in Biology with all of the rights and responsibilities that go with it. Although I didn't expect to teach, I did want to be able to have a laboratory. Then I thought it through and I wondered whether that was the right thing to do and finally decided it was, and so I arranged a transition in which some people who were newly into my lab at MIT came with me to California. Then I really said I was going to have a small lab, and I was going to not take any students, take only postdocs.

ZIERLER: There's a moral responsibility to graduate students.

BALTIMORE: That's right. But there were a couple of students who said that I was the only person they wanted to work with, and so I even took some students, in particular Lili Yang, who played a very important role.

ZIERLER: Those terms of carving out for yourself a little bit of science as president forces you really to choose what's most important to you at that given time. What was? The little time that you had to work on the science, what would you want to do, as you were envisioning this?

BALTIMORE: I had made a move into immunology, so a lot of it was going to be immunology. I decided that I just couldn't continue working with polio, which I had been, up to then. I had my last postdoc—I guess Raul Andino was the last one.

ZIERLER: Had you achieved what you wanted to with polio research? Were there no more frontiers in that area?

BALTIMORE: No, you never achieve what you [laughs]—an end to anything.

ZIERLER: Although from a translational perspective, that had been wrapped up at that point.

BALTIMORE: Oh, it had been wrapped up before I started working on it. I didn't work on it because of its translational importance. It was just the best model of an RNA virus to work on, because first of all, there were a lot of people who cared about it, so there was a lot of background knowledge of the virus. Then the virus was easy to work with, so you could get very detailed knowledge. By that time—this is now the 1990s—recombinant DNA was just a natural part of everything we did, so we had the whole sequence of polio, and we had learned how to regenerate poliovirus from in vitro synthesized DNA, and that was a big step forward.

ZIERLER: You were already getting into immunology before you came to Caltech?

BALTIMORE: Oh yeah. I moved into immunology in the late 1970's. During the time I was building the Whitehead Institute, I was heavily into immunology.

ZIERLER: What was your entrée? What were you interested in?

BALTIMORE: I had always been interested, from way back, from my postdoc really, in how the immune system could possibly respond with antibodies to the whole universe of chemicals, with only what had to be a limited genetic capacity. At that point, we had no idea how much of the genome was relegated to the immune system, but it could only be a small percentage, because the genome wasn't that big. How did it arrange to do that? Tonegawa had done the seminal experiment demonstrating that there was recombination at the DNA level, so we knew what the operative force was that was leading to diversity, but we didn't know how that worked. I thought that was a great puzzle to work on, and that it would be embedded somehow in developmental biology. We would learn about developmental biology through this as a model event of differentiation. Because it was written in DNA, and so I could pinpoint it, I could analyze it, but to do that, I had to develop a whole new technology in my lab, and actually a whole new technology for the world, because Tonegawa had done what he had done without recombinant DNA methods. His experiment is amazingly unsophisticated. It's just hard work, but the right hard work. That's true of many people who have done seminal experiments, that in doing the most important experiments we've done, we're way behind in technology, because we're focused on the question, not on how we get the answer.

ZIERLER: If we can pause on that, if you can develop that a little more—questions and answer—what do you mean by that? What's the approach?

BALTIMORE: The most important thing you do in science is to ask questions. How does something work? Why is it the way it is?

ZIERLER: This applies in theory and experiment?

BALTIMORE: Yes. I had these questions about the immune system. How did it manage to have the diversity that it did with whatever the limited genetic capacity that it used? I didn't care how I found that out, but I did know that you needed to develop the molecular biology of the immune system in order to do that, and that recombinant DNA methods were going to open all of this up to investigation. We needed clones of the relevant genes. We needed probes. We needed sequences. I went to my lab and I said, "Is there anybody in the lab who thinks this would be an interesting direction to develop? It's going to be hard work. It's going to mean that we have to start from scratch." Because we didn't have the clones available. People who were cloning them—and Tonegawa was certainly at that point doing that—were not making them available to others. [laughs] I said, "Look, we're going to do this, and we're going to make it available to anybody who wants them, so we can get this field going." Because it was obviously a really big question.

ZIERLER: Did you see this more in translational terms or basic science terms?

BALTIMORE: Only in basic science terms. I never thought about immunology in translational terms, until many, many years later.

ZIERLER: Because this is so fundamental.

BALTIMORE: Yeah, when I began to think about translation, it wasn't even around antibody-related issues. I developed much more on the T cells. We started out—actually, Fred Alt and Alfred Bothwell, and a guy named Enzo Enea who I've lost track of—were the three who said, "That sounds like a wonderful direction." Fred had already been interested in immune function, and also in particular in a different kind of problem, which was the small pieces of DNA that encoded oncogenes in cancer cells. He had discovered those in Bob Schimke's lab at Stanford when he was a graduate student, so he had a little bit of experience with DNA manipulation, which I didn't, so he was very valuable to have, and has gone on to have a fabulous career. These guys set to work on clones that we needed, the techniques that we needed, the thinking that we needed. We started talking about the problems and how you get into this, what was interesting to work with. I did have one secret weapon, and that is that I knew that we had access to clones of cells of the B cell series, of the immune cells, that were immortalized and that we were growing already in the laboratory. They came from work that we were doing on a cancer-inducing virus, the Abelson virus.

ZIERLER: When you say you had access, what does that mean?

BALTIMORE: We had developed these clones, and there was almost no one else who appreciated what they could teach us. These were clones that we thought could be, and some of them were, in the process of rearranging their DNA in vitro. They're still used for studying that process. (I should note here that I am using the word "cloning" in two senses. There is cloning of DNA molecules to get very specific probes of the genome and there is cloning of cells to get pure population of immune cells. The Abelson virus immortalized immune cells which then grew indefinitely in the laboratory as clones.)

ZIERLER: How new was the technology at that time that allowed this cloning work to happen?

BALTIMORE: It started in 1974, I guess, with the work of Berg and Cohen and Boyer. Cohen and Boyer was 1974, I guess.

ZIERLER: This was established technology at this point?

BALTIMORE: Well, no, it was sort of brand-new technology, because we're talking about 1975, 1976, when I did this, so it was new, and it was very underdeveloped. There was a lot more development that needed to be done, but we understood that it was just technology that needed to be done. Conceptually, the techniques that were around were powerful enough if we could manipulate them in the right way to get us down to the genes that were involved. Remember, that was soon after Asilomar, and the Asilomar meeting had laid out what you needed to do in order to work in that field—use safe organisms and safe methods, and there were limited things, things that couldn't be done. All of that had to be factored in. But I was convinced that that was all going to work out so that it would get more and more powerful and easier and easier with time.

ZIERLER: To bring this closer to your decision to come to Caltech, what did you need to strip down or narrow down to, in order to maintain this research but obviously in a much more limited capacity?

BALTIMORE: Well, this is many years later.

ZIERLER: Of course. But the long intellectual trajectory, going back to my question, with so little time to work on the science, what did you want to work on?

BALTIMORE: So much of it depends on the people I had working in the lab. Since some of them were carryovers from MIT, they were going to continue doing what they have been doing. Some of what I continued with was determined not by any deep consideration of where are we going in the future or anything else; it was just people, and they had theses to finish or postdocs, jobs to get, and they were working in interesting directions, and so we continued with those. I'd have to go back and actually do some research—

ZIERLER: Some students came with you to Caltech?

BALTIMORE: Yeah, right, some.

ZIERLER: With the full understanding that you'd have very limited bandwidth to mentor them?

BALTIMORE: Yeah, they were far enough along in what they were doing that—my style, if you wish, of mentorship, I have called "benign neglect."

ZIERLER: [laughs]

BALTIMORE: I really believe that mentors can overwhelm their students, their trainees, with consideration and help and direction. I've always taken my responsibility as a mentor to be that of a teacher. The important thing about teaching is getting people to learn, and they have to do that themselves. You can't do it for somebody else.

ZIERLER: That requires, of course, taking on the kind of student who thrives with self-direction.

BALTIMORE: Right. I've lost some people along the way, because they just didn't have the ability to take advantage of it, but a surprisingly large number of people have that ability if you give it to them.

ZIERLER: They might not know it.

BALTIMORE: They may not know it. In fact, they don't know it. I had a number of occasions to think about the time when I started doing science, which was at the Jackson Lab. You've read about that?

ZIERLER: Yes.

BALTIMORE: I have often commented that the amazing discovery of that summer that I spent was that I, as someone who literally knew nothing about the science that I was working with—I was a high school student then, nobody in the high school was in a position to teach me anything that would be modern science, and yet I could work at the forefront with these professors or people who were my mentors at JAX Lab, and learn things that no one else in the world knew. They weren't terribly important things, but they were mine, they were new, and there was a moment when I was the only person in the world who knew them. If I could do that with such minimal training, imagine what I could do if I really knew what I was doing. I right then and there made the decision that's how I was going to spend my life, and I did.

ZIERLER: Your style as a mentor, do you take that out of the playbook of your own mentor?

BALTIMORE: Yes. Richard Franklin, who was the guy I did my thesis with, was wonderful in that regard, letting me do what I wanted and just helping around the edges to make it easier and make it more effective. He was great.

ZIERLER: When you accept the presidency at Caltech, you have the conception or the goal or the dream of how much you're going to do in the realm of science, and then there's the reality, looking back on your tenure. How much science were you able to do as president?

BALTIMORE: Oh, a surprisingly large amount.

ZIERLER: Surprising to you, even?

Transition to Translation

BALTIMORE: Yes. Actually, my whole lab changed direction, into a much more translational direction.

ZIERLER: What does that say both about the smallness and the flatness of Caltech, that the president could lead a significant scientific career?

BALTIMORE: What it says is it's easier to lead a scientific career than you might think.

ZIERLER: [laughs]

BALTIMORE: Particularly if you've been doing it for 30 years before that, so you know how. You know the moves. You know what it means to get young people into the lab and how quickly they develop their skills.

ZIERLER: Did you come in with a particular mandate that allowed you to narrow how much of a time-suck presidential duties might have taken?

BALTIMORE: We had, for instance, in the last years I was at MIT, uncovered a whole treasure trove of transcription factors that played a role in the development of immune specificity. I had planned to see if we could work on all of these and see how they integrated. I gave up all of that and said, "I'll pick one of them" and it was NF-kappa B. That was the most intriguing transcription factor. I let all the other ones go and never worked on them again.

ZIERLER: By necessity, because you didn't have more bandwidth?

BALTIMORE: Yeah, I just couldn't handle that. That was fine. All the guys who had been my trainees went off and took these problems and have made them sing. People like Lou Staudt at NIH and Kees Murre in San Diego. There were four or five people that took these over. We published everything, there weren't any secrets there, and so the whole scientific community could build on that. These remain the central transcription factors of immunity.

ZIERLER: The scene when you're beginning to contemplate stepping down, which you did earlier than you had originally intended, the scene is very much one—you're not rooting around for what you might do next scientifically. You were very clear on what you wanted to do, because you had never left it.

BALTIMORE: Yes, that's right.

ZIERLER: What was the redirection during your time as president of Caltech, scientifically, where the lab went in directions you weren't—?

BALTIMORE: That was the T cell immunity. When I got into the immune system, the work on T cells approached fantasy. It was so poor, and so undirected, so misconceived, that it was just a joke. They were barking up all the wrong trees. As opposed to that, the B cell side of immunity was getting very well-developed and becoming very rational, and we had played a role in that. Others also had. What happened was that, largely because of Lili Yang's direction, we started thinking more and more about T cells, and really T cell immunity. From the very start, she wanted to do an experiment that had to do with a subset of T cells that are regulatory. Regulatory T cells. The question was whether the T cell receptors used by regulatory T cells were interconvertible with the T cell receptors that are used for foreign recognition, or whether they were a subset to themselves. We figured out how to do that, which was to get these T cell receptors, put them into ordinary T cells, and see, would they function as ordinary T cell receptors? To do that, you had to clone the T cell receptors, and you had to put them back into T cells, and there was a lot of manipulation involved in that, that had never been done by anybody before. She set about to do that, and she did it; she did it with mice. We looked up one day and said, "You don't have to do anything more than that. That's a huge advance." Now you could actually use that as a way of getting at human T cells that have therapeutic value. We dropped that whole initial question and went after the translational side of using T cells for human immunity. In the end, we connected with a group at UCLA that was looking for just this technology and didn't imagine they could ever find it, and found it across town. We combined forces and to this day we work together. I was on the phone with these guys yesterday. That took me in a direction I never imagined that used viral vectors and T cell receptors and cell cloning and gene cloning and—I mean, everything that we developed over the years, and other people had, focused on T cell immunity, basically on immunotherapy, although we didn't use that word originally.

ZIERLER: Was there something about the intellectual atmosphere at Caltech that might have fostered these new directions that you had not seen coming?

BALTIMORE: No. In fact, they were so different to anything else going on at Caltech.

ZIERLER: It was an island?

BALTIMORE: Yeah.

ZIERLER: No opportunity to collaborate with anybody at Caltech?

BALTIMORE: I saw this thing as potentially a very big new direction, and I talked to the Gates Foundation, because they had a grand challenge program.

ZIERLER: What year would this have been?

BALTIMORE: I stepped down in 2006. It was probably 2004, about then.

ZIERLER: You're starting to think about stepping down at this point already?

BALTIMORE: No, I wasn't. It seems crazy, in retrospect, to approach the Gates Foundation, but what I was hoping was that if I could get a big grant from the Gates Foundation to do this grand challenge, I could get other faculty at Caltech involved in the effort, and bring a new direction to Caltech.

ZIERLER: What was the grand challenge, more broadly? What was the Gates Foundation grand challenge?

BALTIMORE: It was any sort of translational research at all. They never did this again, but it was totally open to what you might want to do. It was just that it had to be so audacious that you could imagine you'd never get support for it.

ZIERLER: Part of this new direction and surprise was it brought you into a translational arena where you had not expected to go?

BALTIMORE: That's right.

ZIERLER: What was the promise? What were some of the clinical values or therapies that might come of this?

BALTIMORE: Well, it was all of immunotherapy, and that's in fact what has come out. There was really only one faculty member who responded to this, and that was Pamela Bjorkman. It was all focused around HIV and new ways of approaching HIV, because the standard vaccine methods weren't working.

ZIERLER: Still aren't. We still don't have a vaccine.

BALTIMORE: Right.

ZIERLER: Was Tony Fauci interested or involved in this at all?

BALTIMORE: No, because I had gone to the Gates Foundation, and he was in the government, although I ended up, because of my involvement with HIV, I had been head of advisory groups to the federal government and worked a lot with Tony, so I knew Tony well. He's such an amazing man. He was already by that time 20 years or something into the head of NIAID and was the most important person in the government in the area of infectious disease.

ZIERLER: Did you have interactions with Bill Gates right from the beginning?

BALTIMORE: I did.

ZIERLER: What were your impressions of him?

BALTIMORE: What a smart and committed man he was, and he just loved to learn things. [laughs] I had a friend who was then working at the Gates Foundation, Rick Klausner. Rick actually worked very closely with Bill Gates. Actually he and Harold Varmus had hatched the plan of the grand challenge. It was the only time the Gates Foundation seriously devoted themselves to basic science, to really innovative basic science. That was because of Rick and Harold. Harold was just an outside advisor; Rick had moved to Seattle and was working with Gates. But what was the question that led me into this?

ZIERLER: You had hoped that the Gates Foundation would have brought people at Caltech into this.

BALTIMORE: Yeah, that this grant would.

ZIERLER: How much money? What were we talking about here?

BALTIMORE: It was something like $17 million over five years.

ZIERLER: And it was set up as what, like a PI program?

BALTIMORE: What I did was I brought in post-doctoral people to head up various elements. Lili was the lab manager. She oversaw the whole thing. There was an aspect of it that was granted to Pamela, and that money just went to her.

ZIERLER: This was a new direction for her too?

BALTIMORE: It was a wholly new direction for her. What she wanted to do was to develop a vaccine, and she got involved in the genes that would encode HIV-protective vaccines. That was great. She's still doing that. The Gates thing is long done, but it set a direction that's now her whole laboratory. But I couldn't get anybody else, so I had to bring in people to head up sub-projects within it. We had three or four different sub-projects. One was on IgA, mucosal immunity. There were vectors to be developed. Those were all postdocs. By the time I stepped down, I had a gargantuan program going.

ZIERLER: Was that a factor in stepping down earlier than you anticipated?

BALTIMORE: Not really. I didn't step down much earlier than I had anticipated.

ZIERLER: You had what, like a ten-year plan?

BALTIMORE: Yeah.

ZIERLER: And you did nine?

BALTIMORE: Right.

ZIERLER: Was the science so exciting, that was a year that you were fine to lop off?

BALTIMORE: I found myself thinking more and more about the science, less and less about the university.

ZIERLER: What about in terms of legacy, accomplishments, satisfactions that you had done the job you were hired to do?

BALTIMORE: The biggest thing that I had done was actually to get the grant from Gordon Moore.

ZIERLER: The $600 million?

BALTIMORE: Yeah, the $650 million or something. It was never a defined amount of money, but anyway, we called it that.

ZIERLER: Was this in the works when you came in, and part of your work was to seal the deal?

BALTIMORE: When I came in, they said that Gordon was interested in making a big gift, but it took years to get to the point where he would actually do it.

ZIERLER: Were there faculty members—I'm thinking of like Carver Mead, for example—that were an asset in terms of developing that relationship with Gordon?

BALTIMORE: No, it was more board members. Carver actually by that time had largely left.

ZIERLER: Yeah, he was Emeritus, I think, 1997 or something like that.

BALTIMORE: Right, so I never had much to do with Carver, because once he stepped down as faculty member, he moved to the Bay Area. He would come down—

ZIERLER: Sure. He still does!

BALTIMORE: I'm told he still does, yeah.

ZIERLER: Superconductivity. He's still after the holy grail of superconductivity. It's amazing. That was a big project.

BALTIMORE: But Gordon was the chair of the board when they hired me, so I had worked closely with him from the very start.

ZIERLER: Securing this was not a done deal? You had to articulate a vision for how the funds would be deployed?

BALTIMORE: That's right, and it was probably four years into my tenure when I got the grant. It's an incredible story, which I think I told at that oral history.

ZIERLER: There's no precedent for anything like it.

BALTIMORE: No.

ZIERLER: How do you even make decisions about where it all goes, and the timing of it?

BALTIMORE: Right. It became making sure that it had the transformational effect on Caltech that it should have.

ZIERLER: How proactive was Gordon himself in asking specific questions or desire for where it might go?

BALTIMORE: Not at all.

ZIERLER: Which speaks to his faith in Caltech, I guess.

BALTIMORE: That's right. Yeah. He never [laughs]—I couldn't even get him to be interested in some kind of recognition for having given this gift. We finally named the Moore Walk, because it was something large enough and extensive enough that it matched the influence that his grant had on the school. But he didn't care.

ZIERLER: What else? The original question was about legacy and satisfaction that the science was compelling, and you had done what you wanted to.

BALTIMORE: By that time, his gift had really transformed all of Caltech, into people now thinking about what they could do with new resources and new directions. If I was going to stay on, I had to find a new direction. I had done it, basically.

ZIERLER: The number of women coming on as both students and faculty, that was on the rise.

BALTIMORE: Right. The thing that I hadn't done was to transform Biology and bring it up to thinking about the challenges that biology was facing in the rest of the world. Caltech is a very insular place, and the biology was in particular very insular, but it also had some structural problems. There were people who only wanted to think about themselves. It just was not at the forefront where it should have been.

ZIERLER: Were there any key hires?

BALTIMORE: I had made a deal with myself that I wasn't going to be the head of Biology; I was going to be the president of Caltech.

ZIERLER: You mean the de facto head, just because of who you are?

BALTIMORE: Yeah, so I had avoided trying to take on Biology, and they were also very wary about me, because they thought I would try to take on Biology. They didn't want to be led. [laughs]

Partnering with the Gates Foundation

ZIERLER: How did that dynamic play out when you became a civilian, so to speak, when you just joined the faculty, full-time?

BALTIMORE: Then I could just exert whatever leadership I had through the things I did, the Gates Foundation grant being the lever that I had, but just there weren't many people who responded to it.

ZIERLER: How much ramping up did your lab do when you stepped down and you could devote all of your resources?

BALTIMORE: A lot.

ZIERLER: You took on new students?

BALTIMORE: Yeah, I took on new students.

ZIERLER: Had you taught at all during your time as president?

BALTIMORE: No, but I did teach after.

ZIERLER: Did you miss teaching?

BALTIMORE: Yeah, I enjoyed teaching, and in particular enjoyed teaching virology, because it's such a wonderfully varied field. I started a virology course. Actually, I didn't start it. There was a very good virologist here, Jim Strauss. His wife worked with him, Ellen. They had taught virology, but he had just retired, and he wasn't teaching anymore, so there was nobody to teach virology except me, so I did it for a few years.

ZIERLER: 2007, what does that look like for you? How do you ramp up?

BALTIMORE: I had in a sense already ramped up, because of the Gates grant. I had this big group in new directions.

ZIERLER: Had you kept up with the literature pretty well, as president?

BALTIMORE: No.

ZIERLER: You had some reading to do?

BALTIMORE: I had a lot of reading to do, and I still do have a lot of reading to do. Over those ten years, science had—I've always said that the field that I've worked in, modern biology, transforms itself about every five years, so it had been through two generations in that time, so I was way behind on a lot of things, and I've never caught up with a lot of it.

ZIERLER: Do you rely on graduate students and postdocs to keep you current?

BALTIMORE: Absolutely. And always did.

ZIERLER: What were some of the big developments when you came up for air, 2006 and 2007?

BALTIMORE: A lot of it was in sequencing. The whole way that Eric Lander really had reformed the doing of biology around asking global questions, not just asking questions about one gene but asking questions about all genes, and developing technology that could handle all genes; that was just a wholly new way of doing things. If I was really going to take that on, I either had to develop a whole set of skills which I didn't, or I had to go somewhere else, which I didn't either. I stayed with the things I knew how to handle, which made me increasingly a little behind the curve. In the end, I wasn't getting the very best people that I had previously been getting, for various reasons, so it became harder and harder to—

ZIERLER: Is part of that, in terms of recruitment, the distinction between the basic science and the translational, that the best people might naturally gravitate toward the basic science?

BALTIMORE: Yeah, there is that. I started at least one program of truly basic science, which was to try to understand what microRNAs were doing. We did a lot of programs where I had a lot of people working on different microRNAs and trying to understand how they evolved, why they existed. It was a terrific topic for MD/PhDs, people who had an interest in basic science that came out of a clinical concern.

ZIERLER: What were some of those potential applications, therapies?

BALTIMORE: They actually weren't so much therapies as trying to understand the role that microRNAs played in development, or in particular, in the immune function. I stayed with the things in knew about, but we published a whole string of papers on microRNAs and inflammation. The inflammatory side, which is the innate immune side, played an important role in my thinking at that time.

ZIERLER: Did you work more with Pamela as a result of her getting involved in this new endeavor?

BALTIMORE: Yeah, I did, some, but not a lot. She took her lab in really directions she wanted to go, and still has. I'm on an advisory group to her program, still, but it has become just an incredibly complicated field. It all revolves around an HIV vaccine, still does.

ZIERLER: What aspects of the original proposal for the Gates Foundation—what has been accomplished so far, and what remains to be done?

BALTIMORE: The major thing that we did was to develop vectored alterations in immune function.

ZIERLER: I wonder if you can translate that.

BALTIMORE: You can put genes into virus vectors, viruses, which are now carrying the genes you've put into them rather than their own genes. These viruses can bring those genes into cells, can incorporate them into the genome of the cells. HIV is almost the best vector to use. We strip the genes out of HIV and put in the genes we care about, and then the machinery that HIV has evolved brings those genes into the cells and incorporates them into the cells' DNA. This is now done widely. It's the basis of modern immunotherapy, is using these viral vectors. The big change that Moderna and Pfizer made was to get away from viral vectors and to use pure RNA therapeutically. It's in a sense the same kind of thing we were doing, but now without an artificial use of a virus, but just using pure chemicals. It's terrific.

ZIERLER: There's still no HIV vaccine, though.

BALTIMORE: No.

ZIERLER: Why not?

BALTIMORE: Because HIV evolved to be so plastic, so able to incorporate alterations in its structure, that it's not a defined entity. It's constantly changing, and so it eludes immune attack in the process of changing. No one has figured out how to find a stable part of HIV that you can attack with standard immunological thinking. What they're trying to do is to learn how to direct the immune system to produce extremely rare antibodies that do see HIV in a stable way and that can provide real protection. This whole process of guiding the immune system to make these rare antibodies is brand-new, and no one has cracked how to do it. But Pamela's lab is trying to do that. There's a lab in San Diego which has made great advances. There are laboratories in Seattle. There are laboratories in Boston.

ZIERLER: There's a Nobel Prize for whoever cracks this code.

BALTIMORE: Oh, yeah. Absolutely.

ZIERLER: What's the urgency for developing an HIV vaccine given the drug cocktails, given the understanding we now have about sharing needles and unsafe sex?

BALTIMORE: The answer to that is that for the last close to 30 years, the number of people infected with HIV in the United States hasn't changed. For all of the technology and all the drugs and everything else, there are 50,000 people a year that get infected.

ZIERLER: But it's not a death sentence, anymore.

BALTIMORE: It's not a death sentence anymore—in the United States.

ZIERLER: But the rest of the world, it's a very different story.

BALTIMORE: Well, it's not the rest of the world, but in Africa, the number of infections continues to be enormous. The statistic I remember vividly is that if you have a clinic in Durban, South Africa, and young women come into that clinic for treatment, if they're 15 years of age, the probability that they are infected with HIV is maybe 1%. If those same women come when they're 25; the probability that they are infected with HIV is 70%.

ZIERLER: Which is a way of conveying just how urgent it is to develop this vaccine.

BALTIMORE: Right.

ZIERLER: Obviously they don't have access to the expensive drugs and therapies we have here in the United States.

BALTIMORE: Also, that they don't have a culture that allows them to protect themselves against the infection. They're at the whim of the men in their culture. It's just awful. A vaccine could take care of all of that. Yeah, we need a vaccine desperately, still, in spite of all the wonders.

ZIERLER: Have computational advances changed the game at all?

BALTIMORE: Yes, they've given us the opportunity to work with larger numbers, larger concepts, but they haven't changed the core issue, which is how do you get the immune system to make a predetermined antibody.

ZIERLER: To pick up a thread from earlier, where Pfizer and Moderna got involved with mRNAs, is that directly connected with the HIV research and the new directions they went, or that's a separate story?

BALTIMORE: It's a separate story.

The Miracle of mRNA Technology

ZIERLER: How did they get involved, or how did they focus interest on mRNAs?

BALTIMORE: [laughs] It's all biotechnology. We have an active biotechnology culture, mainly in the United States, although some of it came from Germany, of young people thinking about new directions, trying to make new things happen. Moderna was deeply involved in that, and BioNTech in Germany picked up—I don't exactly know how they were involved. The two scientists who are credited with doing the most work are both American scientists. But this is completely a consequence not so much of academic research but of biotech research.

ZIERLER: What's the takeaway there? Flexibility? Daring? Profit?

BALTIMORE: All of those. Biotech is driven by all the things you say. It is driven by profits. It's driven by a sense of, "Can I get rich?" It is driven by curiosity. "How far can I take technology?" It's driven by just the joy of doing science. In some sense, because of the enormous amount of money that has been poured into biotech and continues to be poured into biotech, if you're in the right situation, you can actually get a lot more done in biotech than you can in an academic lab, because of the focus and the resources that are available. One of my very good friends who was just deeply involved in basic science and said he would never do anything else slowly began to realize that Genentech could do things he couldn't do in his basic science lab, and he moved to Genentech. He didn't work out very well there, but that's another story.

ZIERLER: As a segue to subsequent conversations where we'll trace historically the significance of messenger RNA, to what extent, going all the way back to Crick, for example, where do you see the COVID-19 vaccine in historical perspective? What aspects of it are a culmination of all of the amazing work on mRNA and what of it is just a remarkable isolated case that we found ourselves in, in 2020?

BALTIMORE: An enormous amount of it is just people following their noses and seeing how far they can carry ideas. I wasn't actually aware of the Moderna developments until they broke on the scene. There were other people more aware of it than I was.

ZIERLER: Was it obvious when the WHO declared this a pandemic in whatever it was, January of 2020, that mRNA research was the solution? Was that obvious at the time?

BALTIMORE: No.

ZIERLER: Wow.

BALTIMORE: No, it was not at all obvious.

ZIERLER: That's amazing.

BALTIMORE: Because the people who developed the technology had not yet applied it to any practical problem. This was the first practice problem to which it was applied. It's crazy.

ZIERLER: The general course of events is there's decades of basic science, lots and lots of applications, and then some new problem to apply that application to? This did not apply here.

BALTIMORE: No. It's so stunning.

ZIERLER: No precedent like that in modern science, right?

BALTIMORE: You might say that monoclonal antibodies were similar. They came out of lots of basic science, and some very good basic scientists were behind it—César Milstein, George Köhler and others. But we had no idea that it was useful for anything, and the first attempts to make it useful failed. They just weren't good enough. I don't know if there is a good book about this; there might be. There should be! Interestingly, the whole biotechnology development in San Diego can be traced back to a failed monoclonal antibody company that was then bought by Eli Lilly, which just drove it into the ground. But many executives got experience in this company; it was called Hybritech. These executives went on to do other things and built a whole industry in San Diego. Meanwhile, one company, IDEC, developed I guess the first usable monoclonal antibody, I think, Rituximab, an anti B cell antibody. Now it's just an industry that knows no limits, but it took a long time to get to that point. But people were ready to give it up.

ZIERLER: Aren't we lucky they didn't!

BALTIMORE: Oh, boy.

ZIERLER: Last question for today—just a snapshot in time, circa late December 2021, what are you currently working on? What are your projects? What are your days looking like now?

BALTIMORE: I don't have a lab. I closed my lab a couple of years ago. I'm working with companies that are developing —one of the major things I'm doing is with a company called Appia that is developing technology that came from Lili Yang, and that dates back to the Gates grant. [laughs] That's the major company I'm working with. And, I'm just trying to stay healthy.

ZIERLER: You're not Emeritus, though?

BALTIMORE: I'm not Emeritus, because I didn't want to be called Emeritus, because when you see Emeritus on somebody's title, you assume they're out playing golf, and I don't play golf.

ZIERLER: [laughs] Practically, though, you're Emeritus?

BALTIMORE: Yeah, practically I am.

ZIERLER: You're not sitting on committees, you're not taking students?

BALTIMORE: No.

ZIERLER: You're not teaching?

BALTIMORE: I don't have a lab, and no, I'm not teaching. I am fundamentally retired, but I am continuing various advisory roles, advising government panels and private companies and all sorts of people.

ZIERLER: I hope you're trout fishing, though. Maybe you don't play golf; you do a little fishing?

BALTIMORE: I do trout-fish. We have a home in Montana where we spend time, and I fish up there.

ZIERLER: Have you been able to get to it during the pandemic?

BALTIMORE: Yeah. Even though Montana has been an epicenter of the spread of this disease, those of us in the little community in Hamilton, Montana, have been pretty safe.

ZIERLER: Sure. This is a vaccinated mini-population.

BALTIMORE: Right.

ZIERLER: Thank you so much. Next time we'll pick up all the way back to the origins of messenger RNA.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, January 12th, 2022. I am delighted to be back with Professor David Baltimore. David, it's good to be with you again.

BALTIMORE: Hello.

ZIERLER: Today we're going to start looking at messenger RNA in historical context. To start, of all the things that we could have talked about, you chose mRNA. Why?

BALTIMORE: Wait a minute, I didn't choose it. You chose it.

ZIERLER: [laughs] I'll remind you in our original discussion, I said, "You've already given oral histories. You've talked about so much." Of all the things that you want to talk about, why mRNA?

The Caltech Origins of mRNA Research

BALTIMORE: Oh, I know why!

ZIERLER: You said, "Let's talk about mRNA."

BALTIMORE: Right. But it was not because of my central role in messenger RNA. It was because the discovery of messenger RNA and the proof of its function provided the last piece of information about the central dogma and really opened up our understanding of information flow in biological systems, in cells, in organisms. It was a seminal discovery, and it was made at Caltech. It was made at Caltech because there was technology at Caltech that had been used in the very famous Meselson-Stahl experiment, and that technology was adapted to test the idea that there was messenger RNA. Brenner, from England, and Jacob, from France, came to Caltech that summer and worked with Meselson.

ZIERLER: Why was this technology at Caltech?

BALTIMORE: It was really because Meselson and Stahl had recognized that heavy isotopes would provide a marker for recently made molecules. They used that to show that the two strands of DNA come apart during replication, which was the Meselson-Stahl experiment. I don't know where the idea came from, maybe from Brenner, that you could use that technology, but there was probably nowhere else in the world where the technology was so readily available as Caltech.

ZIERLER: What were the questions that Meselson was after before they were thinking about mRNA?

BALTIMORE: You mean in the Meselson-Stahl experiment?

ZIERLER: Right.

BALTIMORE: The Meselson-Stahl experiment was just done in about 1957. Let me go back a step. When Watson and Crick discovered the structure of DNA, or announced their model of the structure of DNA, in their famous single-page paper in Nature, the world didn't come knocking at their door. In fact, I once asked Watson, had it disrupted his life, all the requests for seminars? He said, "No." He said the world was silent. There were very few people who really understood how important it was, and who were able to change the way they thought about biology to take into account this new understanding. Which I must say surprised me, when he said that.

ZIERLER: When did you ask Watson this question? Roughly when would that have been?

BALTIMORE: I had Watson here at Caltech for an open discussion which we had on the stage of Beckman Auditorium. It was there that I asked him, in public, that question. He said one of the very few people who did understand, and who got very excited by it, was Delbrück, at Caltech. Delbrück in fact invited Watson to come and give a seminar here in 1953, I guess—I may be a little off—and then offered Watson a job. Watson's first job in the United States was at Caltech. He says in his flip way in his biography that there were no girls here, because it was a men's school at that time, and so he moved to Harvard.

ZIERLER: What was Delbrück working on at that point, that this would have resonated with him?

BALTIMORE: Delbrück wasn't working on anything that I know of that was relevant. Delbrück was a general intelligence in molecular biology. He saw the big picture. The history of molecular biology really is very much focused on Delbrück and Luria, and they talked about the central issues together for many years, particularly at Cold Spring Harbor in the summers, where they were, because Luria was in the Midwest and Delbrück was first actually at Vanderbilt and then later at Caltech, and then spent the bulk of his career here. When they announced the structure of DNA, and a few people began to talk about, "What does this mean?" Delbrück was skeptical. He said it was beautiful, he was entranced by it—and Delbrück was a sort of contrarian, so it's not surprising. It was good for the field that somebody was asking questions. The thing that bothered Delbrück—and I must say the thing that bothered me when I first heard about it—was that the two strands of DNA in the double helix are wound around each other. To take them apart requires an enormous topological activity.

ZIERLER: What does that mean, "topological activity?"

BALTIMORE: It means the organization of the two strands in space, so that they're literally wound around each other. If you pull at either end of a string that's wound around itself, you end up with a knot, because all of that energy of coiling, which is topological in origin, because they're around each other, means that they don't smoothly go away from each other. In order to replicate the DNA, it had to come apart, and if it was going to come apart, you had to deal with all of these coils, in which it was wound around itself, and it wasn't clear how that happened. Now, it turns out that the way it happens is that the DNA is constantly being cut, and the energy of coiling is relaxed, and then it's resealed, and it's cut and resealed, cut and resealed, cut and resealed, all the time. That relieves the strain and allows the DNA to be taken apart. But we didn't know that, and we didn't know there were enzymes that could do that in 1953. Over the period from 1953 to about 1957 or so, there was a lot of discussion in the field about this among people who cared, and it wasn't resolved. The Meselson-Stahl experiment was an experiment that asked the question, "Do the strands come apart when they're duplicated, or is there some mechanism for impressing the sequence in DNA onto another molecule that doesn't involve taking apart the helices?"

ZIERLER: What were some of the advances in microscopy that allowed for these questions to be answerable?

BALTIMORE: It wasn't microscopy. It was done by really very intelligent use of heavy isotopes. Basically what they said was that if you took a piece of DNA and it duplicated itself and it came apart, that there would be one new strand and one old strand on both daughters. If you could label the new strand, so you could tell it from the old strand, you should get a hybrid molecule in the beginning and then that would resolve later, but when it's duplicated, it would be a hybrid product. They saw that this implication was there, and that the heavy isotopes existed to label the molecules. They used the ultracentrifuge, the forces of the ultracentrifuge, to separate the half isotope containing DNA, and you get just these beautiful pictures as a result. But you weren't taking pictures of DNA; you were taking pictures of bands in the centrifuges. You weren't resolving the structure of DNA in these pictures. That was the Meselson-Stahl experiment. They were a student and a postdoc. Stahl was a postdoc of Delbrück's, and Meselson was a student of Linus Pauling, and they talked, and they got this idea, and got a lot of help from Jerry Vinograd, who was a physical chemist here at Caltech and was sort of an unsung hero of that whole time. You don't hear his name much anymore. Certainly when I was a young scientist, he was one of the gods, and he was in the Chemistry Department at Caltech, if I remember correctly. Somehow he had moved from industry. I mix up his story and that of another great scientist at Caltech, so I'm just not sure which—the point is that Meselson was still here. I don't know where Stahl was; he may have left. He became a professor in Oregon and lived out his life there. He may even be alive, now; I don't think so. But Meselson is; I see him in the summers at Woods Hole. They had this idea that you could use the same technology to tell whether the ribosomes—I think the experiment really was to say, "Is there a separate RNA that carries information, separate from ribosomal RNA?" They infected bacteria with phage (bacterial viruses) and did a pulse labeling with radioactive RNA precursors and showed that the ribosomes had preexisting RNA in them but there was also a new, rapidly synthesized and degraded RNA that came from the phage and they believed, correctly, was messenger RNA copied from the DNA of the phage. That experiment was done in the summer of 1960. Up until that time, it was not clear how information got from DNA into protein.

ZIERLER: The assumption was that it was ribosomal RNA up to that point?

BALTIMORE: Yeah, because we didn't know about any other RNA. Yet ribosomal RNA—all the ribosomes had the same RNA.

ZIERLER: It was obvious something was missing?

BALTIMORE: Right. Actually my statement that ribosomes all have the same RNA is wrong. They didn't know that, because you couldn't sequence RNA at the time, so I don't think they did know that the bulk ribosomal RNA had a common sequence. Because DNA clearly had the information, and DNA and RNA are really pretty similar molecules, and the bulk RNA of the cell cytoplasm is ribosomal RNA, I suppose there were people who thought that the ribosomal RNA somehow served as an intermediary, because protein was clearly made on ribosomes. It was the demonstration that there was a new rapidly turning over RNA that hadn't been known before. Actually, if you go back into the literature, there were a few people who had seen this RNA, but they hadn't really known what it was all about. The most famous of those, because they have just these wonderful names, were Volkin and Astrachan. Volkin and Astrachan had seen this as phage-specific RNA, not bacterial RNA. They were two scientists at Oak Ridge. The interesting thing is people were aware of it. The field was very small. The number of observations that were key were very small, so when something came up that didn't fit the generally conceived picture, it was in everybody's mind, and everybody talked about Volkin and Astrachan's RNA.

Undergraduate Days and a Revolution in Biology

ZIERLER: As an undergraduate at Swarthmore, for you, were these developments registering? Were you following them? Were you already keyed into these things?

BALTIMORE: Yes. I actually ran a biology club at Swarthmore in my junior and senior years. There was a small group of us who were aware that there was a revolution going on in biology. There were no faculty who were aware of it.

ZIERLER: Were faculty in the Biology Department involved in research, or it was strictly teaching?

BALTIMORE: They were involved in research, particularly in the summers. The head of Biology, a man named Enders, different from the one who won the Nobel Prize, ran a laboratory called the Rocky Mountain Laboratory. I don't know where it was. He would take some students there. It was all embryology. So many biologists were focused on embryology as being the major mysterious part of biology, because just watch an organism go from a fertilized egg to a whole organism, and with the right systems like chick eggs and things, you could see all this happen. Biologists were just fascinated. The faculty at Swarthmore, led by Enders but all of them, were involved in historic biology in embryology and physiology, in certain kinds of microbiology. But the idea that molecules were the central consideration in thinking about how biology works, it wasn't there.

ZIERLER: Kind of like quarks in physics; there's something more fundamental at play.

BALTIMORE: That's right. But it wasn't in biology. It was in physics, it was in chemistry—but particularly in chemistry. There was no biochemistry at Swarthmore at that time. When I came back to Swarthmore, many years later, after I graduated, they proudly showed me their young biochemistry faculty, and there was just for the first time a recognition. In a field like physics, that doesn't matter so much, because introductory physics and basic physics is the same today as it was when I was an undergraduate.

ZIERLER: Sure, it's an older field, a much more developed field.

BALTIMORE: Right, whereas there's no relationship between biology today and biology when I was an undergraduate. Suddenly this exploding field was happening, the explosion was happening, without any guidance for students. The great thing was that Swarthmore was organized so that you could, if you were an honors student, for the last two years, take seminars. The seminars met once a week, and you wrote papers for the seminars, and presented papers to the other students in the seminar. We, the students, sort of took over the seminars and defined what was interesting, and the faculty was just overjoyed to be able to help us do that, not defensive at all, so that's what we did.

ZIERLER: Obviously you were on top of the literature?

BALTIMORE: We weren't on top of it, no, because we had no guidance. There were people, famously—Sol Spiegelman was saying things which were simply contradictory to what Jacob and Monod would say. Jacob and Monod had it right; Spiegelman had it wrong. But who's going to tell me that? I read Spiegelman and I couldn't understand why there were these two worlds and they didn't seem to mesh. Lots of other stuff like that. So no, we lacked guidance, so we had to try to suss it out for ourselves. Only when I went to graduate school did everything fall into place.

ZIERLER: This idea that you lacked guidance, hypothetically, if you were at a place like Harvard or Caltech, would it have been the same situation?

BALTIMORE: Well, no, you would have had much better guidance. At Caltech was where things were happening. Before I was at Swarthmore, there was one very famous person at Swarthmore, Howard Temin, with whom I shared the Nobel Prize. Howard was four or five years older than I was. He singlehandedly did what I did with a group. He must have come in 1952, roughly, so it was just the time when the Watson and Crick paper came out. He saw that and he knew that there was a revolution going on. He was singularly way ahead of everybody at Swarthmore at that time. He came to Caltech as a graduate student in 1956. I think I have the year right. He created a revolution here. But I can only imagine—I've never talked to him about it—what it felt like to come where Delbrück was, and the school around Delbrück. There was a whole school of young faculty around Delbrück, they knew what was going on, and they all came to Cold Spring Harbor in the summers and connected with the French school, connected with the British school, the people in Cambridge, the people at Pasteur. As I said to you, somebody needs to be writing this history. There is a pretty good reflection of all of that in The Eighth Day of Creation, but somebody else could do a better job.

ZIERLER: For you, when you graduated, the excitements specifically around mRNA, did they guide you in terms of what you wanted to do next?

BALTIMORE: No, no. Only when I got to graduate school was mRNA discovered.

ZIERLER: You graduate in 1960, and it's really 1961 that these things are happening?

BALTIMORE: Right. The reason that those dates stay in my mind is because I remember—I was a MIT graduate student at that point—coming back to MIT after the summer of 1961 and running into Cy Levinthal, who was a young faculty member there, in the hall. He said, "Have you heard what happened?" I said no, I hadn't, and he described it to me. [I have the date wrong here. It must have happened in the summer of 1960 because that is when the messenger RNA experiments were done at Caltech.]

ZIERLER: What did he say? What was the exchange?

BALTIMORE: He said it was proven that there was a separate RNA that was carrying information from DNA to ribosomes, and that that was sort of the last piece of the central dogma that had come together.

ZIERLER: The term "messenger RNA," was that in use from the beginning?

BALTIMORE: Yes, it was used from even before it was discovered. They wrote a paper from the work at Caltech that summer that was published in Nature and used the term "messenger RNA".

ZIERLER: Did hearing this news influence your plan of study, what you originally came to MIT to do?

BALTIMORE: Yes, in a very profound way, because what it said was that when a virus comes into a cell, the virus has to make messenger RNA as its first and most important job. Different viruses can do that in different ways. We knew that there were RNA viruses and DNA viruses.

ZIERLER: What would be an example of each?

BALTIMORE: DNA viruses are papillomavirus and herpes virus and vaccinia virus, smallpox virus, and almost all phage. RNA viruses are the respiratory viruses that we all hear about now daily.

ZIERLER: Including COVID-19?

BALTIMORE: COVID-19, but also poliovirus, and all the common cold viruses.

ZIERLER: This distinction was known at the time between RNA and DNA viruses?

BALTIMORE: Yeah, it was, and people sort of didn't know what to make of RNA viruses. But the guy I decided to do my thesis with worked on RNA viruses, so I worked on RNA viruses.

The Impact of Cold Spring Harbor

ZIERLER: Who was your advisor?

BALTIMORE: His name was Richard Franklin. In 1958 or so, he started teaching a course at Cold Spring Harbor in animal viruses. When I got interested in working with animal viruses, Salvador Luria at MIT, and who was really my most important advisor, suggested to me that I go and take that course and see if this is what I wanted to do. I went to Cold Spring Harbor that summer and took the course.

ZIERLER: Tell me about the intellectual atmosphere at Cold Spring Harbor. What was it like there?

BALTIMORE: Oh, it was stunning, but it wasn't the first time I was at Cold Spring Harbor. I went to Cold Spring Harbor from Swarthmore. This was in the Spring of 1959, roughly, maybe 1958. I wanted to see what a phage plaque looked like. I had no idea. I had been reading about phage, but at Swarthmore we had nobody. I went to the microbiology professor, because I was taking microbiology seminar, and I said, "Could we see what phage plaques look like and just play with this?" He said, "I don't know how. I have no idea." He said, "However, if you can find the materials, we could do that." The only place I knew of to find the materials—you need phage and bacteria and agar and various things—was at Cold Spring Harbor, because it was so famous. I grew up on Long Island, and I knew Cold Spring Harbor because my father used to take us on weekends occasionally to the fishery at Cold Spring Harbor, just to watch the fish going around, because it was so amazing. My father was from the Lower East Side in New York. The idea of watching fish—

ZIERLER: [laughs]

BALTIMORE: —was amazing to him! So he took his kids to see the fish. I knew where Cold Spring Harbor was, and I knew that when I went home for vacation, I could drive out to Cold Spring Harbor, because now I can drive. I said, "I'll go to Cold Spring Harbor and look." There was another reason I wanted to go there, which was I wanted to invite a speaker to come and talk to the biology club, because I appreciated her work. It was in drosophila. I went and drove out to Cold Spring Harbor, to the laboratory which is literally across the highway from the fish hatchery. I had written to her, and so we had a date. I was expected. I invited her, and she said yes, she'd be happy to come. Then I said, "I also want to see if I can find the materials." She said, "Well, the work that you're familiar with occurs in the summers here, mostly." This was in April. It was Easter vacation. She said, "The only person who is working here on phage is George Streisinger, a name I had never heard. George was famous for not publishing, and so he was unknown to almost anybody except the aficionados, who knew him very well. She called George and said, "Would you see this kid?" He said, "Oh, yes." George was a man of just the most wonderful instincts. Anybody who ever knew George loved him. For him, it was just part of a day's work. I went up to his office and we sat and talked, and I told him why and what I was interested in. At the end of the conversation, he said, "What are you doing this summer?" I had actually planned to work in a laboratory in New York City. He said, "We have a new program starting here at Cold Spring Harbor. We got a grant from the National Science Foundation. It's called the URPP program, Undergraduate Research Participation. And we don't have enough people to fill it, so I can offer you a slot." Great fear, because I had worked very hard to get this job in New York.

ZIERLER: What was the job in New York?

BALTIMORE: It was—everything's a story!

ZIERLER: [laughs]

BALTIMORE: It was at the Haskins Laboratory. Caryl Haskins, who was president at Carnegie, had this lab in New York. He was a very wealthy man. There was a small group of scientists who worked in the lab. It was independent. It was in sort of an old tenement building. But he put in the money I guess that they worked from, or maybe they got grants from somewhere. I don't really know. They specialized in providing education for students, particularly from the New York City schools. I came from Great Neck. I can even tell you how I made a contact with them, but it has to do with a Jewish camp; we'll leave that alone. I had met some people, and they thought I was worth it, and invited me to come for the summer to work with one of the faculty at Haskins. It was a special honor and people had gone out of their way. I had to then call the guy I was going to work with whose name was Corky Aaronson. With some trepidation I called him, and I said, "I have this offer." He said, "If you can go to Cold Spring Harbor, go."

ZIERLER: Ah, very nice.

BALTIMORE: Yeah. There have been a lot of lucky things. That's one of the luckiest. I went. After my junior year at Swarthmore, I spent the summer at Cold Spring Harbor, so I knew Cold Spring Harbor very well.

ZIERLER: Was the atmosphere there more people presenting the research that they had done from their home institution, or was—?

BALTIMORE: It was everything.

ZIERLER: Research was actually happening there also?

BALTIMORE: Yes. Oh, yeah. The labs—it's sort of easy to do phage work. [laughs] It doesn't take fancy equipment and stuff. Most of it was phage-based. There was actually a lab there from the Carnegie Institution of cytogenetics. Famously, Barbara McClintock was there. She got the Nobel Prize for work that she did at Cold Spring Harbor. She was there full-time. They had a field where she did her plant work, and then there was a drosophila group. There was a guy named Milislav Demerec who ran the place. It was a functioning lab, and the people who came there for the summer, they'd open up a couple of buildings that were not heated, so you could work there in the summer but you couldn't work there in the winter. There were a whole group of people who came there, lived in cabins—the cabins are probably still there—and who did lots of experiments, and who taught the courses. Everybody in my generation was involved in the courses at Cold Spring Harbor. You were either taking them or teaching them. You took them one year and you were teaching them the next year. That's what happened to me. I took this animal virus course. Every year thereafter, I went back to Cold Spring Harbor and taught the animal virus class.

It was a very functional part of the scientific community. Also, it was the place where foreign scientists came and contacts were made, and plans were made. I don't think anybody remembers this except the people who were involved, and most of them are dead, but after World War II, Jacob and Monod came back from the Resistance. Monod writes—both of them write about this—Jacob writes in his autobiography about this, beautiful stuff. If you've never read that, and you want to read one book, The Statue Within, it's called. They came back to the Pasteur Institute and picked up on experiments that they had been doing before the War, during the beginning of the War, until the Germans took over Paris. It was regulatory biology. How do organisms change their activities? Now, if you look at cells developing in a chick embryo, the cells are constantly changing what they're doing. They start off being totipotent cells, and they go on to become individual muscles and whatever else. But how do cells make a decision like that? That was the kind of problem that Jacob and Monod were interested in, and Lwoff, who shared the Nobel Prize, the three of them—Lwoff, more from the point of view of viruses, Monod and Jacob from the point of view of bacteria, and bacterial making, changing. If you give bacteria glucose, they'll live on glucose. That's where they'll get their energy and their carbon. If you put the bacteria on galactose, they'll use galactose and do all the same things. But it takes different enzymes to work on galactose and glucose, so obviously, if you shift them from glucose to galactose, things change. How do they change? What happens? That was their question.

They had nothing to work with. They had no money. They managed to eke out the ability to make agar plates and to grow bacteria and to test for glucose and galactose and whatever else. I remember very well my friend, faculty member at MIT—actually, there's a complication there, but let's leave it alone—Maury Fox, who said to me, "I'm going to work in Paris for"—I don't know, the semester, some reasonable length of time—"so that I can see what these guys are doing. What I'm going to do is to fill my suitcase with reagents and plates and materials to do experiments with, because they don't have anything there," with a sort of underground developed of bringing resources to Paris, so they could do those experiments, from American labs. Amazing. And amazingly important, because they worked it out. They figured it out.

Everybody would come to Cold Spring Harbor, give a few lectures in one of the courses. There were courses on bacterial genetics, on phage genetics, on animal viruses and whatever. That was the center of international science, or international molecular biology.

MIT and the Centrality of Virology

ZIERLER: When you came to MIT, were you already on a path toward virology, or it's really the mRNA developments that put you on that path?

BALTIMORE: No, I was already on a path to virology. It was the only thing to do. That's what everybody did. But what they did was phage work, because it was the simplest thing in the world to do. You can get really precise quantitative information.

ZIERLER: Why was it so simple?

BALTIMORE: Because you made a monolayer of bacteria, and you just dropped on it some phage, and they made holes—those were the plaques—in the monolayer. I could tell you overnight, literally overnight, that this tube has ten to the eighth bacteria per milliliter—of phage—per milliliter. If I irradiate that tube, and take samples during irradiation, I can watch them die. It's just a nice quantitative experiment, beautiful experiment. If I mix bacteria in there, the bacteria will get infected, and there will be more phage, so it will go from having ten to the sixth, to ten to the eighth, to ten to the tenth, and I can tell that, and I can follow the kinetics of it. All of that is cheap and trivial to do and happens overnight. Not even overnight; if you wanted to come in at midnight, you'll find the plaques are there, and you can set up a new experiment and get data in the morning. I can tell you, everybody who worked in the field did that. When you got excited, you just compressed it all. It's better than working on computers. [laughs]

ZIERLER: Was there the sense that this was low-hanging fruit at the time, that the problems would get more difficult as advances were made?

BALTIMORE: I guess so, but they had been doing it for quite a while. This goes back to before World War II, phage work was done in Germany. Delbrück came from Germany. They had been doing the same experiment for 20, 30 years. I'll tell you what my question was. It goes right to what you ask. I came to MIT. I knew about phage work. I knew that Luria was there and worked on phage and bacteria; that Levinthal was there, who worked on phage. Because at Cold Spring Harbor, I had met these people, because they came to Cold Spring Harbor for the summer from MIT, and they were just starting for the first time a training program in molecular biology. There were very few in the whole world at that time. They met me, and they recognized something in me, and said, "Would you like to come to MIT?"

ZIERLER: What were you good at, at that point? What did they recognize?

BALTIMORE: I don't know.

ZIERLER: Lab work?

BALTIMORE: Lab work.

ZIERLER: Ideas?

BALTIMORE: I was working in Streisinger's lab, and they may have heard me give a presentation. I sat in on a lot of the lectures in the courses.

ZIERLER: Did you consider Caltech for graduate school?

BALTIMORE: No. I didn't. The idea of coming to California was so foreign.

ZIERLER: [laughs] Long Island boy, it's a little far away?

BALTIMORE: It was inconceivable, although Howard Temin had done it four years earlier, and had come from Germantown, Pennsylvania.

ZIERLER: On the East Coast, was MIT the place to be for what you were doing?

BALTIMORE: Yes, because Luria had come there. If you go to 1955 or so, Caltech was the center of the world, and MIT was nowhere, but the administration had been smart enough to recognize that something was going on. Somebody invited Luria to come from the Midwest—he was then in Illinois—for a year, on a sabbatical. It was a test. Then they offered him a job at MIT. This is 1958, roughly, or 1959. He had been at MIT for a year or two, as a visiting professor, and then started as a faculty member, but he was already famous. He was—not a chair, because—but he was a builder. He was an institution builder. He was the right person to do this. He found Levinthal and brought him. Levinthal was a physicist who had gotten excited about biology and had made the switch into biology. He was a young guy. I knew them, so when I came to MIT the next fall, or it was a year later, I was keyed in to work on phage. Levinthal gave me a little place in his lab.

ZIERLER: What was Levinthal's lab doing at that point?

BALTIMORE: [laughs] He recruited me into this experiment. He was doing a very famous experiment. I haven't thought about it in years. Ah! The question was, how many molecules of DNA are there in a phage particle? Basically, how many chromosomes does a phage particle have? That was very important for interpreting a whole lot of genetic experiments, whether there was freely combining separate molecules, or it was all one molecule in which case there was genetic recombination between—if you had two different molecules coming into a bacterium at the same time, but there were two presumably linear—although that was a problem in itself—molecules that interacted. Levinthal wanted to know—and people had tried to measure the molecular weight of DNA extracted from phage. You would think it would be a simple job to put it in a centrifuge and look at the rate of migration in a centrifuge tube. It was a simple job to do that experiment, but you always got heterogeneous results, and it was never satisfying. In particular, what you were looking for was a nice coherent band of DNA of a certain size, and you never saw that. There was suspicion that there were multiple sizes of DNA in there.

The other possibility was you were breaking the DNA. It turned out that was what was happening. I can remember at Cold Spring Harbor one summer, Hershey brought together everybody there and said, "I have to tell you something very important. When you shake a tube of DNA, you break the molecules. The molecules are so long that the forces on the molecule cause it to break, and you can shake hard and break it into small pieces. You can shake it gently and break it into larger pieces. You can control that." He showed data to—and the place was silent. Nobody had imagined that you could break molecules by shaking a tube. No one! Everybody had to go back and reinterpret all of the data on the physical chemistry of phage DNA and of chromosomes.

ZIERLER: This was back to the drawing boards for everyone?

BALTIMORE: It really was. Cy said, "I'm going to find out what's in there." He said, "Clearly it's too dangerous to extract DNA and shake it and stuff." The problem was, when you put it in the ultracentrifuge, to get it into the tube you used a syringe. That broke the DNA, so you were killing the experiment before you got started. Cy said, "Look, if you put radioactive phosphorus in the DNA, and you wait over time"—we knew this was true—"you will slowly inactivate the virus, because the radioactive decays break the molecules. They're bad chemically for the DNA. But, every time one of those phosphorus molecules decays, it liberates an electron. And you can see the path of that electron in a photographic emulsion. So, if phage particles containing DNA that has radioactive phosphorous and you suspend them in a solution of photographic emulsion and let it dry on a slide, you can see the tracks coming out from one point, which is the phage particle. If you liberate the DNA from the phage very gently you do the same thing with the liberated DNA. If the phage and the liberated DNA have the same number of radioactive decays in a fixed time, then there was only one molecule of DNA per phage. . That was the experiment.

To do this experiment required somebody to look in a microscope at the tracks that the electrons had left and get the average number of tracks produced by phage or free DNA, and compare them. It is just painstaking work to do that because you've got to use a microscope and constantly be focusing up and down in order to follow the track, because you follow the plane of resolution of the microscope. Cy had a microscope in his house, in Brookline, Massachusetts, and he would have people come over and score these photographic emulsions. So, I did that. I'm thanked in the paper. You didn't know what you were doing, because it was done double-blind. The investigator—I was the investigator investigating these things—didn't know what kind of sample he had, and it was all randomized. We did it, and there's a paper in the world on the molecular weight of phage DNA. There was one chromosome per phage. At the same time, Charlie Thomas was trying to do the experiment physically by looking at the DNA, and he got the same answer, I think, if I remember correctly. They were in competition with each other. Charlie was at Johns Hopkins I think.

In any case, I came to MIT and I had a little desk in a lab, and I took courses. I needed courses, because Swarthmore was great but limited.

ZIERLER: You were not as well prepared as students coming in from bigger schools?

BALTIMORE: Yeah. I had prepared myself, in a lot of ways. I was actually a biophysics major at MIT, so I had to learn some biophysics. I had this lab desk and I did some experimental work, but nothing serious because I just didn't have time. I took courses. Somewhere around the middle of that year, I had a question. I said to myself—this goes back to what you asked me—"If I want to prepare myself for the future of biology and be an experimental biologist, I can't plan to spend my life counting phage plaques."

ZIERLER: It's like stamp collecting?

BALTIMORE: No, no, it's not like stamp collecting. It was very powerful, very great science, but limited. It was a physicist's kind of science, because you were interpolating a lot from the data. It's sort of like electron tracks in an emulsion. ?

ZIERLER: Accelerator?

BALTIMORE: No, no, to look at decays.

ZIERLER: Cyclotron?

BALTIMORE: No, no.

ZIERLER: Bubble chamber?

BALTIMORE: Bubble chamber, yes. It's like a bubble chamber. You actually physically see something, and you interpret it, but you're actually thinking about radioactive decays and particles and quarks, whatever. It was that kind of science, whereas biology historically had been the most sort of visual—embryology, you looked at embryos growing. It occurred to me: "Phage had been so powerful in allowing questions to be asked about bacterial molecular biology. I wonder if animal viruses will give you the same power for the investigation of animal cells?" Because after all, what we care about is animals, as biologists. I had spent a summer at Jackson Lab when I was in high school, looking at what mice did. That had a profound effect on my thinking ever after. My idea of biology was the biology of mice. There was no intersection between phage and mice.

ZIERLER: Why not?

BALTIMORE: Because phage don't grow in mice; they grow in bacteria. But there are a lot of viruses that do grow in mice, so maybe if we study them, we'll learn things about mice and mouse cells that will be different than what goes on in bacterium. Actually, it was an interesting leap, because we didn't know there was anything different. We had no idea whether the molecular biology of bacteria was all the molecular biology there was in the world, and we'd learn everything about everything we care about from bacteria, or whether there were special things happening in mammalian cells. Mammalian cells or higher cells have a nucleus. That already makes them very different, because there's no nucleus in a bacterium, but beyond that simple observation, we didn't know much. I went to Cy Levinthal, and I said, "I've been thinking about this question. Should I focus my career on animal viruses rather than on phage?"

ZIERLER: Why was Levinthal the person to ask this question?

BALTIMORE: Because I was in his lab, and I was used to asking him questions. He said, "I have thought about that question, and I don't know the answer. I just don't know whether what's going on in animal viruses is tractable, is interesting, can you actually work on it." I went to Luria, and I asked him the question. Now, Luria had written the only textbook in virology at the time, a book I later wrote one edition of. He knew the range of viruses, animal viruses. Phage were the central focus, but there was plenty on animal viruses, plant viruses, other kinds of viruses, so he had the perspective. He said, "I don't know the answer."

ZIERLER: Are these conversations happening before or after your Cold Spring Harbor visit when you were at MIT? This is right away?

BALTIMORE: This was the first year I was at MIT. I was only at MIT one year, because of—the end of the story. Luria said, "I'll give you some advice. Why don't you find out? You can come and tell me. I know a guy who does quantitative animal virology whom I respect." There aren't many people in animal virology he would respect, because there was no quantitative tradition. There was no link with the phage world or any of these people. But this guy Phil Marcus—and there was a course that had just been started at Cold Spring Harbor in animal virology. "Why don't you go work for the early part of the summer with Phil Marcus and then take the course at Cold Spring Harbor, and then you can come back in the fall and tell me? And we have a guy coming in the fall, because I wanted to get animal virology to MIT, and so maybe you could work with him if that turns out to be what you want to do." Named Jim Darnell. I did that. I arranged it. Luria helped me. One of the people teaching the course was Richard Franklin. Richard Franklin was a young, thoughtful guy with a background in biophysics, who had gotten interested in animal viruses, who had gone to Germany to study because some of the best animal virologists were in Germany, brought back a beautiful wife. He was a bit of a loner. He and another guy taught the animal virus course. They had people come and talk, and Darnell came from MIT, I guess, and talked. I met Darnell. By that time, I was convinced from the course and from working with Phil Marcus that it was the thing to do. I asked Darnell whether I could come and work in his lab.

We differ now—we've talked about it since—about what he said to me, but I took it to mean that he wasn't sure. He had other people asking him whether they could come to his lab. It wasn't a guarantee that I could work with him. He, on the other hand, says that he thought he could give me it, that he was just being slightly equivocal. I went to Richard Franklin—I really appreciated the work he was doing—and said could I work with him, which would mean moving to Rockefeller University, which is where his labs were. He said, "If you can arrange to come to Rockefeller, I'd love to have you." Now, to get into the Rockefeller graduate program required jumping through a variety of hoops, one of which Luria helped me go through. I can tell that story, but I don't need to. Luckily, there was one open slot in the program, because one of the guys who was in the program had dropped out because he'd rather play cello than do science. To go to the Rockefeller program, you had to be accepted by the president of Rockefeller, whose name I'm blocking right now. Detlev Bronk. I was accepted by Detlev Bronk, so that fall I moved from MIT to Rockefeller.

Risky Advice to Transfer to Rockefeller

ZIERLER: Did you see that as a risky decision to some degree?

BALTIMORE: Oh, yeah, but Rockefeller was the greatest graduate program in the world. It was the richest. It was in the most extraordinary place on the east side of Manhattan, and only the very best students ever got to go there. But going to work with Richard was taking a big chance, and working in animal virology was leaving behind everything that had been so successful, to go into something which had not yet been successful at all.

ZIERLER: What was the frontier at that point? What did you envision?

BALTIMORE: That's a good question. I think the honest answer is I didn't envision.

ZIERLER: You intuited, though, that this is where things were headed?

BALTIMORE: Yes, there was no question, and if you asked anybody in molecular biology, there was no question in their mind that this was a revolution that was going to become human biology sooner or later, and that was the direction to move in. I was walking through open doors in thinking that you should care about animal cells. Later, Jacob moved into animal cells.

ZIERLER: At this point, it's all fundamental research? It's all basic science?

BALTIMORE: Absolutely.

ZIERLER: You're not thinking therapies, vaccines?

BALTIMORE: No, no.

ZIERLER: Clinical trials? Nothing like that?

BALTIMORE: Nothing.

ZIERLER: Because it's the ground floor.

BALTIMORE: This is all about the molecules of life, but it's about molecules. It's not about therapies, and it's not about anything else.

ZIERLER: To think farther afield, could you have imagined that this is the pathway to human health applications?

BALTIMORE: No. I didn't really think that was in my lifetime—

ZIERLER: Wow.

BALTIMORE: —to tell you the truth. It was pure science, an end in itself. It wasn't paving the way to vaccines or anything like that.

ZIERLER: What were some of the immediate developments in mRNA during this time from MIT to Rockefeller?

BALTIMORE: What Richard's lab worked on, and what he gave me the resources to work with, were RNA viruses. It did not really occur to me how different an RNA virus was from a DNA virus. That's what he worked on; that's what I was going to work on. I started asking questions about how viruses infect cells. I could take advantage of the fact that you could see inside cells, so you could look at the nucleus and the cytoplasm. You could look at uninfected cells, infected cells, see what the differences were. That's what I began doing. Richard was focused in cytology, in using actually photographic emulsions to look at the uptake of radioactive precursors into DNA and RNA, into different parts of the cells, different kinds of viruses. I picked up all of that technology and really just began to ask, "What happens when a poliovirus"—I didn't actually work with polio; I worked with a mouse equivalent of polio—"when poliovirus gets inside a cell?" Now, this is 1961, I went to Rockefeller, began doing the work in 1962, because I had to take courses and do some other things. We had a tool. The tool was a drug called actinomycin D. What actinomycin D did was to turn off any production of RNA from DNA. Actually, Richard had already done the key experiment and published it, which was, if you treat cells with actinomycin D, do you prevent the growth of poliovirus? You don't. Oh, I know what I was going to say—poliovirus. Polio is no longer a medical problem.

ZIERLER: This was back when everybody took the vaccine they were told to take. [laughs]

BALTIMORE: That's right! Or their parents told them to take, right. That was in 1955, roughly, or 1954. By the time I'm doing all this and working on polio and its relatives, it is no longer a medical problem. No one is interested in it from the point of view of, how does polio work? How does a virus grow?

ZIERLER: But there's a larger appreciation that there are other viruses out there, or not so much?

BALTIMORE: We knew there were a lot of viruses. Mumps, measles, chickenpox, they were all there. Smallpox, flu, the flu epidemic in 1918 was on everybody's mind. No, there was plenty of open questions, but polio in particular—because I then devoted the next ten years of my life to working on polio, and it was not of medical interest. MDs who got into virology—there were some—in general went for viruses that were sort of open medical questions. But actinomycin—it turns off all DNA-dependent synthesis of RNA—did not touch these viruses. That one experiment said that the virus synthesis of its own RNA was totally independent of the key cellular process to make RNA, which was DNA-dependent. It really said that the central dogma of DNA-makes-RNA-makes-protein was not relevant to these viruses. That simplified things in some ways, but then the question was, how does the virus make its own RNA? Where does it get the enzymes to do it from? Does it encode them? Those are the kinds of questions I began to ask. In the end, the end being the next year—because I spent two years on my thesis, because it was walking through open doors—I discovered the enzyme that does that.

ZIERLER: What is that enzyme?

BALTIMORE: It's an RNA-dependent RNA polymerase that copies RNA into RNA. That was not the enzyme that I won the Nobel Prize for. This is much earlier in my career. Once I had done that, I—

ZIERLER: Off to the races?

BALTIMORE: No, I just left graduate school, and went to become a postdoc, and actually worked with Jim Darnell, first went back to MIT and then to New York.

ZIERLER: How were the resources at Rockefeller? Was it a wealthy place?

BALTIMORE: Oh, it was the wealthiest place, absolutely. In particular, the wealth was made available to the students. We got $1,000 a year to just take advantage of the cultural activities of New York.

ZIERLER: [laughs] How did you take advantage of that?

BALTIMORE: Oh, I love New York. My parents, by that time, lived in Manhattan.

ZIERLER: They retired to Manhattan?

BALTIMORE: They retired to Manhattan. Actually my mother didn't retire; she worked for many years thereafter. My father did retire. I went to the theatre and I—mostly the theatre.

ZIERLER: You're a bachelor, still, at this point?

BALTIMORE: Yeah, only when I left New York did I get married. I was married to somebody else for a couple of years.

ZIERLER: What was Richard's style as a mentor? How closely in contact were you with him?

BALTIMORE: He was both very available, and—he was only a little older than I was, so we were pretty close, although he had a wealth of experience that I didn't have. He made the whole laboratory available to me, but he didn't try to direct what I did.

ZIERLER: What else was going on in the laboratory during those years?

BALTIMORE: He was doing his work, which I sort of took off from, and I think I took it all away from him, thinking back. He went off in other directions, and I didn't actually follow it. He got more involved in biophysics, and he left Rockefeller. That's one of the reasons why I didn't follow what he did, because he left Rockefeller shortly after I did. Actually in finishing my thesis, I had to go out to Colorado where he was, just to write up the final thing.

ZIERLER: Given the discovery, were you publishing a lot? Were you on the conference circuit?

BALTIMORE: Yes, I was.

ZIERLER: What was the big news to convey? What was the import of this discovery?

BALTIMORE: I made a series of discoveries over the couple of years I was a graduate student about how the virus turns off cellular activities, turns on its own activities, how the RNA is made, the enzyme, characteristics of the enzyme. I published I think 13 papers.

ZIERLER: Wow.

BALTIMORE: One day I sat down and added them up.

ZIERLER: Tell me about the instrumentation in the laboratory. What were you using?

BALTIMORE: We were using a lot of quantitative growth of virus, looking at inhibition of growth of virus, or stimulation of growth of virus, in various ways. In fact, he had a chief technician who prepared the plates. It's not as simple as working with phage, because you've got to grow monolayers of animal cells. It takes longer. They tend to get contaminated if you're not careful. He had a wonderful technician who did all that, and she helped me a lot. I could sort of order up materials. We did a lot with photographic emulsions. What I realized was Richard would do a lot of cytology along with measuring radioactive decays with emulsions. What I realized was I could use a Geiger counter, if I took off the membrane, to look at radioactive incorporation of tritiated nucleotides. That enabled me to do all sorts of measurements of RNA synthesis, protein synthesis, with different kinds of infections and inhibitors, so I was doing that kind of thing. It was pretty rudimentary but there was a lot to learn. When I wanted to look at incorporation of radioactive nucleotide triphosphates into products, I had to make them myself. When those became available commercially, that made my life so much simpler, but that was years later.

ZIERLER: This is a strictly analog environment? Are there computers, like Fortran, in the laboratory?

BALTIMORE: No? Had they been invented?

ZIERLER: It's all notebooks?

BALTIMORE: It's all notebooks. Actually, the first word processors were big news, but that was later, I think, wasn't it?

ZIERLER: Yeah.

BALTIMORE: I'd have to go back. We didn't have any word processors.

ZIERLER: Did you have thesis committee members outside of Rockefeller?

BALTIMORE: Yes. [laughs] I had Dick Shope on my thesis committee.

ZIERLER: Where was he?

BALTIMORE: He was at Princeton. He was actually at a Rockefeller lab in Princeton.

ZIERLER: Rockefeller funded labs outside of campus?

BALTIMORE: Yeah. The Rockefeller Institute had a laboratory in Princeton, which is where they did virology. He worked on papillomaviruses. He was a very famous man, but I remember when I gave him my thesis and he read the thesis, he said, "I can only barely understand what you're talking about."

ZIERLER: [laughs]

BALTIMORE: He said, "And you use abbreviations that I don't know what they mean." The one that bothered him most was cpm, which is "counts per minute." Everything that you do with radioactivity is in units of counts per minute, decays per minute. The fundamental unit that I was working with, he had never seen before. It was from a different world.

ZIERLER: This was the kind of thesis defense where you knew more than the professors?

BALTIMORE: Oh, yeah. Yep.

ZIERLER: Who else besides him and Richard?

BALTIMORE: I don't remember. Oh! Well, Rockefeller was very hierarchical, and there was a professor of virology, and everybody at their university who worked in viruses was in his department, so he was on the thesis committee, Igor Tamm. Igor was helpful, but again, he had no idea what I was talking about. These were old-time virologists.

ZIERLER: This generational divide that you're talking about—

BALTIMORE: It was all because of Richard. Richard was the only reason I was there.

ZIERLER: This generational divide, to the extent that you were aware of what was going on elsewhere, was your sense that in virology the most exciting work was being done by the younger generation at that point?

BALTIMORE: Oh, yeah.

ZIERLER: New methods? New ideas? What would account for that?

BALTIMORE: New considerations. Focus on nucleic acids, focus on information. Most virology focused on the virus particle, and the virus particle is a way of getting from one person to another.

ZIERLER: What does that mean, virus particle?

BALTIMORE: Well, a virus is a little entity that's transmitted through the environment from one animal or one person to another. That's a virus particle. It's called a virion, but that's not a word that people generally know.

ZIERLER: The stuff that's airborne, that's transmitted, that's the virus particle?

BALTIMORE: Right. And it's fundamentally dead. That is, it doesn't have any metabolism, and it's waiting for a cell to come along that it can get itself inside of and take over, and that's what viruses do. There was nothing known about what happens when a virus gets inside a cell. Even the people working on phage had not worked on that problem very much, again because it was a physicist's view of science.

Investigating Viral Activity at the Point of Infection

ZIERLER: You're saying that studies up to this point were focused on the particle before it found its host?

BALTIMORE: Right. But what I was interested in was what goes on inside an infected cell.

ZIERLER: That's where the action is, so to speak.

BALTIMORE: Right, that's when it comes alive. Interestingly, I've never thought of it this way before. That's absolutely true; that's where the action is. That just seemed so natural I never even thought about it as a question, but it's actually a very fundamental change in the focus. The people who had won Nobel Prizes in virology were people who had studied the virus particle. The very famous experiments that showed you could crystallize viruses raised the question whether viruses were chemicals or whether they were living. That's what Wendell Stanley won the Prize for. But that's not the interesting part of the virus.

ZIERLER: Did you see your research as standing on the shoulders of those people who did focus on the particle?

BALTIMORE: Oh, yeah, inevitably. Absolutely. And once I got into trying to understand the proteins that were made by the virus, many of those proteins contribute to the virus particle, so that then now produced the kind of perspective you're talking about.

ZIERLER: How did you deal with the differences between molecular biology and structural biology at this point, thinking about proteins?

BALTIMORE: Structural biology is older and is more static. It's more chemical kind of considerations. Molecular biology really was the sort of active activities of the proteins, but the two are very close to one another. That's why when I went to MIT, I was in biophysics, because that was the discipline that harbored molecular biology.

ZIERLER: By the time you defended, what would you have called yourself primarily, a virologist?

BALTIMORE: Virologist, yeah.

ZIERLER: What postdocs did you consider? What was exciting at that point?

BALTIMORE: There was one guy, Darnell, who was using some new techniques that we had never adapted, centrifugation techniques and electrophoretic separation techniques. I really went to his lab in order to have experience with the techniques and the perspectives that he was developing.

ZIERLER: You saw this as the next step in your education?

BALTIMORE: Right.

ZIERLER: What about this? What was so important about this in terms of the techniques?

BALTIMORE: It opened new questions, and it opened new windows to be able to look at how viruses worked. These were very simple things but they were so powerful.

ZIERLER: Still open doors? It's all fundamental still, at this point?

BALTIMORE: Yeah. I did discover the reverse transcriptase in 1970, so I had been ten years in virology before that. That opened up whole new perspectives in what you could do, what I could do, what I could think about, ultimately leading to my working in immunology. But it was all techniques.

ZIERLER: Did you see this specifically as needing to get out of your comfort zone in graduate school?

BALTIMORE: No, I was never in a comfort zone.

ZIERLER: Because it's all so new?

BALTIMORE: Yeah, it was all so new. Looking back, I've said this often—I felt like I was in a revolutionary situation, a new one every five years. The beginning was even more than that, or closer than that.

ZIERLER: Kind of like physics in the nineteen-teens?

BALTIMORE: It must have been very much like that, because there was a new technique, there was a new perspective, there was a new system, there was a new set of questions, and there was a new level at which you could begin to ask questions.

ZIERLER: What were those new techniques for your postdoc?

BALTIMORE: Centrifugation techniques and electrophoretic separation techniques. Now we could look at, for instance, all the proteins that the virus made, and ask what fraction of those end up in the particle. The answer is about half.

ZIERLER: Why is that significant?

BALTIMORE: Well, because then the other half are doing things inside the cell that no one has ever seen before, and those are going to be the active dynamic things that the virus does to the cell. That's where the virus becomes a probe of the cell. I must say I wish I had done this experiment; somebody else did it—asked the question, how many proteins in the cell contribute to a virus infection? The answer is hundreds of proteins play a role in a virus infection. When you're probing a cell with a virus, when you're looking at it, at the multiplication of a virus inside a cell, you're looking at all of the different activities of the cell. The initial hope that viruses might open up the study of cells was realized in full measure.

ZIERLER: Were you already thinking about immunology at this point, or that came later?

BALTIMORE: No, that came later. I went to the Salk Institute in 1965.

ZIERLER: This is right after you defend? This is your next move?

BALTIMORE: Well, no, I defended in 1964, but I actually left graduate school in 1963, so in 1963/1964, I was a visiting postdoc. I didn't have a degree, but I acted as a postdoc in Darnell's lab.

ZIERLER: That's a fast graduate degree, three years.

BALTIMORE: That's right. Yeah, two years, because I spent one year at MIT, and then I went to Rockefeller, so I did all the experimental work in two years, and then moved to work with Darnell.

ZIERLER: What was Darnell doing at that point?

BALTIMORE: He was interested in poliovirus, very much what I was interested in. The two of us worked very closely together.

ZIERLER: Closer in age?

BALTIMORE: He's a little older than I am. He had an MD.

ZIERLER: Had you worked closely with an MD before, up to that point?

BALTIMORE: No, but his MD didn't—he had gone into research.

ZIERLER: He was never interested in clinical work?

BALTIMORE: He was one of these people who grew up in a small town in the South, had no connection to the intellectual world, obviously was very, very smart. He had gone to I think the University of Mississippi and then been accepted to medical school in Saint Louis, and got an MD from Saint Louis, and then went to NIH. This was not the Vietnam War. He just went there because he had an inkling that he wanted to see what research was like.

ZIERLER: Oh, you're thinking about when the NIH was a place that you could do military service, so to speak, during the draft?

BALTIMORE: Right, but this is earlier than that. He found his way to Harry Eagle's lab at NIH. Whatever training he got was there. There was a group around Harry Eagle that was doing work on poliovirus. This was before really I started work, or about the time I started. Oh, no, he went to MIT the year I started. Right, right. He had gotten all of his training before I went to graduate school. He was a self-made person, a wonderful man in some ways, in some ways flawed. That's a story. But he had picked up these new techniques at NIH actually, and one of them came from another lab at MIT, from Alex Rich's lab, which was sucrose gradient-stabilized sedimentation. It was a way of separating molecules based on size, weight, electrophoretic mobility, centrifugation speed, anything that would separate two molecules from each other. Because if you could separate them, then they were different, and you could then begin to characterize, "What was the difference? What was the interesting thing about this? What was the interesting thing about that?" That general method dominated the science I cared about for about ten years, mainly electrophoretic and—well, it was electrophoretic and centrifugation methods. But for the first couple of years, it just—open doors—because things that had never been separable before were suddenly separable.

ZIERLER: Why?

BALTIMORE: Because we learned how to apply—in the end, it was stabilization. You could always make things move in an electric field faster or slower by the strength of the field and by the size of the molecule. There were all sorts of things you could do. But you couldn't stabilize the movement of the molecule because if you were looking at electrophoresis through a continuous medium, the turbulence would dominate, and you couldn't actually maintain a molecule moving in one direction. It would constantly be knocked around by turbulence.

What these guys realized was that if you polymerize the medium so that it couldn't be turbulent, the flow would be lamellar, and it would move through. A big molecule would move through slowly. There was also a filtering of the polymer, by the polymer. Big molecules moved slowly, small molecules would move fast, but in fact you could make very fine distinctions of molecular weight in that way. I could take all of the molecules in the cell and separate them all in this polymerized gel, each one by size. I could ask now for the first time, "How many proteins does a virus make?" Well, there they were, all displayed out. "What's the relationship between those? Are some precursors, are some products, or are they made individually from the genome?" That turned out to be one of my most important discoveries. You could do all those things. It was a joy.

The Salk Institute and New Directions in Immunology

ZIERLER: What was the Salk Institute like? Was it an exciting place?

BALTIMORE: It was. It goes back now to your question of what got me interested in immunology. One of the strengths of Salk was they had a big immunology program. They had hired two—they had only about ten faculty. Each one was given a huge laboratory. One of them was a virologist, was Renato Dulbecco, who was at Caltech and was brought to Salk. They gave him this huge laboratory. He said, "I don't need this amount of space." He knew me; he came to New York and he said, "I've got all this space; I want to give you some of it. I'll support your work. You'll be in my lab. But I want nothing to do with what you do. You decide. You publish." I never published with him. So, he brought me to Salk. Now, the bottom floor was these two immunologists, Mel Cohn—and Mel was one of the great thinkers of immunology. He was also an experimentalist but he was a great thinker—and Ed Lennox, who was more interested in cellular immunology. Each of those had a big lab, so they brought a lot of bright, young people like me, except interested in immunology. I was exposed, for the time I was at Salk, which was two and a half years—the people I knew, the people I talked to, were often immunologists, so I became aware of the questions in immunology and what was going on in immunology, at Salk.

ZIERLER: They must have been very interested in what you were doing.

BALTIMORE: Yeah, they were also interested in what I was doing. I taught them how to do certain kinds of things, and whatever. The important point was, ever thereafter, I thought about immunology, and followed it, because of that experience, even though I didn't do any work in it. I left Salk in 1967, started at MIT in 1968. I didn't do an experiment in immunology until 1976.

ZIERLER: This planted a seed, obviously. Do you see this intellectually as a logical transition, from virology into immunology?

BALTIMORE: Yeah, it is. It's very much a logical transition, because what is the immune system? It's your defense against viruses. You're going from one team to the other, and they're very closely related.

ZIERLER: Did you see your time at the Salk Institute as getting you closer to translational questions?

BALTIMORE: No. Not yet.

ZIERLER: What does that say about the immunologists that you were working with at Salk? Were they also strictly in fundamental research?

BALTIMORE: Yes. Lennox, not so much. He had some people in his lab who were interested a little more in human immunology, or in disease immunology. But Cohn's lab was very fundamental. The young people who came there, the exciting ones, were very fundamental.

ZIERLER: What was your funding at Salk?

BALTIMORE: [laughs] It was grant funding.

ZIERLER: NIH?

BALTIMORE: NIH funding, yeah. Actually Jonas Salk was given a big bolus of money by the National Foundation. It was a sort of gift to him for his discovery of the vaccine.

ZIERLER: "Thank you very much." [laughs]

BALTIMORE: Right. Somebody said, "What is it you want to do most in the world?" "I want to set up a laboratory of fundamental science." The National Foundation said, "Okay, we'll give you the money to do that." The problem was, he used all of it to build the building.

ZIERLER: Just the building?

BALTIMORE: Yeah. The building is one of the iconic buildings of America. It's truly one of the great buildings ever built.

ZIERLER: This is why he's a scientist and not a fundraiser. He didn't get a rich person to put their name on the building. [laughs]

BALTIMORE: Yeah, it was a different time, and he wasn't interested in raising money. He was in some ways a far-out thinker, and in some ways an absolutely naïve man who thought he could be a philosopher and wasn't a philosopher. He did build a great institution in the end, but getting money was a really serious problem. Everybody was on grants.

ZIERLER: What were your most significant discoveries as a postdoc?

BALTIMORE: It was mostly about the proteins and RNAs of viruses, and using these techniques which I had found, and biochemical techniques. After I was at MIT with Darnell, I spent a year or eight months with a biochemist at Albert Einstein, Jerry Horwitz. That was very important because that really taught me strict biochemistry, which is what I used, and that's why I was able to discover the reverse transcriptase, because I had all those techniques as part of my armamentarium.

ZIERLER: Why don't we pick up next time on your focus on biochemistry and where that takes the story?

BALTIMORE: Right, yeah.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Friday, January 21st, 2022. Once again, I am so happy to be back with Professor David Baltimore. David, good to be with you again.

BALTIMORE: Hello.

Einstein Medicine and Biochemistry Fundamentals

ZIERLER: Today we're going to pick up on when you got to Albert Einstein. I'll start off with a point that you emphasized last time, which is biochemistry becomes really important for you at this point. If we can zoom out a little, in what ways was biochemistry new as a field, and in what ways was it new to you specifically?

BALTIMORE: It wasn't new as a field.

ZIERLER: The term was in use, though? People referred to biochemistry?

BALTIMORE: Exactly. There was a lot of biochemistry, and it really had started, I think, in Germany with an interest in the chemistry of life and the chemicals of life, and actually spawned the beginnings of the pharmaceutical industry in Germany, which came out of chemical companies which in turn came out of dye companies, if I remember correctly. There were biochemists. I can remember when I was at Rockefeller, biochemistry was a very important part of the overall scientific effort at Rockefeller, even though it was a medical research institution, because there was a recognition that living systems really are chemical systems, and that the chemistry of living systems involved mainly carbon chemistry and was generally called organic chemistry because it came from organic life. But the biochemistry I was interested in was the biochemistry around nucleic acids, because that was the biochemistry that determined a heredity that allowed DNA to be the repository of the information of the living system, and ultimately would allow for the translation of that information—well, transduction, as it came to be called—of that information into protein and into the functioning behavior of living systems. I had gone to graduate school in biophysics, and that was a sort of better—well, it wasn't better developed; it was different sort of people who got involved in biophysics, who were closer to genetics. The biochemists were sort of looked down upon by the people who came from physics, and that has always been true.

ZIERLER: It wasn't "real" physics.

BALTIMORE: It wasn't real physics. Chemistry is a sort of approximation of physics. It's actually a story that could be told at great length about why the early molecular biologists didn't appreciate the importance of chemistry. And the phage people never really asked, "How does a phage work? What's the chemistry of a virus?"

ZIERLER: If you're willing to name names, who are some people who come to mind who missed that?

BALTIMORE: Well, I'll tell you, I know for sure Salvador Luria was one of the people who—I don't know that he missed it exactly, but he never saw its importance. I asked Luria once—oh, I remember what it was—the structure of DNA was announced, or the hypothesis of the structure, in 1953. Watson told that very few people took an interest in this. It didn't have the revolutionary impact that we now imagine it had. It took a long time for that to develop. I said, "How could you have not become all excited and seen that this now made biology the information science that it has become, and that that involved the chemistry of genes?" He said, "We just didn't think that way. We saw the tremendous variety of proteins, and we said proteins must be the repository of information, also, as well as the functional molecules."

When it became clear that you had to look at DNA, not at proteins, when you wanted to understand the inheritance of information, they didn't think about that. In fact, even Crick says in his book that it required an inquiry from—what was his name?—a physicist, who was in the background [George Gamow was the man]. I've blocked his name, but he sent a letter to Crick asking about what kind of code there was. Crick said he really hadn't even thought much about that question, at first. This is now just in the early stages. They were much more focused on the geometry of the molecule of DNA, the double helix structure, than they were about the implication that there had to be a code. And yet that implication just screams at you when you look at the structure. All of this is to say that biochemistry was slow to have an impact on the geneticists.

ZIERLER: But by the time you got to Einstein, it was already entrained?

BALTIMORE: It was the reason I went to Einstein.

ZIERLER: This was a center?

BALTIMORE: Well, no, it wasn't a center. There was one guy there. During the time I did my thesis at Rockefeller, one of the questions that I investigated was, could you demonstrate that there was a new enzyme in infected cells that was the enzyme that copied the RNA of the virus into more RNA, so it was replicating RNA. No one had ever seen an enzyme that could replicate RNA, and it wasn't known whether such a thing existed. I taught myself or got some help from other people about how to ask that question experimentally. Could I demonstrate that there was an RNA-dependent RNA polymerase in infected cells? Importantly, it would be an enzyme that was not found in extracts of uninfected cells. That way you could argue it was encoded by the virus and was a way the virus duplicated its RNA? In 1962 at Cold Spring Harbor, at the animal virus meeting in Cold Spring Harbor, we gave a paper that led up to this discovery.

ZIERLER: We is who? Who else?

BALTIMORE: Richard Franklin and me. Actually, Richard gave the paper, describing the work that we had been doing, mostly that I had been doing, because he was off in other directions—it was work we were doing. I came away from that meeting—the meeting is in early summer—with a feeling that the question that needed answering was, was there an RNA replicase. There were people who had looked at DNA replication. Kornberg, famously, found the DNA polymerase and got the Nobel Prize for it, even though it turned out to be the wrong polymerase, because it turned out there were lots of polymerases and this was the most obvious one. The methodology for how to look for a polymerase was established, and there was even a demonstration of a DNA-dependent RNA polymerase, very rudimentary but it had been done. I could look up those papers and see how they did it, and I had done that, and had set up a test for the RNA replicase, which was successful. Now, there's a year issue here. I think actually this must be 1962. I came back, and I got started working on this in the Fall of 1962. I was able, actually quite easily, to demonstrate that this enzyme existed, and we had some very good ways of showing that it was RNA being copied into RNA.

ZIERLER: Good ways of showing, meaning what? What was the technology?

BALTIMORE: This is what Richard actually was best known for. He and another guy at Rockefeller, Ed Reich—Ed had done more of the chemistry; Richard had done more of the biology—actinomycin D was the drug, and it inhibited DNA-dependent RNA synthesis, so it got rid of the background of the normal route of RNA production and allowed the viral enzyme to be evident. The fact that you would do the experiments in the presence of actinomycin meant that you were looking at RNA replication, not DNA-dependent RNA synthesis. That was pretty well established by that time, so that the community understood that that was a very definitive experiment. That's what had gotten me actually interested in Richard's lab, because he was at the nexus with that drug. Now, other people could get the drug. It was made by one of the pharmaceutical companies; I don't remember which one. I set this up and we did it, but I was doing it in a very amateurish way, because I had nobody to guide me. There was nobody at Rockefeller that did that kind of experiment. Richard certainly had zero idea of what that was about, so I sort of invented. I got a lot of help from a guy in Fritz Lipmann's lab who did in vitro synthesis I think of proteins.

ZIERLER: Lipmann was at Salk?

BALTIMORE: Rockefeller. Lipmann was one of the great biochemists of the day who had come from Germany, been driven out by the Nazis, and Rockefeller provided a home for, actually, a number of the Jewish refugee scientists. Being in New York, it was a good home for this kind of thing. They had always had Jewish scientists at Rockefeller, but Fritz was a special person. There was a guy in his lab named Dan Nathans who later won the Nobel Prize himself. I had a friend in the graduate school who was in Lipmann's lab, and who introduced me to Dan Nathans. Dan just showed me how you work with the test tubes and the pipettes and all that, that are necessary in order to do in vitro biochemistry, which was what I was trying to do.

I had really been helped by them, but not in a direct way, because they weren't looking at nucleic acid synthesis. They were looking at something else; I don't remember what, I think protein synthesis. All of this is background to, first of all, how I managed to do the experiments, because I demonstrated the first RNA-dependent RNA polymerase ever known. It turns out there was a guy trying to find it at NYU, and I scooped him, and I didn't even know he was doing it, but later I got to know him very well, Charles Weissmann. When I finished at Rockefeller and went to Jim Darnell at MIT, Jim decided to move from MIT to Albert Einstein. He had only been a couple of years at MIT. He was an MD, actually, so it made sense for him to go to a more medical environment. MIT obviously never had a medical school. But I think actually the thing that moved him most was that his wife wanted to move to New York City. She found Boston to be—

ZIERLER: Provincial?

BALTIMORE: A hick town, provincial, right, which it was. It was intellectually the center of America, but it was socially provincial. I had to decide what to do. I felt that I had learned what I wanted to learn from Darnell's lab, which as I said to you before was very much about using some new methods. We published a couple papers. I said, "But the thing is, I've never had a rigorous training in biochemistry." There was a guy at Rockefeller who had trained with Kornberg and who knew the moves as well as anybody in the world. I said, "You know what I'm going to do if I can?"—and I could—"is to do a year with him, rather than staying in Darnell's lab." But I would move to Einstein, because it just happened that's where he was. This was a guy I actually knew. Because when I was writing the first paper about the RNA polymerase, Richard Franklin said to me, "Why don't we take this paper and show it to Jerry Hurwitz?"—who was then at NYU.

ZIERLER: This is who you would go on to work with at Einstein?

BALTIMORE: Right. "Because he knows about this stuff." Jerry very kindly took what was about as amateurish a job of writing a paper as you can have, and made it professional. We had the right units, the right jargon, the right abbreviations. It was all mechanical stuff.

ZIERLER: He did this in the background or he was a coauthor?

BALTIMORE: No, he did it in the background. I think we thank him in the paper, but he wasn't an author. I knew Jerry, from that experience, and he, as I said, was now at Albert Einstein.

ZIERLER: You said he was the guy. It wasn't a center; it was him.

BALTIMORE: It was him.

ZIERLER: What was he known for at that point?

BALTIMORE: He had worked with Kornberg. He had done his thesis with Kornberg at Saint Louis. Then Kornberg moved to Stanford. He continued to work particularly on RNA synthesis, but everything in vitro. He never wanted to work on real living systems. He wanted to work on enzymes. He worked on the mechanics of RNA synthesis. He discovered new enzymes that were involved in DNA synthesis, that are involved in DNA replication. [Hurwitz worked on enzymes that affected both RNA and DNA synthesis.]

ZIERLER: He was really working at the frontier.

BALTIMORE: Oh, absolutely. He was world-famous for the work he had done. That's why hiring him to Einstein was a big deal. It put Einstein on the map. He was probably an untenured associate professor at NYU, and Einstein offered him a full professorship.

ZIERLER: He was not yet, but he was on his way to being a superstar.

BALTIMORE: Yes. There were very few superstars in this business at the time.

ZIERLER: It's all so new.

BALTIMORE: Exactly. And again, there was this denigration of biochemistry by the mavens of molecular biology. There was one guy in the phage field who was interested in the biochemistry of the growth of phage, Seymour Cohen. They all thought Seymour Cohen was useless, and couldn't understand why he persisted in doing biochemistry, when the interesting thing to do was genetics. There was another guy whose work I came to really appreciate, whose name I'm not going to be able to remember, who also worked in the biochemistry of phage. I personally thought biochemistry was very important and was the right way to ask these kinds of questions, and had shown that I could do that.

ZIERLER: In the way that you emphasized learning techniques as a source for going to Salk, what was the game plan, what was the motivation at Einstein? Was it additional techniques? Was it intellectual? What was the impetus there?

BALTIMORE: It was to just get experience with real professional biochemistry, because I had been doing it sort of without a license up to that point. I knew that the experience of being in Jerry's lab and working on the problems that he defined would give me a depth in biochemistry that I simply didn't have.

ZIERLER: As a means to what? Where is this headed? Greater understanding in virology, immunology?

BALTIMORE: Yes, virology. At that point I had no interest in doing anything else.

ZIERLER: What were—I don't know if shortcomings is the right word—but in what way did you see biochemistry as a means to accessing these questions in virology?

BALTIMORE: I had already shown that biochemistry was a way of asking questions, because I had found this enzyme working on my own, working with Richard, at Rockefeller. There was no question that there was a lot to be learned by probing increasingly deeply into the mechanisms that the virus used to take over the cell.

ZIERLER: Jerry was the person to serve as a mentor in this path?

BALTIMORE: Right. Jerry had those skills and had that perspective, in spades, because that's all he cared about. I knew there was a lot to learn from him, and to be in his lab meant that I would interact with his students and postdocs, all of whom were doing this kind of work. His lab was a center of nucleic acid biochemistry, nucleic acid enzymology. I came there in the summer of 1964. Jim Darnell also moved his lab to Einstein at that time, so I kept a hand in the poliovirus work by talking with the people in Jim's lab, and there were some papers he had to write that we were doing, so it was very convenient, and I kept that connection. Actually in the end, one of the people working with Darnell moved with me to California, Marc Girard.

ZIERLER: Einstein was generous to Jerry? They gave him what he needed?

BALTIMORE: Yeah, Einstein had set him up very nicely.

ZIERLER: They had the resources to do that? They were in good shape at that point?

BALTIMORE: Yeah. They were the medical school of Yeshiva University, and Yeshiva had put up resources, or had used their fundraising ability to get resources to build a medical school. They did it with a great emphasis on basic science, so it wasn't set up to just produce doctors; it was set up to produce knowledge about the fundaments of human biology. Hiring Jerry and other people was an indication—and Darnell for that matter—of their seriousness about basic science, because these were people—Jerry didn't have an MD. Darnell did have an MD but—and actually never had a PhD, but he saw science the way a PhD does.

ZIERLER: What was your funding at Einstein?

BALTIMORE: I don't remember.

ZIERLER: You were a postdoc, or a staff scientist?

BALTIMORE: I was a postdoc, with Jerry. I might have been on one of his grants. No, I know what. Harry Eagle had moved to Einstein, and Harry was the one that got Jim Darnell to go there, because Jim had worked with Harry at NIH. Eagle was one of the very early real pioneers of cell biology at NIH, and then when Einstein was set up, had moved to Einstein. Einstein reached out to mostly Jewish scientists around the world and brought them into this center. I think by taking the name of Albert Einstein, they—

ZIERLER: That helps.

BALTIMORE: No, it's not only it helped; it signaled that they were really serious about basic science, and so people responded and came there, and many stayed for the rest of their lives. Darnell later moved to Rockefeller and is still there, actually. But Eagle retired from government service. He had done his 20 years; he was probably on a great pension, so it probably worked well for him. But he headed the division, the department of cell biology. He actually had a grant—I think it was a training grant—from the federal government, and supported me for that year at Einstein. It turned out to be less than a year, actually.

ZIERLER: That was the plan from the beginning, you'd be there for such a short time?

BALTIMORE: No. I don't think there was a plan. I thought I'd be in Jerry's lab for a couple of years, but two things changed that perspective. One was I got frustrated, because Jerry's focus on in vitro biochemistry I found ultimately limiting. I had developed my own program at Rockefeller and with Darnell by studying infected cells, not cell extracts, not enzymes, except in the moment when I wanted to understand the synthesis of RNA. But most of what I had done was in cells, and what I wanted to do was to analyze the molecules of RNA that were made in cells. Jerry didn't ever want to look at cells. The only thing important about growing cells was to break them open and get the enzymes out. As I say, I found that limited.

ZIERLER: Why was it limiting?

BALTIMORE: Because you couldn't ask questions about what really went on in an infected cell, or in a cell at all. You could only ask questions about what went on in a test tube. Connecting that to the actual processes in cells was something I felt was critical, and Jerry was uninterested. Jerry was also uninterested in moving to mammalian cells, which is where poliovirus grows, obviously.

ZIERLER: What cells was he working on?

BALTIMORE: He was working with bacterial cells, and phage-infected bacteria. Later in his life he worked on mammalian cells, but at that point had never done that. When I said, "Could we set up a little part of the lab—?" and it would be easy because at Einstein, there were lots of people who knew how to do this, Darnell's lab in particular—he said no, he didn't want to see me do that. That was not what he did.

ZIERLER: In retrospect, are you surprised at your frustration? In other words, why wouldn't you have known this or appreciated this going in, even before you got to his lab?

BALTIMORE: As I said, the reason I had gone to his lab was to get the experience, and I had gotten that pretty quickly.

ZIERLER: Then once you had, you came to this realization?

BALTIMORE: Right. Then as I thought about spending more time there, I realized that it was just not going to be valuable.

ZIERLER: That probably was valuable, just going through that process?

BALTIMORE: Oh, it was, and I stayed friends with Jerry afterwards.

ZIERLER: Even though you were leveling a somewhat existential critique about his research approach?

BALTIMORE: Yes, and I was very clear about that. He was really taken aback: "What was this kid doing telling me what to do?"

ZIERLER: [laughs] "Who I was so nice to, helping him with a paper!" [laughs]

BALTIMORE: Exactly. He was very unhappy that I was not more—

ZIERLER: How big was his lab? What were some of the other postdocs doing?

BALTIMORE: His lab was pretty big and always had been. He got people from India, from other countries as well as from the United States. He trained up a whole generation of people in his way of thinking, his way of doing science.

Life is Good in California

ZIERLER: When you came to this realization, did you start putting out feelers?

BALTIMORE: I said there were two things that had affected me. That was one. The other was that the Salk Institute was in formation at that time in La Jolla, and they had contacted arguably the premier animal virologist in the world, Renato Dulbecco, and asked Dulbecco to move from Caltech, where he was a professor at the time, to this newly formed Salk Institute. They offered him a full professorship, which meant that you got half a floor of space, and half a floor at the Salk Institute is an enormous amount of space. Renato said he didn't need all that space. They said, "It's up to you. You can build a department around it if you want." He said he was going to segregate off a significant amount of the space for independent investigators that he would ask to come in and work in his space. Some of the other professors at Salk did the same thing and brought in some wonderful, actually, young people, some of whom are still there. Renato knew I existed and had actually come and lectured at Rockefeller? No, no, that's not right. He had come and visited? I had met him. He contacted me and said, would I like to come and have an independent position within his laboratory that he was going to build at Salk. I had never spent any time in California. I had at that point once taken a trip there, been invited to give a lecture at Caltech.

ZIERLER: Do you remember who brought you out?

BALTIMORE: It was young people from Renato's lab, who were my sort of coequals, because I was still a postdoc at that point. These were postdocs in Renato's lab. There was a particular guy who was a friend of Richard Franklin's from Germany, because Richard had worked in Germany, who actually took me around La Jolla at the time. No, I guess it must have been in Pasadena. It will take a little research for me to figure that one out. But I had been once to California, but other than that, it was a brand-new idea. Salk was a great opportunity, because really they were aggregating an extraordinarily group of people. The answer to my unhappiness at Einstein was to take Renato's offer and to move to the Salk Institute, so I did. At that point I had just gotten married, not to Alice, to Sandra, and she thought it was a great idea. She was an artist and she thought it was a great idea.

ZIERLER: Life is good in California.

BALTIMORE: Life is good in California. She was a painter and she actually really loved the light in California, so I up and moved. I set up a lab at Salk. I was then working out of a temporary building, because the great Salk Institute building was under construction. I moved into the basement of this wooden building. It's still there, the building. Famously, the day I arrived, a wonderful scientist who became a good friend, Leslie Orgel, said, "I want to show you something. Would you come up to my lab?" He was on the second floor of this wooden building. I went up and he showed me in a terrarium the rattlesnake that they had found in my laboratory when they were cleaning it out to give me this basement space. There was a rattlesnake in it. I had never seen a rattlesnake before. It certainly was a symbol to me of the fact that I was going to a new world. Salk is right on the coast and there are canyons that go down, Salk into the beach, and there are a lot of rattlesnakes in there.

ZIERLER: What was your appointment initially at Salk?

BALTIMORE: That was an issue, and it comes back to haunt me later. I don't even remember what the title was.

ZIERLER: But it was more than a postdoc?

BALTIMORE: It was more than a postdoc and less than a professor. There was no established track for promotion yet. They just hadn't worked it out.

ZIERLER: Would they hire with tenure for more senior people?

BALTIMORE: The senior people, Renato and the other six or eight faculty who got these half-a-floor laboratories, they were all tenured full professors. They in fact were I think Members. I think that was their title.

ZIERLER: But a tenure track, a seven-year review, that was not part of the process?

BALTIMORE: No, they hadn't established that. They didn't have many people in the kind of position I was in. The way they had set things up, the senior faculty were the only people that they cared about, and then each one of those senior people could build their laboratory any way they wanted. I didn't go there with the idea that I was in a hierarchy of the Salk Institute. I was in a hierarchy of Renato's lab. I had a couple of rooms of space and some money that he had available and other things, and I could do with that what I wanted. I hired some technicians and initially actually just technical people working with me. Then I had one postdoc who came from Einstein with me, Marc Girard, who then went back to France and became a professor at the Pasteur Institute.

ZIERLER: Were there institutional affiliations with U.C. San Diego at that point?

BALTIMORE: No, distinctly not. The Salk Institute was set up totally separately from the university. The university was very young at that point, but functioning. The first college had opened. Because that's how it's structured; it's structured around, I don't know, by this time, 12 colleges or something. The first one was Revelle College. They had started a biology group. They hadn't yet started a medical school. I knew those people and they provided a culture, a university culture, around Salk, because Salk was given by the city this space on the coast, but within the orbit of where the university was going to be, or was then developing.

ZIERLER: Did Salk grant degrees? Were there graduate students?

BALTIMORE: No. That's an interesting question.

ZIERLER: The senior people were professors, but they weren't teaching anybody?

BALTIMORE: Right. And they did have graduate students. Oh, yeah, and I ultimately got a graduate student, Mike Jacobson, from UCSD, so he was in their program as a student and took courses and got certification and whatever through UCSD, but worked with me. Many of the other faculty had students from—when Salk was set up, they had an agreement—

ZIERLER: Like a courtesy appointment kind of thing?

BALTIMORE: I never had a courtesy appointment, and I've forgotten the details of it. It evolved. Today, if I'm not mistaken, Salk still doesn't give degrees, but the Salk faculty all do have adjunct appointments. You see, there were no junior faculty at Salk, so there was no reciprocity that was possible at the time, because Salk just hadn't yet designated anybody except these senior members. I don't know whether they had appointments at UCSD or not. I'd have to go back and see.

ZIERLER: The experience at Einstein, where you came to this realization and you got frustrated, in what ways were your antennae up that you should not repeat this at Salk?

BALTIMORE: I now had an independent position. I didn't anymore—

ZIERLER: You were not under anyone's thumb.

BALTIMORE: I didn't have to answer to anyone. Renato never took an interest in the science that I was doing. He was aware of it, and he was glad to see that I was publishing and had made some discoveries and whatever, but I never published with him.

ZIERLER: What was the game plan? What did you want to work on when you got to Salk?

BALTIMORE: I wanted to go back to working on the synthesis of poliovirus. How did the RNA get made? How did it get packaged? What kinds of signals were in it? How did it code its products? What were the products? What did they do to the cell? What did they do to allow the synthesis of more virus? We focused a lot on the replication of RNA. If you fed infected cells a radioactive precursor to RNA for a very short time, then you could label the molecules that were in the process of replication, so we could find out where replication occurred in the cell, and what the nature of the molecules were that were being made. Those were the kinds of questions we asked.

Mike Jacobson focused on the synthesis of viral proteins. Now I could take the techniques that I learned in Darnell's lab and apply them to the synthesis of viral proteins. Then we showed, famously actually, that the whole genome was copied into one long protein which was cut up into pieces, many pieces. That was just a brand-new idea, that that could be. I spent a lot of time thinking about the implications of that. Why did the virus choose to be that way, and what were the implications for how proteins were made, and how proteins were made by cells? We wrote about that, and I became probably better known for that than anything, that work. Mike was my first student. Then Alice joined me as a postdoc. During that time, my marriage broke up, and I ended up with Alice. That was two and a half years at Salk.

ZIERLER: But it wasn't a term-limited appointment? It was more open-ended?

BALTIMORE: Yeah, it was totally open-ended, but there was no ladder. I began to be a nuisance to people [laughs] about why there was no ladder, and how they could have junior people without thinking about their careers. People recognized that this was a problem, but they were slow to develop a structure around it. Now they have a well-established route of movement for positions. It was partly because there were very few people who were in these positions. Most labs had a lot of postdocs, and postdocs are by definition there temporarily, whereas I was not a postdoc, and so what was I?

ZIERLER: A forever junior faculty member.

BALTIMORE: Well, yeah, that's how it was looking there, and that wasn't happy. I had by this time become reasonably well known in the scientific community, and people were very surprised that I didn't have a professorship.

ZIERLER: Were you working on your own? How collaborative were you at Salk? Were you bouncing ideas off of your colleagues, or this is a one-man operation with some students?

BALTIMORE: My laboratory was a one-man operation with students and postdocs, trainees, because there was no one else who cared about viruses except for the young people in Renato's lab, and he had some very good people, but they were interested in cancer, which was not a problem that I had yet gotten an interest in. They were working largely on—I guess entirely on—polyoma and SV40, two DNA viruses that cause tumors in mice and even in humans. I knew what these people were doing, and talked to them, and they provided an environment, but the people in my lab were responsible to me and didn't interact a whole lot with the other people even in Renato's lab, never mind in the larger Salk Institute. At that point, Salk had two faculty in immunology. During this time, we moved into the new building from this wooden shack with its snakes. I identified them by where they were in the building. The basement was two immunologists, Mel Cohn and Ed Lennox. The second floor was Renato. There was nobody in the other lab. Ultimately it became Bob Holley's lab. Then there was one more floor, because there was three floors of laboratories, Leslie Orgel had his labs there. He was actually by training an inorganic chemist and had written the textbook on ligand field theory.

ZIERLER: Are there other institutions where you could have been among more likeminded people in your age group, or it didn't really matter?

BALTIMORE: Any established university—

ZIERLER: —would have had a core of people interested in what you were interested in?

BALTIMORE: Yeah.

ZIERLER: It begs the question, why Salk, then, besides the environs?

BALTIMORE: It was an adventure, to go to Salk. There was also a little bit of connection to Jonas Salk. Not that he was interesting scientifically; actually he had a lab there, working on poliovirus, but working at such a different level, because it was largely about vaccines, protection against virus.

ZIERLER: Did you interact with him at all?

BALTIMORE: No.

ZIERLER: Because he was removed, larger than life, or you just weren't interested?

BALTIMORE: The issues that they were dealing with and the technology that they were using was just uninteresting to me, and uninteresting to almost anybody else, too.

ZIERLER: [laughs] But I guess if you're Jonas Salk, you can work on things that are of no interest to anyone else.

BALTIMORE: That's right. He had space, and there was a neuroscience group. Or maybe there wasn't yet a neuroscience group. In the summers, they brought neuroscientists there. I think they didn't have their own group yet.

ZIERLER: This was a 12-month position? You were there for the summers?

BALTIMORE: Yeah. Summer is great. There were people who came only for the summers, visitors, particularly in neuroscience, and I learned a lot of neuroscience from them. They had one neuroscientist there, at least he thought of himself that way, Jacob Bronowski. Bronowski, you may remember.

ZIERLER: Sure.

BALTIMORE: I became quite friendly with he and his family. He was a special person there. Salk had this romantic view of bringing humanists in, and that's where Bronowski fit in. Some good things came out of that, but in the end Salk has become just an amazing biological research institute, and some of the more romantic visions of what it might have been are—

ZIERLER: When you started to make noise about needing a ladder, did they simply not have a means to retain you at that point? If you got a good offer from somewhere else, were they not even in the position to counter?

BALTIMORE: Right, they were not. Because I was not responsible to the institution; I was responsible to Renato.

ZIERLER: This is a real fiefdom.

BALTIMORE: Yeah. Renato could have given me more space or more money or more something, or he could have worked to try to keep me there—

ZIERLER: But that's not a professorship.

BALTIMORE: Right, but it's not part of an institutional ladder. There was also another thing about my leaving that involves an art show. I was a real nuisance to them. Because it was a very conservative environment in San Diego.

ZIERLER: What's the art show story?

BALTIMORE: This has to do with my wife at the time. There was a lot of space at Salk that wasn't being occupied, so she said, "We could hold an art show. It could be an opportunity for young artists." Because there was a sort of underground of artists.

ZIERLER: It's the 1960s.

BALTIMORE: Yeah, it's the 1960s, and it's San Diego, so Pacific Beach and whatever. She had made friends with some of those artists. She said, "Why don't we have an art show?" Her work would be shown. Her work was very sort of outdoors art. But there was this guy, Hugh Duckworth, who was doing art that was part of the 1960s movement, very left-wing in orientation, but very—I don't know how to characterize it, but in particular, used the flag in ways that were not—

ZIERLER: Norman Rockwell.

BALTIMORE: Not Norman Rockwell, right. When we put up the show, there were people who took umbrage at his work and wanted to take it down, and I was not going to countenance that. The show was actually taken down, it was closed, and that was a reason why I felt that without a hierarchy, with the political opposition, maybe this wasn't a place I could make my life. By this time, I had been there for two years. Salvador Luria at MIT had always said, "When you're ready to come back to MIT, let me know." There was a professor at Harvard, Bernie Davis, who said, "I want to consider you for a position at Harvard." He invited me to come and give a seminar at Harvard and talk to him about the position, which ultimately they didn't offer me. When Luria at MIT across the river heard that I was coming and thinking about a position at Harvard, he simply organized his MIT to offer me actually a better position, and had told me that he was doing that. I had in my desk a letter of an offer from MIT at that point, which I had not tried to get, but Luria wanted to make sure that if I was going anywhere, I was coming back to MIT.

ZIERLER: As a full professor?

BALTIMORE: As an associate professor. As an untenured associate professor, so I was going to skip the assistant professorship, and that was a recognition that I was further along in my development, but I didn't have an academic position at Salk, so this was actually a very audacious thing to do already, to offer me an associate professorship. The combination of push and pull, and my marriage had broken up and she was going to stay. We didn't have any children, so that was—

ZIERLER: It was easy?

BALTIMORE: It was an easy breakup.

ZIERLER: What year was this?

BALTIMORE: This was 1967. I came there in April of 1965, and this was now the Summer of 1967, or I guess the beginning of the summer, maybe the spring. I had never taken any time off from my trip through academic life, and I said, "The best way for me would be to spend a few months in Paris, and then come back to Salk, pack up my stuff, and start at MIT in January 1968." That's what I did. I spent three months in Paris.

ZIERLER: Pasteur?

BALTIMORE: Half in Pasteur, and half in Villejuif where there was a very well-known cell biologist from whom I thought I could learn a lot about cell biology.

ZIERLER: Who was this?

BALTIMORE: Boris Ephrussi.

ZIERLER: What was he known for?

BALTIMORE: He was known for his work in drosophila genetics actually, and had later moved to cell biology. Never did anything terribly important in cell biology, but did very important work in early genetics, here, at Caltech, actually.

ZIERLER: Late 1967 must have been an interesting time to be in Paris. Had the student protests started already?

BALTIMORE: I think I missed that.

ZIERLER: That was just getting started?

BALTIMORE: Yeah, that was more in 1968, by which time I was back. I had been involved in politics here in La Jolla.

ZIERLER: Antiwar stuff?

BALTIMORE: Antiwar stuff and spoke at rallies.

ZIERLER: You must have been unique among the faculty at Salk? The older generation probably was not involved?

BALTIMORE: Yeah, that also made them unhappy with me. There was an organized group in San Diego, which was left over from earlier years. They were Trotskyites, and they were very passionate about Trotsky. The important thing about them was they were organized, and so if you wanted to have a rally, they knew where to get microphones and amplifiers and how to get a hall and all that sort of stuff, because they had been doing that sort of thing in the background, nobody paying attention to them, for years.

ZIERLER: When you were doing your antiwar stuff—and this is my thesis dissertation; I focused on Arthur Galston, Matthew Meselson, and—

BALTIMORE: Oh, I see.

ZIERLER: —the Agent Orange stuff in Vietnam, and they leveraged their authority as scientists to make the case that this was a scientistic catastrophe and all that. Were you involved in your capacity as a scientist, or you were doing it more like citizen protest stuff?

BALTIMORE: Citizen protest stuff.

ZIERLER: Were you aware that this was a time when scientists were sort of—?

BALTIMORE: Oh, yes, I knew Galston, I knew Matt. I still see Matt. In fact, I wonder how he's doing. His wife died.

ZIERLER: You know about his daughter, too, right?

BALTIMORE: That was earlier.

ZIERLER: A few years ago.

BALTIMORE: Yeah, Matt has had a hard time. He's a wonderful man.

ZIERLER: Yes. You knew about this? You knew what they were doing?

BALTIMORE: Yeah, and I knew about the bees and all of that.

ZIERLER: That was a productive time in Paris?

BALTIMORE: Mildly. It turned out Ephrussi—there wasn't anything really going on there that was important. I worked more at Pasteur with Marc Girard, so the guy who had been my postdoc, I was now his visiting faculty member. It was wonderful to be at Pasteur.

ZIERLER: They were doing good stuff?

BALTIMORE: Yeah. My French wasn't terribly good, which limited how much I could interact with him, but to be with Jacob and Monod and Lwoff at that time was—it was before they got the Nobel Prize, I think? We had lunch. People went out to the local charcuterie and got materials and everybody made a communal lunch.

ZIERLER: Sounds delicious.

BALTIMORE: Yeah, it was. I got to meet all of the people working there that way.

ZIERLER: When it was time to join the faculty at MIT, where did you see yourself slotting in, in terms of your research agenda at that point?

BALTIMORE: It was still poliovirus.

ZIERLER: Was there anybody at MIT who was doing that?

BALTIMORE: No, there was not, but there were cell biologists. In particular, there was one cell biologist who had worked in Darnell's lab when I was at MIT, and he had stayed on. He had been offered an assistant professorship, stayed on, and become I think by that time a full professor. Sheldon Penman. One of the reasons why I was really glad to go back to MIT was that I wanted to work with Sheldon. Sheldon was interested in poliovirus but his own lab was more cell biological than viral. He was actually a physicist. I think he had been at Bell Labs, had been brought to MIT by Alex Rich, who had the lab on the floor below us. Sheldon had wandered up from there to Darnell's lab because of just the environment and the kind of questions that they were asking. Then when Darnell left to go to Einstein, maybe it was then that they hired Sheldon. I don't know exactly what happened. By the time I came back, he was an established professor. He actually became very right-wing and we ultimately parted ways.

ZIERLER: Did you stay up with the activism in Cambridge?

BALTIMORE: Oh, yeah.

ZIERLER: This is an exciting time in Cambridge, also.

BALTIMORE: Right. Yeah, I was part of the March 4th movement.

ZIERLER: Oh yeah?

BALTIMORE: Yeah.

ZIERLER: The protest against Lincoln Lab, that registered with you, all of that stuff?

BALTIMORE: Oh, yeah. The big thing was the invasion of Cambodia. But that's now part of another story.

ZIERLER: That's a little farther afield, too. That's 1970, already. We're still in 1968.

BALTIMORE: That's right.

French Interlude and Return to MIT

ZIERLER: Did you bring equipment with you from Salk, or you set up a brand-new shop?

BALTIMORE: I set up a brand-new shop.

ZIERLER: Were there advances? Was this an opportunity to get new stuff, better stuff than what you had?

BALTIMORE: No, I think it was the same things that I had. I might have even taken some things with me, but I don't think so, because it all belonged to Renato. He didn't have somebody moving in, although ultimately people did move into my space.

ZIERLER: After all these postdocs, this is your first professor appointment. What were your teaching responsibilities at the beginning?

BALTIMORE: I taught virology for a number of years. I taught cancer biology once or twice.

ZIERLER: These are seminars or lectures?

BALTIMORE: These were lectures. I wasn't a great teacher, because my core interest was research rather than teaching, and what I knew was mostly about viruses. Then I got very busy with other stuff, which we'll get to. By 1970, so I had been there at that point two years, I discovered the reverse transcriptase, so from then on, I was—

ZIERLER: Different course?

BALTIMORE: Yeah, and I was so busy with stuff at MIT and elsewhere in the world that it was hard for me to teach much.

ZIERLER: Let's bring it back to messenger RNA by the end of the 1960s. What are some of the advances happening in your immediate milieu and more generally? What's going on over the course of the decade, since Caltech in the early part of the decade?

BALTIMORE: That's an interesting question, because I was involved in the discovery of splicing, and so I can date that. We had already built the Cancer Center. We had hired Phil Sharp. He came. Someday I'll tell you about my contribution to that. But you really couldn't understand the synthesis of messenger RNA without understanding splicing, and so even though messenger RNA was discovered in 1961—

ZIERLER: You couldn't do much with it?

BALTIMORE: —we really didn't understand how it appeared, how it came about in a cell, until splicing had been defined and until we began to understand the biochemistry of splicing.

ZIERLER: What years is this? What's the chronology?

BALTIMORE: That was probably—it was after 1974.

ZIERLER: Oh, wow.

BALTIMORE: Phil only came to MIT in 1974, because we opened the Cancer Center and that's when he came. For 15 years—

ZIERLER: Not that much going on.

BALTIMORE: —in mammalian cells, the key thing about messenger RNA was not known. It's actually amazing as I hear it.

ZIERLER: It's the technical breakthrough that allows this, and you know all along; it's just a matter of getting to the technology? What's the sequence of events?

BALTIMORE: You mean for splicing?

ZIERLER: In other words, for splicing, is it known before 1974 that for there to be these advances in mRNA research, you need the splicing? Or does the splicing come along, and retrospectively you understand now we get why we weren't making much progress in mRNA?

BALTIMORE: The latter. Very much the latter. Because there are an awful lot of people who will tell you that they were blocked in their ability to move forward by not understanding that splicing existed, and they had data that implied splicing that they didn't see implied splicing, because if they had, they would have said there was splicing.

ZIERLER: When you say, "not aware of splicing," you mean splicing as a technique?

BALTIMORE: No, as an event of the lifetime of a messenger RNA. A messenger RNA is made as a long precursor and then cut down by splicing.

ZIERLER: Precursor to what?

BALTIMORE: To messenger RNA. But it's got all sorts of other stuff in it, and all of that is cut out by splicing, and so you're down to maybe 10% the size that it started off. The famous person who worked on the precursor for much of his career was Jim Darnell. When Sharp and Roberts discovered splicing, suddenly everything that Darnell had been doing fell into place, but he didn't understand it. He didn't lead to that understanding.

ZIERLER: What does the word "splicing"—if we were to visualize—we can think of other things that we splice. If we can visualize the splicing process of mRNA, what does that look like?

BALTIMORE: The precursor is a long RNA, and there are pieces of that RNA which are cut out, and they are cut out because they are circularized and then joined here, and this whole circle is thrown away.

ZIERLER: This is all passive voice. Who is doing the cutting? Who is throwing it away?

BALTIMORE: It's all enzymes of the cell. There are literally hundreds of proteins involved in this process. It's carefully regulated. There are still very deep aspects of it that are not understood. But virtually every—nothing is ever "every"—messenger RNA is made as a long precursor and then there's stuff cut out and thrown away, which would interfere with the function of the message, so you have to get rid of it, in order to get a functional messenger RNA.

ZIERLER: Before the splicing breakthrough in 1974, is it impossible to make the connections between virology and messenger RNA? Is that why it's not a focus of yours during this whole time?

BALTIMORE: No. RNA viruses don't splice. That's about 70% correct, maybe even 90%. Splicing is not an event that ever worried me, or the lack of knowledge of splicing never bothered me.

ZIERLER: Because it's outside of your focus at this point?

BALTIMORE: Totally outside my focus. The people who were blocked were working on cellular genes. I later worked a lot on cellular genes, but by that time splicing was known, was in the lexicon.

ZIERLER: Since you're sensitive to ladders at this point, when you arrive at MIT, what's the messaging on tenure prospects, timing?

BALTIMORE: It's all written down, and it was a joy to go to someplace where all of this was established. There's an infrastructure. You knew what the hurdles were.

ZIERLER: What do you have, a three-year review at that point?

BALTIMORE: Since I was an associate professor—well, it didn't matter. Like any new, young faculty member, I had seven years before I had to be given lifetime tenure or let go. But when I discovered the reverse transcriptase, that was all accelerated [laughs], and I became a full professor in the early 1970s.

ZIERLER: Let's bring the narrative for today's session up to that point. What's the connecting point? What were you doing before that, that gets us to this breakthrough in the early 1970s?

BALTIMORE: You mean what's the background to the reverse transcriptase?

ZIERLER: Right.

BALTIMORE: I arrived in January of 1968. In a snowstorm. I set up a lab working on polio.

ZIERLER: This is the Department of Biology?

BALTIMORE: It's in the Department of Biology, yeah.

ZIERLER: They had a Biochemistry Department at that point?

BALTIMORE: No, biochemistry was in the Biology Department.

ZIERLER: Did you find that regressive? Did that make sense for you?

BALTIMORE: No, that was fine. Everything that was going on in molecular biology up to 1960 was focused in phage, and focused in pure genetics. The people interested in cell biology were not participating very much in the revolution that was going on, because mammalian cells were so complicated and so big and had so much garbage DNA in them. Remember, when we finally get to the understanding the genome, it's only 1% protein coding. What they had always been looking at, from microscopes and whatever, were these chromosomes that were 99% something else, not protein coding, and the only thing we were thinking about was protein coding at that time, so there was a huge gap between what cell biologists were doing and what molecular biologists were doing. That's why when I decided to work in animal viruses, it was in a sense to bridge that gap, although I couldn't have defined it that way at the time because I didn't know about the gap. There were other people trying to bridge that, because in the end, biology has to be about human biology and human mammalian biology.

ZIERLER: Why do you say that? Why does it have to be about human biology? From a translational perspective?

BALTIMORE: No, because we're humans.

ZIERLER: Oh, okay! [laughs]

BALTIMORE: And we care about ourselves.

ZIERLER: This is the approach even if you're not thinking in clinical terms.

BALTIMORE: Right. Luria was an MD, but even if you talk to Delbrück, who was the purest of the pure, he would have said that human biology is important. He couldn't approach it. Delbrück moved all of his work actually to neurobiology for the last years.

ZIERLER: What was Luria working on, at that point, when you got to MIT?

BALTIMORE: Luria was working on colicins, I think, mostly; bacterial antibiotic kind of things. He never did much that was important after coming to MIT. His important work, which was in pure genetics, was much earlier, the work that he did when he was in the Midwest. I mentioned him because he was somebody whose work was entirely in bacteria, but who thought more broadly and was always thinking about what the next step was. The reason he wanted me to come to MIT was he saw that the next step was going to involve animal virology, and he wanted to be there for that. Then he saw that cancer biology was going to be very important and set up the Cancer Center at MIT. We'll get to that later. But Luria was always guiding to the next step. That's how Penman ended up at MIT as a really unusual cell biologist.

ZIERLER: This is something that Luria did; he recruited at the vanguard?

BALTIMORE: Yeah.

ZIERLER: This wasn't specific to you?

BALTIMORE: No. He was always on the lookout for people who could bring us to the next level of biological complexity. That's really what I mean by level.

ZIERLER: Did you feel like you had more freedom setting up your lab the way you wanted to than you did at Salk?

BALTIMORE: No.

ZIERLER: Same scenario?

BALTIMORE: Yeah. I had a little more space, and I had more opportunity. I was better known. People wanted to come to work with me, so I could build a larger lab pretty quickly.

ZIERLER: You took on graduate students right away?

BALTIMORE: I did, grad students and postdocs. By the time I discovered the reverse transcriptase, I already had a significant size laboratory, maybe 20 people.

ZIERLER: Were there new questions that you wanted to pursue that you didn't, for whatever reason, at Salk?

BALTIMORE: Yeah, that's now the next step. I had only worked on polio and its relatives up until this point. When I was at Salk, I had a very small lab. Just Marc and Alice and Mike Jacobson, the one student, and some technicians, was all I had working with me, I think. That was the core of what I set up. Mike came with me from California to MIT, and Alice did, so there was continuity. I didn't have to totally repopulate it. Somewhere around the end of 1968 or 1969, Alice and I said to each other, "Maybe we should have a broader program and work on other viruses." That was the nature of the broadening of the program. She actually had worked on a virus that was very different from polio, for her thesis, which was at Johns Hopkins. When she came to work with me, it was very much to develop the skills that we applied to polio with the long-term perspective that she would go back to working on this other virus and use the techniques. But we said, well, she didn't have to wait until then. Why don't we sort of open up a section of the lab to work on vesicular stomatitis virus, which was that virus.

ZIERLER: That's an RNA or a DNA virus?

BALTIMORE: It's an RNA virus, but an enveloped RNA virus, one that has a lipid-based envelope around it, much bigger physically than polio, and clearly has a very different life cycle than polio because of just its physical nature. But it had a secret that we didn't know at the time. We said, "Well, why don't we just see if there's something interesting in this? Maybe it will broaden the perspective."

ZIERLER: Of the lab, or for your specific work on polioviruses?

BALTIMORE: No, of the lab.

ZIERLER: You were looking to do that generally, to broaden out?

BALTIMORE: Yeah. I had been doing it for ten years by that time, and I didn't see why—

ZIERLER: It's probably good for the graduate students too.

BALTIMORE: Right, a lot of positive things about it. I had a young woman who had come to the lab, a student, who was very excited by that idea, because she could have something that was separate from the rest of the people in the lab, Martha Stampfer. I said why didn't Martha work closely with Alice, develop the ability to work with this new virus, and we'll see where it goes. It was just as simple as that. That was after I had been at MIT for maybe a year, and I had people working on polio from various points of view. Here I don't remember the timing perfectly well, but by the end of 1969, we had made a remarkable discovery about vesicular stomatitis virus, and that was that the RNA in the virus particle was not the messenger RNA for the synthesis of the viral proteins; it was the complement of the messenger RNA.

ZIERLER: You went in assuming it was the mRNA?

BALTIMORE: We went in assuming it was going to be the same thing as polio.

ZIERLER: Why? What's the theoretical basis for that? That just generally this is how viruses work?

BALTIMORE: Yeah, all RNA viruses that we knew about had a viral RNA—had a messenger RNA—had an RNA in the virus particle which was also the messenger RNA for the synthesis of viral proteins. We knew that you could purify it, you could add it back to ribosomes. It would encode viral proteins. We didn't know the sequence of it, because you couldn't sequence RNA at the time, or DNA for that matter, but we did know that it was the messenger RNA. It came as a bombshell that there was a class of viruses, which are now called negative-strand viruses, which had the complement of a messenger RNA. We published that.

ZIERLER: The complement—what does that mean?

BALTIMORE: DNA is a double helix; one strand has a sequence, and the other strand has the complementary sequence. Where this strand has an A, that strand has a T. Where this strand has a C, that strand has a G. That's what I mean by complement. It's sort of a fundamental truth about DNA, about nucleic acids. Actually, I helped to isolate first in Darnell's lab the polio virus double-stranded RNA, because as an intermediate in the synthesis of polio RNA, the plus-strand, which is the messenger RNA strand, has to template the minus-strand, which is the complement, and then the minus strand has to template the plus strand, and that's what actually the duplication of the virus means. It means that the strand that comes in makes its complement, the complement in turn makes more of the messenger RNA, and now the virus has duplicated itself, and it's asymmetric so it makes lots and lots of messenger RNA. But that's not true for vesicular stomatitis virus.

ZIERLER: What was the technology or the instrumentation that allowed for this breakthrough observation?

BALTIMORE: It was really to go into the infected cells and to look at what RNAs were on the ribosomes.

ZIERLER: And this is microscopy?

BALTIMORE: No, you purify the ribosomes and see what RNA have attached to them and you characterize it by size. It was much smaller, so the genome was maybe around 10,000 nucleotides long. The RNAs that we found on the ribosomes were much smaller. That immediately suggested that something was going on. Then we found that you could hybridize the messenger RNA to the genome RNA.

ZIERLER: What does that mean, "hybridize"?

BALTIMORE: That you could make them come together—[laughs] they would form a double strand, so that the double-strandedness of DNA is equivalently found in RNA. You could make a double-stranded RNA. We found in poliovirus—in fact, that's what we studied for a long time—that there was a poliovirus double-stranded RNA, as an intermediate between the messenger RNA and new messenger RNA, so the minus strand was made as part of the double strand. That's what the lab had been working on for all these years. But that was no longer true for vesicular stomatitis virus. It had this minus strand as its genome, instead of the plus strand. That got me thinking, "How does it ever start an infection?" Because if you put the minus strand into a cell, it will just sit there.

ZIERLER: Inert, essentially?

BALTIMORE: Inert. Its sequence is meaningless, except if you copy it into the other strand, at which point it becomes very meaningful, because it encodes protein, but as a complement, it can't make protein. We knew all that. That was all an implication. For one reason or another, almost nobody else thought about that, but it struck me just from the first moments. I said there were two possibilities. One possibility was that it came into the cell and that the cell had the ability to duplicate it somehow, even though we had never seen an enzyme in an uninfected cell that could copy RNA. Maybe it was there and we just hadn't seen it. That would make a lot of sense. It's putting the minus strand in the cell, copied by a cellular enzyme, and now it has a plus strand. Or maybe, the enzyme exists in the virus particle. There were other viruses that had nucleic acid synthesizing enzymes in them. That was not a new thought. But they weren't viruses like vesicular stomatitis virus.

ZIERLER: What do you mean? What was unique?

BALTIMORE: They were either DNA viruses or they were double-stranded RNA viruses. There was a double strand. There's a class of viruses that have a double-strand genome, but they were not single-strand, minus-strand viruses. That had not ever been seen, except now we knew it existed, and we very quickly showed lots of other viruses were like that, viruses that people had worked on—mumps, measles. Maybe it was in the virus particle. That was an easy thing to test, because as I've been saying, I knew how to do that kind of biochemistry in my sleep and had been doing it ever since I started working in virology. What I needed to do was to make some virus, break it open, and see if it had an enzyme in it. I did that, and lo and behold, there it was. This virus, and it turns out this whole class of negative-strand viruses, carry with them an enzyme, and they go into the cell, and the enzyme now copies it into plus-strand, and the plus-strand is messenger RNA now—this is why messenger RNA was so critical to be able to think about viruses—and it makes messenger RNA and the messenger RNA gets on ribosomes and encodes viral proteins. Now you're off to the races. That was extremely exciting. We published that actually a little after we published the reverse transcriptase because Nature got the reverse transcriptase paper out so quickly.

ZIERLER: Was the realization that because this was so fundamentally different, that it had this complement, did that tell you that it opened up a whole new world that viruses—it wasn't just these two classes? That there could be other possibilities, other permutations out there? In other words, if the original going assumption was, "This is how viruses work," and now you're working on a lark on this new virus and all of a sudden you see this complement, is that telling you now that there's a unitary, and now it's a binary? Or is it like wide open and there could be all kinds of ways that viruses operate?

BALTIMORE: The latter. But at that moment, I'm not focused that broadly.

ZIERLER: But it's in your back pocket, something to return to.

BALTIMORE: Right. Actually there was a very important event that comes out of exactly that kind of thinking, but it's a little later.

ZIERLER: This paper, you and Alice are coauthors?

BALTIMORE: Yes. And Martha.

ZIERLER: This is great, having women coauthors on such an important paper, too. This is early.

BALTIMORE: Right. I never thought about that, I must say.

ZIERLER: That's good.

BALTIMORE: I had women working with me from the start, and I really think it's because of my mother. It was not a surprise to me that a woman was an effective academic, an effective scientist, because I had grown up with one.

ZIERLER: Did you recognize at least what a pathbreaker she was in that generation?

BALTIMORE: Oh, yeah.

ZIERLER: There were not many.

BALTIMORE: That's right. No, and she had had a hard time with the juggling. There were two of us kids to worry about, and a husband who was very traditional in the sense that he didn't do anything around the house. I'm pretty sure I was the first author on that paper, because I did those experiments. I knew how to do them.

ZIERLER: I'm always interested in breakthrough research, the decision on where to publish. What were your options? What was the biggest impact for publication?

BALTIMORE: I think we published that in PNAS, and I think Luria sent it in, because in those days, you had to have a member of the Academy send the paper in. I think Luria did.

ZIERLER: What was the reception?

BALTIMORE: Oh, it was immediate.

ZIERLER: Game-changer.

BALTIMORE: Recently, I asked myself, what exactly was the sequence of events in there? It's partly because I knew I was talking to you and I wanted to get it straight. I couldn't remember whether there was anybody else who saw that there was a minus-strand.

ZIERLER: You mean within your lab or somewhere else totally disconnected?

BALTIMORE: Another lab.

ZIERLER: Like a multiple independent discovery kind of thing?

BALTIMORE: Right. Oh, I know—somebody was writing about this and quoted a paper that described the minus-strand. It wasn't vesicular stomatitis; maybe it was. He gave us credit but also gave credit to another lab, so I went back to look at that paper. The paper, sure enough, shows that there were small RNAs attached to ribosomes. But, he never looks at the possibility that the genome RNA is the other strand. He never actually shows that it's a plus-strand on the ribosomes and a minus-strand in the virus.

ZIERLER: The fact that you did is a lark? Is it deeper thinking? How do you understand that?

BALTIMORE: I think it's probably deeper thinking.

ZIERLER: Because something looked funny to you, and you investigated further?

BALTIMORE: Also, I was able to think about the problem in a larger context. Because what he had done, and this was really amazing, is to assume that the virion RNA is messenger RNA. You find in the writing of the paper that he just assumed it. He never thought there was any other possibility, and so he missed the whole thing, because he just hadn't thought flexibly enough about what might be true. But it was sort of cute that somebody thought to reference that, because it's true that he showed there were small RNAs on the ribosomes, which I didn't know that he had done until I read that paper, but he didn't understand the significance of it. The significance of this made huge waves in virology, because now there's a whole new class of viruses, the minus-strand viruses, to contend with. The fact that the key experiment was to show that there was a polymerase in the virus particle is now the beginning of the reverse transcriptase.

ZIERLER: This is the bridge?

BALTIMORE: This is the bridge.

Pathway to Discovering Reverse Transcriptase

ZIERLER: Where did this take you next that would get you to the reverse transcriptase? Maybe that will be our last line for today.

BALTIMORE: I taught virology.

ZIERLER: Which is good for thinking about virology.

BALTIMORE: Right, and it's one of the reasons why I had a broad view of viruses. I was aware from that of the literature about tumor viruses. There was a class of tumor viruses that had RNA as their genome, the RNA tumor viruses. The first of those was Rous sarcoma virus, discovered by Rous in 1911, and shown to be an RNA virus unequivocally. Howard Temin had worked on this virus at Caltech and then then when he left Caltech, in Wisconsin, for by this time 15 years, and had 10 years before said that it doesn't make sense that you can change the properties of cells from being normal cells to cancer cells with an RNA virus, because RNA is largely a transient molecule in cells [it has a relatively short lifetime after its synthesis whereas DNA is very stable over very long times]. Now, we didn't really know that at the time, but we did know that DNA was the hereditary material in everywhere else in the world, and there were DNA viruses that could cause tumors. That's what in fact Dulbecco worked on, so it made sense to think about RNA viruses having a DNA part of their life cycle.

ZIERLER: As opposed to what? What's the alternative?

BALTIMORE: The alternative is that somehow the RNA is able to make a permanent change in the cell.

ZIERLER: Although the "somehow" is clearly a gap in the thinking?

BALTIMORE: Right. It was that "somehow" that Howard was trying to understand. He had tried to find an experiment that would show that there was a DNA copied from the RNA and had published many times over these ten years with things that just were not convincing, so almost nobody believed him. But I said to myself, "It would be an easy job to look for an enzyme that copied RNA into DNA"—in the same way I had done with all these other viruses, just by looking in the virus particle.

ZIERLER: You have a game plan, essentially.

BALTIMORE: Yeah, and all I need to do is find some virus, physical virus, because I didn't know how to grow this thing. I needed a source of virus. This all is in the beginning of 1970. I did a number of things to try to get virus. I talked to people who I knew worked in the field, but most of them, if they made virus, they just made very small amounts. One guy, Peter Vogt, sent me some material, some Rous sarcoma virus. But one person I called, George Todaro, was at NIH, and he had worked on viruses that cause cancer for a long time. I knew him well because he was a Swarthmorean, although I hadn't gone to school with him. He's a little older than me. I said, "George, can you think of any way I can get some physical virus?" He said, "There's a program at NIH which has been storing large amounts of virus for years and years and years. Nobody has ever found a use for it, but they keep making more. Why don't you call the guy who runs this program?" I called the guy who ran the program and said, "Can I get some virus?" He said, "Oh, it's wonderful that you're interested. How much do you want?"

ZIERLER: [laughs]

BALTIMORE: I said, "I haven't the slightest idea how much I want." I said to him, "What units do you use to measure it?" He said, "Milliliters." I said, "Wait a minute."

ZIERLER: [laughs]

BALTIMORE: He said, "We have a contract to harvest from infected animals and to freeze it away, and the contract is in millimeters of fluid." I said, "Well, how much is in there?" He said, "I have no idea." In terms of physical material. I said, "How do you have it packaged?" "It's in vials." "So, send me some vials." He packages up and sends me, I don't know, 24 vials, and these things come. This is now late April, I think, 1970, and I get virus, or I get this fluid, frozen. I broke open one of the vials, and I took the liquid in it, and I put it in a reaction to measure synthesis of DNA.

ZIERLER: Is this a dangerous thing? Is this like a hazmat suit? What are you working with here?

BALTIMORE: No, in those days we didn't worry about hazmat suits, or we didn't worry about danger.

ZIERLER: Even though you probably should have?

BALTIMORE: Even though we probably should have, right.

ZIERLER: "Just don't drink it"—that's what you know?

BALTIMORE: Yeah, although I even, in those days, would pipette by mouth. With the vesicular stomatitis virus, we famously did that, and Martha ended up with a huge mouth infection.

ZIERLER: Oh! [laughs] Surprise, surprise!

BALTIMORE: Yeah.

ZIERLER: [laughs]

BALTIMORE: Actually, I don't know if I—

ZIERLER: Level 5 biosecurity, that's not happening here, nothing like that?

BALTIMORE: No, this is the beginnings of biosecurity. Because once I had done this, then people began to wonder, and worry. One very good friend of mine on the faculty at MIT worried very deeply about this. That's one of the things that led us to start the Cancer Center, was to segregate this kind of work off from the rest of the university. You raise a good question.

ZIERLER: It's kind of like JPL and Caltech in the 1930s—"Get this stuff outta here!" [laughs]

BALTIMORE: Right, right, exactly. Anyway, no, I didn't worry about it. It came, I broke open a vial, and I tested it. I have the lab notebooks, and there was nothing there. But, there was a hint. It wasn't statistically valid. Alice has always said that only I could believe that that might be a hint. I said, "Well, if that doesn't work, since I have all these other vials, why don't I take a couple of vials, concentrate the material from the vials by spinning it down in the centrifuge, and bring it up in a very small volume, and now I can add much, much more to a reaction mix than I could in what they sent me." Remembering that I had no units to think about. I put this now probably 100-times-concentrated material in a reaction, and lo and behold, there it was. It was like two days of work. Then I had to do all the controls and show that it really was copying an RNA into DNA, but all the controls worked. Now that I knew all I needed to do was concentrate it, I can get lots of reaction mix, I was able to do a lot of experiments. It was just breathtakingly exciting, because nobody had ever seen RNA copied into DNA before. Crick had set up the central dogma as DNA makes RNA makes protein, and he said the central dogma only flows in one direction. This was a violation of central dogma. It was big news.

ZIERLER: It added to the dogma, or it scrambled the dogma?

BALTIMORE: No, it violated the dogma, because here was RNA copying into DNA. It reversed the flow of biological information. That's why it's called a reverse transcriptase.

ZIERLER: Why don't we pick up on that note in more detail for next time?

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, January 26th, 2022. I'm delighted to be back with Professor David Baltimore. David, good to be with you as always.

BALTIMORE: Hello, hello.

ZIERLER: Today what I'd like to do is pick up on a very interesting phrase that we left off on last time—"RNA copied into DNA"—which of course is the basis of the discovery. Take me into that moment. First, is it one moment? Is it a series of moments, where you come to this conclusion slowly? How did that work in terms of appreciating what you had seen?

BALTIMORE: I was looking for the copying of RNA into DNA. I decided that the place to look for it was the virus particle on the basis of an analysis of the situation, and as I think I said to you already, that it had to be in the virus particle or else in the cell, and we didn't know anything like it in the cell. When I found it in the virus particle, that was a pretty close to unambiguous discovery the first time I saw it. I didn't have to play around very much.

ZIERLER: It was a single moment?

BALTIMORE: It was a single moment, in May of 1970.

ZIERLER: Do you remember the date, by any chance?

BALTIMORE: No I don't, but I could find out.

ZIERLER: You know it was May of 1970?

BALTIMORE: Yeah.

ZIERLER: Did you write something down, like a diary?

BALTIMORE: I kept a notebook of my doings, day by day, and it's in that notebook. It's not here. It's in the office in the lab. I had some cleanup things to do to be sure that it wasn't faking me out in some way.

ZIERLER: What were the concerns? What might it have been?

BALTIMORE: I didn't actually know initially that it was copying RNA. I didn't know it was copying anything. I knew that it was making DNA, and that it was in this virus preparation, and that it was dependent on having all four nucleotides in the reaction mixture, and therefore it was copying something, because you wouldn't need the other—if it was just making, for instance, a homopolymer, and there were enzymes known that could do that, then you wouldn't need the other nucleotides there. I think in the first experiment—I'd have to go back and check the notebook—but I had a control to say that it was sensitive to a drug that bound—wait a minute, now—later there was an argument based on the lack of sensitivity of the enzyme to a drug that bound to DNA , but I did not test that on the first day. From the very first day everything behaved in a way that was consistent with this being RNA-dependent DNA synthesis; it could have been fooling me, but that seemed pretty unlikely.

ZIERLER: Were there any theories or orthodoxies that suggested that it couldn't be RNA copied into DNA?

BALTIMORE: No, in fact this is one of those things where science is not scientific.

ZIERLER: [laughs] That's great.

BALTIMORE: There was absolutely no reason in the world why it shouldn't have been possible to copy RNA to DNA.

A Case of Multiple Independent Discovery

ZIERLER: The only thing that was stopping you or anyone else was simply not seeing it yet?

BALTIMORE: That's right, and most people not having assay for it, so they couldn't have seen it. But because I had a reason to look for it, which really came out of, as I said before, Howard Temin's ten years in the wilderness—

ZIERLER: Were you following what he was doing?

BALTIMORE: At a distance. Not close up, but I was aware of his various attempts to prove it.

ZIERLER: Do you have a sense if he was following you?

BALTIMORE: No, he had no idea what I was doing, I think, because it was not at all evident that what I was doing was the right way to look for it. [I was recently talking with a student of Howard Temin who said that he thinks (but has no direct evidence) that Howard did know what I was doing and had actually attracted his co-worker, Mizutani, to Wisconsin to use the techniques I had pioneered to search for an enzyme in virus particles. We may never know if this is correct.]I wasn't part of the tumor virus field because I had never worked in it, which was the field that he worked in. No, I think when I called him and said that I had done this experiment, it was to him probably a total surprise to hear from me. But I was close enough to being able to say I'd really done it that—few controls to do.

ZIERLER: What do you mean, close enough?

BALTIMORE: I only had a few controls left to do, and it really looked like it was behaving very well. I started thinking about the implications of it right away.

ZIERLER: Is it a eureka moment immediately?

BALTIMORE: Yeah. It was all done by incorporation of radioactive nucleotide triphosphates into DNA, and I saw the results on a Geiger counter, and as soon as I saw the results, I knew, because it was a very strong reaction, because I had concentrated all this material so I could look for it.

ZIERLER: Let's survey the implications. Let's start at the most basic level—biology. What are the implications on a biological level?

BALTIMORE: The implication for tumor biology was that these viruses made a DNA and therefore could permanently alter the inheritance of the cells that they infect, if that DNA integrated itself into the cell. We didn't know that it integrated itself into the cell. Certainly from the kinds of experiments I was doing, I wouldn't know that. This is why I say there was unscientific science. But from the very first commentaries on the paper, people almost assumed that it was making a DNA that integrated itself into the chromosomes of the cell, because that seemed so likely, and because they had not been prepared to think about that, because they lacked evidence of the DNA. As soon as I gave them evidence of the DNA, then they made the whole jump, the whole leap.

It was actually work done by other people years later that really nailed it and showed that there was DNA incorporated. My work didn't show that, and I never tried, partly because the community so readily accepted that it was happening that if you demonstrated it, there would be a big yawn, and it was. Most people to this day can't tell you who actually discovered that. That leap that the viruses were transforming cells by incorporating a new DNA into the cell, and that DNA represented genes carried in the virus, that was all an immediate implication, widely accepted but not proven, but what everybody started thinking about right away. What that meant was that there was a gene in the virus that was taking control of the cell. That was really the first introduction of the notion of oncogenes [Although Huebner and Todaro had coined the word in an earlier PNAS paper.]. Now, there had been other people talking about that. In particular, Todaro and Huebner had been talking about oncogenes.

ZIERLER: The term was already in use?

BALTIMORE: I'm not positive; I think it was.

ZIERLER: But certainly nobody was thinking about it in the correct way until this?

BALTIMORE: Right. They were thinking about it in terms of a cellular gene, and what this said was that the virus had such a gene. Also, we had some evidence from DNA tumor viruses that that happened, but no one imagined it happened from RNA tumor viruses. Even at that time, we didn't recognize that the gene that was involved was one that the virus had captured from a cell, but rather we thought it was a gene of the virus. Really that provided a strong paradigm for saying that cancer was caused by genes.

ZIERLER: RNA tumors or all tumors?

BALTIMORE: If you extrapolate from the RNA tumor viruses, which caused all sorts of cancers, to the generalization for all cancer, it wasn't a huge leap at this point. Now the question was, what genes, and where from, those genes?

ZIERLER: Prior to this moment, is the thinking on tumor biology wrong, or is there no thinking? Is it just question marks?

BALTIMORE: No, there's a huge amount of thought that has gone into that question going back to some of the earliest days of genetics. The best way to look at the question is to remember that when a fertilized egg divides and becomes two cells and then four cells and eight cells in an organism, there is a continual restriction on the differentiation of cells, so that you start off with a cell that can become any cell. It has to be, because you start off with a single fertilized egg, single cell, so that cell is totipotent. It can make skin, make muscle, make brain. But then you get this differentiation, and now you can only make skin from a cell, or you can only make brain, so it has lost an enormous amount of potential and focused down on one or another need of the organism. If you're a plant, it makes something else; it doesn't make a brain, or whatever. It's a generalized principle of biology. There are genes in cells that don't actually do anything, because they're genes of the wrong kind of cell, and the milieu is not set up to involve that gene, and so the gene just sits there.

ZIERLER: Why would evolution have created that situation in the first place?

BALTIMORE: That's my point. That's the nature of differentiation. It's not that you create genes. The genes are all there in the fertilized egg, the genes for every kind of cell, and then there's a process of selection, so you select out skin genes to be active in skin cells, and muscle genes to be active in muscle cells, and muscle genes to be inactive in skin cells. That's the truth of biology. Same thing in a plant—root cells and phloem cells and leaf cells and whatever. What that means is that there is the genetic potential for everything in the organism in every cell of the organism. You might think—and people did think—that cancer was due to the reactivation of embryonic genes that should have been suppressed, but that in a cancer cell, they've been de-repressed. No one knew why. The assumption would be that it's a pathology; it's not a natural process. But it doesn't violate anything, because we know the genes are there. All the embryonic genes are there in every cell of the body. If they did get reactivated, they could produce growth in the cells that would be inappropriate, produce a cancer. One of the most prevalent theories, probably the most generally thought about—I wouldn't say anybody was sure of it, but a theory—of cancer was that cancer was due to activation of embryonic genes.

ZIERLER: Where are environmental factors in this thought process?

BALTIMORE: They are obscure. They remain obscure, actually, in some ways. No one had a mechanism, because we didn't understand differentiation. We had no idea what it means to say a gene is active or inactive. All of that came later. Without molecular biology, you can't think about these problems. People did think about them, because cancer was such an obvious pathology of human life, and clearly cellular in origin. A pathologist could look at a slide and tell you that you have a breast cancer, even if that cell is not in the breast, it's somewhere else in the body, because it has metastasized. But still it maintains the characteristics of the cell that it was. We understood what cancer was about, but we didn't know what was driving it.

ZIERLER: What about the anecdotal reality of family traits, cancer that your parents had that you have, and that your children have? Where does that factor into this?

BALTIMORE: I don't think it did.

ZIERLER: But surely people must have understood at an elemental level that there's got to be some correlation where you see in a family tree the same cancer, generation to generation?

BALTIMORE: Right, and you could imagine that that means that there's something wrong with the cells, which is inherited.

ZIERLER: Which is genetic.

BALTIMORE: Which is genetic. But since before 1953—and I'm talking about now well before 1953—we didn't know that DNA maintained the information of a cell, because it was very hard to even formulate that observation.

ZIERLER: Although if it doesn't maintain information, how do you explain similarities?

BALTIMORE: We knew there was information, because of the similarities, and twins are a wonderful evidence of this, but that doesn't lead you to DNA. That doesn't lead you to an understanding of molecular mechanism. It's just an observation that someday needs explanation, and got it, when we figured it all out.

ZIERLER: In concentric circles of the implications, you first mentioned tumor biology. What about biochemistry?

BALTIMORE: The biochemistry of the synthesis of DNA was known already from Kornberg's work. The biosynthesis of RNA was known from the work of a couple people. I had already shown how viruses made their RNA, so there wasn't any biochemical question, really. I was able to set up the experiment and make it work the first time because it was based on well-established principles.

ZIERLER: It's more like the discovery stood on the shoulders of past advances in biochemistry?

BALTIMORE: Absolutely.

ZIERLER: What would be next? What's the next impact out? Virology?

BALTIMORE: The next impact was to ask what genes are involved.

Becoming a Cancer Biologist

ZIERLER: What are the options?

BALTIMORE: Regulatory biology. Cancer is a disease of regulation, in a sense, in an important sense. Regulatory biology was in its very infant infancy, at that time. One of the very interesting things about the history of this field is that we needed to understand regulatory biology to understand cancer, but the way it happened was that we understood cancer first, and that taught us about regulatory biology. It's really interesting that it went that way, and that the people who deserve the credit for—all cancer biologists, many of them starting with cancer viruses.

ZIERLER: Did this make you a cancer biologist unwittingly?

BALTIMORE: Yes.

ZIERLER: Did you join the club essentially at that moment?

BALTIMORE: I did. The whole rest of my career is working out that sentence, but at the moment it was conscious. I said to myself, "I want to work on this thing that I discovered, the reverse transcription. I want to understand how it works and understand its biochemistry, its unique biochemistry, but if I'm going to make any sense of this, I need to have a biological system to work on." The biological system that anybody worked on was Rous sarcoma virus. That's what Bishop and Varmus did, ultimately finding the first oncogene, the SRC oncogene. When I had taught about it, I taught about Rous sarcoma virus. But I didn't want to work on chickens, and I wanted to work in a system where you could do real biology, and there was only one that made any sense, and that was the mouse. I knew that, from my experience at Jackson Lab.

ZIERLER: Because it's a mammal?

BALTIMORE: Because it's a mammal, but because there was—by this time, we're now talking 1970—almost 50 years of work on the genetics of a mouse. There were inbred strains of mice. There were genes known. There were mice that got cancer. There were mice that got different kinds of cancer. That was all there, and I had seen that, and I knew all about that. My requirements for a system were, first of all, that it be fast, that it cause cancer quickly, because I didn't want to sit around for two years and wait for an experiment to give me a result. That it was a system where you could transform normal cells into cancer cells in the laboratory, in vitro. That was the great strength of the Rous sarcoma virus system, was you took Rous sarcoma virus, you dropped it on a monolayer of chicken cells, and wherever that virus landed, the cell transformed into a tumor cell. The whole process of the creation of cancer was right in front of you. That's what Howard had realized when he worked on it at Caltech with Temin and Rubin. But they couldn't go any further with the biology, because it was a chicken biology, and we didn't know anything about chicken genetics, and actually, chicken genetics is a mess, because there are lots of tiny little chromosomes in chickens. I didn't even know that at the time. You have the tremendous depth of information about the mouse, and you have this lack of information about almost any other organism except humans, but you couldn't work with humans. I wanted mice, I wanted fast, I wanted in vitro, and I wanted in vivo. I wanted you to be able to produce a tumor in an animal so that I knew this thing was actually producing cancer and not just some transformation of cells in culture. There was no such system that I could find out about. Here, serendipity plays a huge role, because it turned out there was a guy working upstairs from me at MIT doing a postdoc who had isolated a virus that had all of these characteristics.

ZIERLER: Do you remember his name?

BALTIMORE: Sure, Herb Abelson. Herb had done this work at NIH. He was an MD and he was doing his military service by working in research at NIH. He worked with the tumor virus people. He had done a very smart experiment, which I could explain to you, but maybe I don't need to.

ZIERLER: No, do, please.

BALTIMORE: The tumor viruses that we knew about in mice, and there were many, most of them caused thymic tumors, blood tumors, but blood tumors of T cells.

ZIERLER: What is a blood tumor? What would be an example?

BALTIMORE: Leukemia. All leukemias are—

ZIERLER: That would be a—even though there's no solid mass, it's a blood tumor?

BALTIMORE: It's a tumor, but the cells are in the circulation of the blood, or they're in blood organs, because they were in lymph nodes, or thymus, which is where cells come from, that populate the blood, as well as bone marrow, which is where it makes cells that populate the blood. He said, "What kinds of tumors are formed if you cut out the thymus?" Because the thymus makes T cells; you can live without T cells. If you cut out the thymus, you won't have any T cells, but you'll be reasonably fine. You still make antibodies. You still have a reasonably good immune system; you just don't have a perfect immune system, but for a mouse in the laboratory that really isn't subject to the vagaries of the world, that's fine. How about if you put this virus in that causes a thymic tumor but you put it in an animal that doesn't have a thymus? The answer was that if you wait long enough—mice have a longevity of about two or three years—they get a tumor. He took that tumor and ground it up and put it into another animal, and it grew, and he made a filtrate of it, and it transferred to another animal, and it still grew. You could transform the cells of an animal with the virus that was in there, and it now had new characteristics. It didn't need a thymus. It caused a very rapid tumor after you concentrated it. The tumor cells looked more like B cells than T cells. They didn't look like thymic cells. Here was a rapid tumor of B cells which were really interesting cells. I was always interested in those cells.

ZIERLER: Why are they so interesting?

BALTIMORE: Because they make antibodies. The mystery of how you make antibodies was in those cells. If you wanted to work on—and I did—at that point I was beginning to think maybe I did want to work on that problem, and that's what I ended up working on, in those cells. It made those kinds of tumors. The cells grew in the animal. They killed the animal, so it was a real tumor. You could put the cells in culture and they would grow in culture, and you'd get large numbers of them. The one thing that you couldn't do yet was transform cells in culture. I said, "We've got to figure out if they can transform cells in culture, and it looks like they should, because they make such a virulent, active tumor." I said to Herb, "Can I get some of this virus?" He said, "Sure." He was no longer interested in it. He was doing a postdoc on something else, cell biology. He later went on to be largely a clinician working in pediatrics. He said, "There's another guy who's interested in this, and he's working at Children's Hospital in Boston"—Charles Scher, by name. At this point, we hadn't yet opened the Cancer Center at MIT which is itself a whole story. I had very little space. Luria had kindly given me some space in his lab, which was on the same floor I was on, but I had brought in a bunch of people, because I was now in a very strong position to attract the best people in the world, and I was committed to working in cancer, not just in cell culture, not just in viruses. I said, "The problem is I don't have any space for anybody."

Then I got an interest to come to my lab from a woman who had very strong recommendations from I can't remember who, named Naomi Rosenberg. Naomi was in Boston, because she was at Tufts. She was really interested in this problem. She thought this would be great to develop this system. To start off where there's no background—nobody has ever worked on this thing before—and to take it into being a usable biological system, was a real bet on the future, because some disaster could happen so easily and you wouldn't be able to go on with it, so she had a lot of guts. She did. I got in touch with Scher, the other guy who was interested in this, and we talked a little bit, and he was interested in the same question I was: could you get transformation in vitro? In particular, could you get fibroblast transformation? Because those were most of the cells that we grew with culture. I said, "I've got this wonderful new postdoc. I don't have any space for her. Can she work in your lab on this problem? And if she can crack it, then we'll both have the cells to work on, and we can continue." He said yes. God, I haven't thought about this in 50 years.

ZIERLER: What aspects of this was him just being generous, and where did he see that this was good for what he was doing, too?

BALTIMORE: Oh, he needed hands. He was not a known figure. He had come from NIH, I think. That's where he knew about this from, because he came from NIH. But to have paid-for hands, because I had support for her, to work on this problem, was to him fabulous, I think. That's what I'm imagining. He was perfectly comfortable sharing. When we published, I don't remember which one of us is the senior author. It could have been either one. She worked on this, and it worked, and she got it to work.

ZIERLER: What does that mean, "it worked"?

BALTIMORE: She showed that the virus would transform cells in culture, fibroblasts in culture, and so you could now work on the induction of cancer by this virus in an in vitro system. It just simplified enormously the ability to understand how a virus causes cancer, because we didn't know how a virus causes cancer. This is before the work of Bishop and Varmus. That work was 1975. We're now in roughly 1970, 1971, 1972.

ZIERLER: Let's go to the phrase "reverse transcriptase." Where does it come from? Who coins it?

BALTIMORE: Nature magazine coined—we called it RNA-dependent DNA polymerase.

ZIERLER: That's too much of a mouthful as far as Nature is concerned?

BALTIMORE: It's a terrible mouthful, right. And some bright—I've never known who—editor or commentator in Nature, in writing about the paper, called it reverse transcriptase. [I have recently heard that it was John Tooze who coined it. He was not on the Nature staff but wrote for Nature, if I remember rightly.]

ZIERLER: How does the phrase "reverse transcriptase" capture what you had seen, and what you had originally named it?

BALTIMORE: Transcription is the transcribing of DNA into RNA, and we talk about transcription factors, factors that allow cells to copy DNA into RNA. The thing that makes a skin cell different from a brain cell is the genes that are transcribed. Transcription is the fundamental process that allows gene expression and that differentiates one cell from another. All of that was established. The synthesis of DNA as a copy of RNA is the exact reverse of that, and so that's why it was called reverse transcriptase. It was a beautiful piece of public relations.

ZIERLER: Who were the people you needed to talk to first, about this? Where do you get the word out?

BALTIMORE: We published the paper.

ZIERLER: "We" is who? Who are the coauthors?

BALTIMORE: There aren't any coauthors.

ZIERLER: Just you?

BALTIMORE: Just me.

ZIERLER: The royal "we."

BALTIMORE: The royal "we." What I meant by "we" was Howard Temin and I published, because we published back-to-back papers in Nature.

ZIERLER: Is this understood as a multiple independent discovery, as clean as that?

BALTIMORE: Yes, because there were two separate papers.

ZIERLER: Were you aware? Was it a race, to some degree?

BALTIMORE: No, I was unaware that he was working along those lines. He was unaware that I was. When I called him, having been successful with the experiments, to tell him about it, that was the first he knew about it.

ZIERLER: It's such an interesting thing, that you're not aware of each other's work, and you come out with this unbelievable finding at the same time. What are the historical commonalities that allowed both of you independently to reach the same conclusion at the same time?

BALTIMORE: Howard didn't know much biochemistry and had not paid much attention to it. He had a postdoc who came to his lab, a Japanese postdoc, who came from a laboratory that had experience in biochemistry. This guy was the one doing the experiments. Howard had, as I said, been working on this for ten years. This was just another approach from his point of view, and it was one that he didn't really fully understand. I don't know how far along he was when I called him. He's dead now, but I never asked him that question.

ZIERLER: It's possible that you bumped him along further?

BALTIMORE: I was almost certain I did. Because it took him, then—I had to wait for a couple of weeks for him to get together the data, and get a manuscript to Nature, but I said I would wait for him, because he deserved that.

ZIERLER: Yeah, although to be super precise, then, maybe "multiple independent" is not right. You got there, you shared the information with him, and then he got there also.

BALTIMORE: Yeah, but it turns out he had talked about this at a meeting that I didn't know anything about, in Texas, before I called him.

ZIERLER: But when you called him, that focused his direction in a way that he was not—?

BALTIMORE: Yeah, he wasn't ready to publish right away. As soon as I said, "I've got a manuscript and I'm sending it in to Nature; I'll tell them that you'll send one"—

ZIERLER: Why Nature? Why not PNAS, for example? Was it because it's a cover story kind of discovery?

BALTIMORE: No, they didn't even put a cover on in those days. No, PNAS didn't have the pizzazz that Nature did. Nature was where the DNA paper was, so if you wanted to announce something about DNA, what could be more appropriate than Nature? Nature at that point didn't have an American office, so you sent the paper with a stamp to England.

ZIERLER: Was your paper less technical than it would have been if it was PNAS?

BALTIMORE: No. I published every figure I owned. [laughs] No, Nature was very technical. It was the single greatest international journal. Science in the United States was sort of equivalent, but not international. I haven't thought about that question in so long that I don't remember what made me send it to Nature.

ZIERLER: Had you published there before? Did you have a relationship with an editor?

BALTIMORE: I didn't have a relationship with an editor, but I had published there before.

ZIERLER: Where did Howard publish?

BALTIMORE: We published back-to-back in Nature.

ZIERLER: In the same issue?

BALTIMORE: Oh, yeah.

ZIERLER: That's quite an issue. [laughs] In what ways was it useful to have the back-to-back publication as confirmation or however you understood it, and in what ways did you share some of the spotlight that maybe you didn't need to share so much?

BALTIMORE: Both things are true. Had I published singularly, Howard would have been eclipsed by it, and I knew the history well enough to not want that to happen.

ZIERLER: Because you wanted him to be recognized for his contributions up to that point?

BALTIMORE: Right. I was an interloper in this thing. On the other hand, we were announcing something that was unprecedented, and it violated the central dogma, and even though it didn't violate any biochemistry and therefore the central dogma was not about biochemistry, it was about philosophy—

ZIERLER: What does that mean, "about philosophy"?

BALTIMORE: It was a phrase that encapsulated the way information generally flows in biological systems, but it wasn't about the chemical reactions that occur. The positive side of our publishing back to back was that no one doubted that it was true, because we had arrived at this independently, published it independently, so the probability that there was anything wrong with it was negligible.

ZIERLER: I assume you got minimal notes from your reviewer before publication?

BALTIMORE: Yeah, none at all, I think. I don't know who reviewed it. Did I tell you the story of Sol Spiegelman?

ZIERLER: I don't think so.

BALTIMORE: The first place that we talked about this publicly in the scientific community was at a meeting at Cold Spring Harbor. The yearly meeting at Cold Spring Harbor was taking place that early June. The paper had not come out yet. Howard actually couldn't make it to that meeting, so I spoke, gave him credit. Sol Spiegelman was a scientist in this field and had become very interested in what caused cancer and had a whole laboratory of people working on various aspects of that question. He heard the presentation at Cold Spring Harbor. It was like on a Friday. Sol's lab was at Columbia University in New York, so he was just commuting out to the meeting in Cold Spring Harbor, which is an hour or an hour and a half outside New York. He went back to his lab after hearing this talk and said, "We've been doing this all wrong. Let's take a look at this question." He got them working over the weekend. He came back on Monday to the meeting and said, "I've verified everything." That was how easy it was to do if you knew what you were doing and knew to ask the right question. He had already extended it to more viruses, and continued to work on it for a long time. It would have been verified very quickly, but the fact that in that issue of Nature we had both of our papers, and Nature then wrote about it as a new established scientific fact, it was very powerful.

ZIERLER: If there was a banner headline or a key paragraph, sentence, takeaway, for anybody to read in that article, what did you want to convey at the most elemental level?

BALTIMORE: Oh, this new life cycle for a virus, and how that fit into the thinking about cancer.

ZIERLER: I want to broaden out the idea that you're an interloper in this field. Given how long you had been thinking about polioviruses, between your training, the way you had thought, why you, at that moment, and not somebody who was more traditionally in cancer biology? What were the things that you had brought to this moment that allowed for you to make this discovery where someone more traditionally in that field otherwise would have done it?

BALTIMORE: The people traditionally in that field really didn't do this kind of enzymology that I did.

ZIERLER: They weren't even equipped to ask the right questions?

BALTIMORE: No, most of them were not. Actually later one guy told me, a guy named John Bader, that he was actually trying to do those experiments, but he hadn't been able to get to any results.

ZIERLER: What's their approach to enzymology that always hit a wall?

BALTIMORE: Nobody tried. You have to be able to think that it might be there. You have to understand the nature of viruses. You have to understand the biochemistry. You have to have the wherewithal to do it. Remember, I told you, I learned how to do these kinds of experiments ten years earlier, working at Rockefeller, where I had to get help from a guy who did biochemistry. It's not that it's hard to do. It's that it involves a whole lot of little technical things, and you're working actually in very tiny volumes. You've got to be able to miniaturize everything, and then you've got to know how to prepare the samples. You have to know how to measure the incorporation of the radioactivity. There were plenty of people who could do that, but the overlap of people who could do that with people who could understand the nature of the problem and the meaning of this solution was tiny.

Connecting Cancer Virus Research

ZIERLER: Polio is not a cancer, so what does that tell us more broadly, the fact that you had been thinking so deeply and for so long about polio, which is—

BALTIMORE: And remember, I taught this material, too.

ZIERLER: Right. You taught it, you thought about it, you wrote about it. The fact that you're focusing on polio, and yet you have this breakthrough in cancer, what does that tell us about viruses that connects cancer and polio?

BALTIMORE: The next thing that I did, after I had written about this discovery and had done a little more work on the biochemistry, was to realize that you could—the discovery of the reverse transcriptase completed a broad understanding of the molecular biology of viruses that was built around the notion that the key molecule for a virus is messenger RNA. That's why messenger RNA is so critical. And that polio makes messenger RNA by copying RNA into RNA into RNA. That DNA viruses make it by copying DNA into RNA and duplicating the DNA, just like cells do. That there are double-strand RNA viruses that have both strands, and clearly one of those strands is messenger RNA and the other one is the copied strand, the negative strand. That there were negative-strand viruses that carried only the opposite strand, and that, like reverse transcriptase, they had to have polymerases in the virus particle, which is what we discovered with vesicular stomatitis virus. Now with reverse transcription, we have the last possibility, which is that RNA makes DNA, and that there are viruses that go back and forth between RNA and DNA. I wrote an article in what was then called Bacteriological Reviews—it later became Reviews of Microbiology—which said that you could classify all viruses into seven characteristic classifications—I think it was actually six but became seven—and that this was a much easier way to think about viruses than all of the Linnaean names which they had given to viruses and which are the standard classification of viruses which make each virus have a different name, and nothing tells you anything about what kind of virus it is. There were positive-strand viruses, there were negative-strand viruses, there were double-strand RNA—positive and negative RNA viruses, there were positive and negative DNA viruses, there were double-strand DNA viruses, double-strand RNA viruses, and viruses that mixed it up and went both ways. You could teach virology from that perspective and get rid of all the names that different viruses have. You don't have to think about anything else other than how does the virus make its messenger RNA. That became known as the Baltimore classification. It is known to this day as the Baltimore classification. I see it in the literature. People who work on evolution of viruses constantly come back to the Baltimore classification.

ZIERLER: I wonder how many people think this was discovered in Baltimore.

BALTIMORE: I'm sure there are people who do. I'm sure. [laughs] It really sort of wrapped up virology and made it a mature science.

ZIERLER: Let's move on to translational thoughts. Are they occurring to you immediately? We can broaden out here, and this is going to be a chicken and the egg—of course Nixon in 1973 announces his War on Cancer.

BALTIMORE: No, 1971.

ZIERLER: Earlier? It was 1971?

BALTIMORE: Yes.

ZIERLER: This is obviously responsive, to some degree, to all of these developments.

BALTIMORE: Right.

ZIERLER: What's the mode from what you and other people are doing in cancer biology to the Oval office? Do you have an awareness of this?

BALTIMORE: I don't. I've never been sure—

ZIERLER: Who's politically connected at MIT at this point?

BALTIMORE: Nixon's War on Cancer was actually appropriated from Ted Kennedy, the senator from Massachusetts, who originated the idea of a War on Cancer. He allowed Nixon to take that from him, because that way it happened, and it did happen. His role there has been lost, but those of us who were around at the time remember it very clearly, because Nixon of course turned out to be such a negative figure. I was just at an event celebrating 50 years of the War on Cancer at the Nixon Library.

ZIERLER: Was Kennedy a factor? Was he acknowledged?

BALTIMORE: No.

ZIERLER: I assume it's no coincidence that you're at MIT which is in Boston which is in Massachusetts which is where Senator Ted Kennedy is from?

BALTIMORE: That's right.

ZIERLER: What would have been the connection there? Not direct to you, I assume?

BALTIMORE: No, not direct to me. Through the Cancer Institute.

ZIERLER: Let's go there. When did discussions about the Cancer Institute start? Right away?

BALTIMORE: You're thinking about the MIT Cancer Institute. I'm talking about the National Cancer Institute.

ZIERLER: Oh, I see.

BALTIMORE: What we were doing, the cancer hierarchy very quickly knew about it, because we published it and it was talked about, and Nature made a big deal of it.

ZIERLER: I assume that the nature of the hierarchy was reshuffled as a result of what you found? All of these dogmas came crashing down.

BALTIMORE: Yes, but there were people already working in Washington on cancer viruses, at the National Cancer Institute. Bob Huebner was the leader of that group, but there was Rauscher who was the head of the National Cancer Institute, and who had a virus named after him, the Rauscher virus. In fact, the work I did was on Rauscher leukemia virus. Frank Rauscher was the head of the Cancer Institute, and they had started a Special Virus Cancer Program, because they were convinced that human cancer was going to be caused by these viruses, which turns out not to be true. They appropriated a lot of money for the Special Virus Cancer Program, and there were a lot of people working on it. Remember, I told you my story of my calling my friend George Todaro, and asking him, "Where am I going to get virus from?" That virus was stored by this program, and these people worked through this program. Ultimately I got money from that program. Actually, Huebner and Todaro had coined the notion of oncogenes. As I said, they had it slightly wrong, but—more than slightly wrong—but that's where the first use of that phrase comes from.

Behind all this was Mary Lasker. Mary Lasker ran the Lasker Foundation. She was a socialite. She was married to Harold Lasker, who was one of the first advertising moguls, and in particular for cigarettes, ironically, so she had a lot of money. She decided the most important thing was to increase the funding for cancer research. She was particularly able to do that because she got nothing from it. It was a pure citizen effort to increase the funding for cancer research. She started the Lasker Prizes, which I just won one of, and the Foundation goes on now and actually gives the most prestigious prize in American biological science. She was very connected to the Kennedys. Exactly how the Kennedys heard about it, whether through—and Kennedy himself was interested in medical research, even before this. Whether he got it from Lasker or it was a combination, or talked with Lasker about it—but that's where the impetus came from. I believe this has all been written about. Then Nixon takes it over.

ZIERLER: This is all MIT? What about up the street? What's going on at Harvard at this point?

BALTIMORE: [laughs] Their tongues are hanging out. They hated me, and we will someday come back to that.

ZIERLER: Because you're an interloper?

BALTIMORE: Now, I'm an interloper not only in cancer biology, which that, they didn't care about, but in molecular biology.

ZIERLER: Who are the chief antagonists over there?

BALTIMORE: Watson, Ptashne, Gilbert. I was violating the dogma in a different way. The dogma was that science flowed from England to Harvard, and I wasn't in any of that.

ZIERLER: From England to Harvard, with the names you mentioned, also has a WASPy connotation to it as well?

BALTIMORE: No, Gilbert is Jewish, and Ptashne is Jewish, I think. Watson was anti-Semitic, but it was because he was jealous of Jews. He was from an Irish family, and he always sort of hated the fact that Jews had this culture of intellectual culture that he didn't inherit. He did his thesis with Luria who was Jewish, a very famous Jewish family. That's another story, an interesting story.

ZIERLER: What about the Cancer Institute at MIT? When did those discussions start?

BALTIMORE: As soon as I did these experiments, two things happened. One was Luria looked at it and said, "This is the new world. This is going to change how we investigate mammalian cells." He was right.

ZIERLER: He meant that universally?

BALTIMORE: Yeah, he meant that universally, but in particular focused on cancer. The other thing was that some of my colleagues, one in particular, were terrified to discover that somebody is working with a cancer virus in the MIT Biology Department. They had no idea. It was bad enough that I was working on polio; now I was working on cancer. This guy, Maury Fox, in particular, felt that I needed to be segregated off someplace, just so that people didn't run into my lab walking down the halls, students weren't exposed. The idea was that maybe a virus could float around in the air and be caught and cause cancer.

ZIERLER: That was the idea at the time; you could catch cancer, so to speak, like you could catch COVID?

BALTIMORE: That's what he worried about.

ZIERLER: Was there any basis to that, up to that point?

BALTIMORE: No.

ZIERLER: Maybe we should talk about that very briefly. Why can't you catch cancer if it has a viral basis, like you can catch COVID or polio?

BALTIMORE: First of all, you pretty well have to inject it to get it to work. Then there are very few viruses—remember I looked for this one virus that Abelson found, and then set up a whole program around it. We're leaving a number of—

ZIERLER: Open threads. We'll come back.

BALTIMORE: Open threads, dangling threads. Because it was rare. There weren't many viruses known that you could catch. Abelson virus, you probably couldn't catch, if you were a mouse. It never caused human tumors. No, Maury was very much a lefty. He was antiwar. He was a powerful figure. He was a very good friend of Leo Szilard's and came from that group around Szilard at the University of Chicago. That's where Maury came from. He was a very good friend of mine for—he was part of the reason I was at MIT, and he was somebody I greatly respected. The reason there's a Two Grey Hills rug over my fireplace, if you walk by, is because Maury collected Two Grey Hills rugs, and he introduced me to them. He was also a sort of scaremonger, so if there was anything to worry about, Maury worried about it. This got him, and he got worried. Some other people were worried with them, so there was a strain of concern about doing this kind of research in a laboratory that was contiguous to the other labs of the department, which was the negative side, and then there was the positive side that Luria began to say, "We should think about a Cancer Center."

ZIERLER: Mostly out of concern for biosecurity, essentially? That's the motivating factor?

BALTIMORE: There's the biosecurity concern, but Luria's concern is not that, although it fed into it. Luria saw this as an opportunity. He understood—god, I give this man the greatest of credit—he understood right away—no, he understood before, I'm sure before this—that the future of medicine was in molecular biology, and in particular the future of cancer research was in molecular biology. What I had done was to underline that and provide a defined direction, but there was a lot more to it. Luria went to the then-president of MIT, Jerry Wiesner, and said, "Jerry, we have an opportunity to develop a Cancer Center at MIT that would be unique, because it wouldn't come from a medical environment; it would come from a scientific environment."

ZIERLER: Which would distinguish it from the NIH immediately.

BALTIMORE: Which would distinguish it from Memorial Sloan Kettering, from Texas, from Buffalo—Roswell Park—which were the three great cancer centers outside of NIH.

ZIERLER: Fundamental research.

BALTIMORE: Fundamental research, MIT research. Already, the Nixon War on Cancer was—that's why I said 1971, because this is earlier—already the Nixon War on Cancer was being formulated.

ZIERLER: The money was flowing?

BALTIMORE: Not yet, but Luria said, "There is going to be money. This is going to happen." This was his political sense at work. "We should be there ready the moment there's money for it." And we were. Luria came to me and said, "I want you to help me do this, because you understand the science." He of course had literally brought me to MIT. He had been behind my whole career. I was overjoyed.

ZIERLER: And Maury was thrilled because you'd be contained.

BALTIMORE: Absolutely. The whole Biology Department breathed a sigh of relief.

ZIERLER: I want to return just very briefly to the idea of transmissibility. Cancer viruses are not airborne. You can't catch it that way. You did say you can inject it. That makes me think about HIV and intravenous drug use. Why can't people who share needles, who engage in risky behavior, why can't they transmit cancer, if one has it, to the other, like you do with HIV?

BALTIMORE: Oh. [laughs] Because human cancer is not transmitted by viruses. Viruses are a very important route for the transmission of cancer in animals, but not in humans. Viruses do cause human cancer, but they're hard to transmit. Actually hepatitis virus causes liver cancer, which is a big problem. Papillomavirus causes it. It is transmitted from person to person, particularly papillomavirus is, but not airborne. Papillomavirus, it probably is transmitted by people who are injecting, although I must say I don't know that for sure.

ZIERLER: Well, it's for sure sexual activity.

BALTIMORE: That's right. That's why I suspect it.

ZIERLER: And humans are truly unique in that regard?

BALTIMORE: No, not truly unique.

ZIERLER: Primates?

BALTIMORE: Primates in primate centers do transmit cancer-inducing viruses. Primates in the wild—we don't know a whole lot about primates in the wild. I don't think they do, but I'm not sure. But mice do a fair amount, particularly mice in labs transmit viruses. Do you know the story of Rous sarcoma virus? Rous was working on cancer at the Rockefeller University, Rockefeller Institute of Medical Research in New York, in the first decades of the twentieth century, just after Rockefeller was set up. He was known for doing that and had been written up in the newspapers that he was working on this. A chicken farmer noticed that his chickens had tumors, so he brought one of his chickens to Rockefeller and said, "Hey, doc, my chickens have tumors. Can you do something about it?" He [Rous] ground up the tumor, got out an extract from those cells in it, injected it in another chicken, and it got a tumor. That's why it's called Rous sarcoma virus, because Peyton Rous did that experiment in 1911. He probably did it in 1910 and published it in 1911. It's sort of amusing that the scientific community said, "Psh, chickens, who cares?" instead of saying, "My god, cancer can be transmitted by a virus." It took many, many years before—anyway, Rous got out the field entirely, worked in chemically-induced tumors.

Federal Support and Institute Building

ZIERLER: Let's go back to the building of the Institute. You bring the scientific expertise that Luria wanted you to bring.

BALTIMORE: Yeah.

ZIERLER: Who do you make the case to? What's the campaign?

BALTIMORE: They set up in Washington under the Cancer Institute Act, cancer centers. The way the bill was written, or the way the program was announced, cancer centers would largely be at hospitals or associated with hospitals, but you could read it that there could be a basic cancer institute. Luria said, "There's an opening here for us to get money to build this Cancer Institute." We wrote an application to the program to make MIT a center for cancer research.

ZIERLER: The program is run by NIH?

BALTIMORE: The money would come from NIH. The program would be run at MIT.

ZIERLER: No, but who is the application to? Who are you writing this to?

BALTIMORE: To the National Cancer Institute. The National Cancer Institute gave grants to cancer research. They had never given a center grant, so this program set up centers, geographical centers and research centers and clinical centers, all in one place. There would be one in New York, and there would be one in Boston, but if you read it right, you didn't have to have clinical facilities; you could just be a basic cancer center. Luria said, "We're going to apply for a basic cancer center at MIT." This was visionary. This was why Harvard hated us, because we were successful. We built a cancer center. NIH saw that this was an opportunity and funded it. We went out and we found a building that MIT owned and we could renovate. We built it. We hired some of the established people in basic science who were interested in cancer—cell biologists, immunologists, virologists.

ZIERLER: Who all had home academic appointments, or this was their appointment?

BALTIMORE: We hired them to MIT. They got positions in the Biology Department.

ZIERLER: This is faculty or staff?

BALTIMORE: Faculty. This was Herman Eisen, who was one of the great immunologists of all time, a wonderful, wonderful man. Me, running the virology. Richard Hynes, who was already at MIT but was a cell biologist running the cell biology. Each of us were on separate floors.

ZIERLER: How much was the original ask from NIH?

BALTIMORE: I don't remember.

ZIERLER: But it was soup to nuts? You asked for building, faculty, instruments, everything?

BALTIMORE: Yeah.

ZIERLER: You weren't looking for a benefactor's name to put on the building?

BALTIMORE: No. In those days, that was rare. Inconceivable. I then hired into the virology unit Phil Sharp, later got the Nobel Prize for discovering splicing; Bob Weinberg, yet has not gotten a Nobel Prize but deserves one.

ZIERLER: For what? What did he do?

BALTIMORE: He discovered the first oncogene in a chemically induced tumor and linked human cancer to the virus work that had been going on for years. He worked with me as a postdoc.

ZIERLER: Where is he now?

BALTIMORE: He's still at MIT. He moved to Whitehead with me and still has a lab there. He's almost retired now, or maybe he has retired.

ZIERLER: You moved your whole lab to the new Institute?

BALTIMORE: Yeah. Luria said, "We're going to hire people. This is going to be their full job. Everybody is going to honestly work on cancer. This is not a cover for doing undifferentiated molecular biology. We've got to be serious about it."

ZIERLER: Did the new appointments have teaching responsibilities?

BALTIMORE: Yeah. Bob Weinberg has taught basic biology at MIT for years and years and years, but all of us were full members of the Department. We had full responsibilities of faculty.

ZIERLER: Let's go back in the lab.

BALTIMORE: This is MIT's style. You set up a center for research, but your academic appointment is through a department, and you are a full member of that department.

ZIERLER: What's the advantage to that style?

BALTIMORE: There's a center for research that can draw in money, that can keep together the people with a common research interest. The Center for Theoretical Physics, Center for—we have all sorts of centers.

ZIERLER: New members of the Institute would have access to a pot of money that was part of the original grant?

BALTIMORE: Yes.

ZIERLER: Wow, so they're not even spending their time writing grants.

BALTIMORE: All of us had independent grants along with—the Center money actually—

ZIERLER: It would supplement.

BALTIMORE: Yeah, it helped produce central facilities, space, helped run the building, and maybe helped a little with salaries, probably not a lot. But most of our research efforts were still done on independent grants, either from the government or somewhere else.

ZIERLER: What's the timeframe? When do you move in?

BALTIMORE: The end of 1974.

ZIERLER: Back to 1971, on the research side. What's the next question for you?

BALTIMORE: The next question is to set up the Abelson system and to develop a program focused on real tumors in mice where we could ask the question, "How is cancer formed?" We actually were a step behind the Rous sarcoma virus people, and they made the great discovery that oncogenes were the basis of cancer, and that the oncogenes were derived from normal cellular genes. I didn't make that discovery partly because I had to set up this whole system in mice, a totally different kind of research, different for me, but there was nothing like it anywhere. By the time I got that up and running, which was 1974 or 1975, Varmus and Bishop had done or were about to do the experiments showing Rous sarcoma, the nature of the Rous gene.

ZIERLER: Setting up the Abelson system, what does that mean? What are you setting up?

BALTIMORE: I'm setting up a knowledge of how you induce the tumors, how you derive cells from the tumors, the nature of those cells, and then work on the virus. What gene in the virus is causing the Abelson tumors? Where did that gene come from? Ultimately, what is it about that gene that allows it to cause cancer? We found the gene, we found the protein that the gene makes, and then we purified that protein. By this time, somebody—I'm blanking his name—had shown that the SRC gene of Rous sarcoma virus was a protein kinase, catalyzed the transfer of phosphate from ATP to the protein, which is what a kinase does. It puts a phosphate residue on a protein. When we purified this thing, we assayed it for whether it was a kinase, and sure enough it was, and sure enough we could show that it phosphorylated itself.

Then my background in chemistry came into play, and I said, "Well, where is it linked on the protein?" All kinases up to that point, except for some minor things that most people paid no attention to, all kinases phosphorylated a serine or a threonine residue in the protein. That's what Krebs and Fischer had gotten the Nobel Prize for, was the discovery of that reaction, how extensive it was. Fischer just died. I knew that there was a simple test that would tell you whether it was on a serine/threonine, which was to take the protein and incubate it in a basic pH, and the base would just cleave off the phosphate, and so you would clear off the phosphate, and it would be obvious. We did the experiment, and it didn't work. That told me instantly that it was not on serine or threonine. What was it on?

Then that started—Owen Witte and another guy in my lab, but Owen was the central figure—searching for other phosphate linkages, and we discovered that it was on tyrosine. The full significance of that was not clear, but the significance at the time was that no one had ever seen a kinase like this that phosphorylated tyrosine. This tyrosine phosphorylation was linked to cancer. It doesn't take a lot of imagination to say, "We may have found one of the key characteristics of cancer." It turns out it's a key characteristic of signaling systems, not just cancer but normal.

ZIERLER: What are other signaling systems?

BALTIMORE: Everything that goes on in the body involves sending signals around, and a lot of those signals involve phosphorylations, and some of those phosphorylations are on tyrosine, but just people hadn't seen it, because it's a very low level. But they are critically important for cell gravity, for differentiation, for all the dynamic things that happen in a living system. At the same time, another guy working with Rous sarcoma virus discovered that all the people working on this thing had missed the fact that their phosphorylation was on tyrosine also.

ZIERLER: Why had they missed it?

BALTIMORE: I don't know. I can't imagine why. Well, no, I can tell you what Tony, this guy—oh, I'm blocking his name; he's at the Salk Institute—what Tony did. He saw that the phosphorylation was occurring on the protein. He degraded the protein, and was showing that it was on a serine residue, because it migrated in a chromatographic system, like serine phosphate. But one day, he made a mistake in setting up this chromatographic system and ran it at the wrong pH, and what happened was that it separated from the serine. It wasn't serine; it was something that ran like serine, but was in fact tyrosine. Tony, being a very smart guy and clued in, said, "We've got to find out what it's linked to. It's not linked to serine." He found it was linked to tyrosine. We actually ended up publishing that result separately. We published in PNAS. He published somewhere else, I forgot where. That opened up the whole signaling field. There are many tyrosine phosphorylations. Then many tumor viruses carry tyrosine-phosphorylating proteins that are different from the Abelson protein.

ZIERLER: When you moved to the new building, was there opportunity for better equipment, better instrumentation?

BALTIMORE: Yeah, we got some new instrumentation, although I moved stuff from my old lab over. We built some central facilities. We had a good animal facilities. Up until we started the Cancer Center, there was nobody that worked on animals in the MIT Biology Department and there was no animal facility. There was another department, there was a Department of Applied Biology, that did in particular work on toxins, and they kept animals, but in Biology, nobody did. When we started the Cancer Center, having a place to keep animals and to do work on animals was brand-new and wonderful. It allowed us to hire some new kinds of scientists that never would have come to MIT before, because we couldn't work with animals.

ZIERLER: I wonder what your reaction was to the administration's rhetoric, the notion of a War on Cancer, the notion that cancer can be defeated, the notion that cancer can be defeated not in the long term?

BALTIMORE: I hated the notion of a War on Cancer, because that's not how you do science. You do science by finding your way and the things we're talking about. These are not wars.

ZIERLER: There's nothing to attack.

BALTIMORE: There's nothing to attack; it's curiosity. I actually spoke out against the War on Cancer, and actually I'll never forget, when the Cancer Act was passed, they set up some oversight groups, in particular a Cancer Panel, which was three kind of graybeards. Actually, because everything was so political when Nixon was involved, they weren't graybeards of cancer research necessarily. Some of them were just political figures. But one of them was—god, I've forgotten his name. [I remember his name, it was Benno Schmidt. The rest of this about Giamatti can be ignored It was Benno who had a son. But the elder Benno was a great man for cancer research] I should know it perfectly well. Wait a minute, now. Who is the guy who played the major male role in the movie about wine, and the pinot noir of—

ZIERLER: Paul Giamatti and his father?

BALTIMORE: Right.

ZIERLER: His father was the president of Yale.

BALTIMORE: Right. No, it's not—I'm wrong. It's not Giamatti. What is his name? Yeah, his father was the president of Yale.

ZIERLER: Same movie?

BALTIMORE: No, no, no, no, no, no. Forget I asked. It's somebody else. He was a financier. I can find out, but I've just forgotten. There was a hearing in Washington, and they invited me down to speak in this hearing. I went down to Washington and I said, "You don't want a war. You want to do serious research." He came over to me, and—because you have to remember, there's something very important here: that cancer research was second-rate research up to that point.

ZIERLER: It had to be.

BALTIMORE: It had to be. You're right. Because there was nothing to look at. Even Sidney Farber, so famous for his work in drugs, he didn't save anybody. He worked hard at trying to find drugs that would kill cancer cells, and he did find some drugs that would kill cancer cells before they killed the patient, so they did prolong life, some, and he was a great man; I don't want to argue about that. But the only reason cancer research existed at all was because cancer was such an awful disease that you had to work on it. Somebody had to work on it. If the public was going to have a National Institutes of Health, it had to work on cancer, along with other things, even though working on cancer was sort of a fool's errand at the time. Now Nixon had said, "We're going to put a lot more money into cancer research." If it went into the same things that people had been doing for years, it wasn't going to do anybody any good. That was why I was skeptical of the War on Cancer, because the people who were in charge of it were the same people who had been in charge of cancer research all along, and the centers were going to be the same centers—Memorial Sloan Kettering, Roswell Park, and MD Anderson.

ZIERLER: Old dogs, old tricks.

BALTIMORE: Right. He came over to me and he patted me on the head, more or less, either really or imaginary, and said, "Young man, I'm going to make sure that that doesn't happen. I'm in charge of this money, and it's going to go to the new concepts of cancer and cancer research, molecular biology at the fore." I said, "If you do that, I'm going to be dead wrong and this is going to be a great success."

ZIERLER: You'll be happy to be wrong.

BALTIMORE: I'll be happy to be wrong. And he did it. He is actually one of the real heroes of that time.

ZIERLER: We've got to find the name.

BALTIMORE: Yeah.

ZIERLER: To zoom out, socioeconomically, post-war America, people are living longer, people are leading more sedentary urban and suburban lives. Cancer is just more prevalent at this point, too. It's more around American society. I wonder if there was some urgency in that regard that might not have existed earlier?

BALTIMORE: As people live longer, they get more cancer, so there has been over the period of the twentieth century in particular, and twenty-first century, a continual increase in the frequency of cancer, which is actually not an increase in the occurrence of cancer, age-corrected, but because the population is aging, the number of people getting cancer increases. I'm sure you're right that it became an increasing political issue as the population got older.

ZIERLER: What about the environmental movement—Rachel Carson, Agent Orange, pollution, toxins? Were people thinking along those lines, too?

BALTIMORE: They were, but the actual role that those things played in the overall incidence of cancer was not great. There was only one that was great, and that was smoking. As we have decreased the number of people who are smoking, we have decreased particularly lung cancer but all of the kinds of indications that were associated with smoking.

ZIERLER: What about asbestos and mesothelioma? Was that registering at that point?

BALTIMORE: Yeah, that was a pretty obvious association, and very real, but as a fraction of the population, negligible.

ZIERLER: Were there mesothelioma cases that did not have any obvious connection to asbestos exposure?

BALTIMORE: I believe the answer to that is yes. I'm not sure. I do know that there were cases of mesothelioma in people who had no obvious exposure to asbestos. They didn't work in plumbing. They didn't work in plants that produced asbestos. They didn't make—what do you call the stuff that protects you against—? Insulation. A lot of insulation had asbestos. What I don't know is whether those people still had an exposure to asbestos but didn't know it. The famous guy who died of mesothelioma was the evolutionary biologist, whose name I'm going to block. Oh, come on. Very popular guy, wrote wonderful books about evolution. Here he was, an academic at Harvard and—

ZIERLER: Not Stephen Jay Gould?

BALTIMORE: Right, it was Stephen Jay Gould. He gets mesothelioma. It was very hard to see where—but somebody told me that there is a known exposure that he had to it. I don't know if it was in an elevator that he took, or something. All I'm saying is that even the people who weren't exposed overtly to asbestos may have an asbestos exposure, and I'm not sure whether anybody who gets mesothelioma doesn't have one. Now, it's notoriously difficult to be precise about 100% of cancer diagnoses, so if there's a 10% probability that if you are getting mesothelioma without an exposure to asbestos, that may be because 10% of the diagnoses are wrong.

ZIERLER: I guess we'd have to look before the industrial age, when asbestos is—

BALTIMORE: That would be hard.

ZIERLER: But that would be [laughs] the control, I guess.

BALTIMORE: Actually, asbestos is a natural material.

ZIERLER: Oh, is that right?

BALTIMORE: Yeah. It's mined. It's not produced by technology. It's a natural substance. That's one of the reasons why a lot of people have been exposed to it who don't know it, because it's adventitiously around other materials that are mined and they get some asbestos.

ZIERLER: This is way afield, but at this point, are you starting to think about efficiencies in understanding DNA that will ultimately lead to DNA sequencing? This is small enough science. You have small enough samples where this is not necessary?

BALTIMORE: Oh, no, no, if we could have had sequencing earlier, we could have known all sorts of things that we only learned once we get sequencing.

ZIERLER: Because that's a manpower issue?

BALTIMORE: In order to sequence DNA, you've first got to be able to purify DNA of a defined sequence. It's actually easy for a virologist to do that, because viruses are awfully small. But even so, if you try to sequence the genome of a virus, until recently it was a big job, because it's like 10,000 nucleotides long. To make a piece of DNA of 100 nucleotides, when it's 100 nucleotides out of 10,000, means you've got to purify it a lot. It's not straightforward. That required a whole new technology, but you needed the chemistry to be able to distinguish one base from another. That was only developed in a usable fashion by Fred Sanger, for which he won the Nobel Prize.

ZIERLER: Did the Institute at MIT allow you to collaborate with people in different fields that you wouldn't otherwise have been able to, or at least the interactions would not have been as natural?

BALTIMORE: Sure. We could do whatever we wanted. There was nothing proprietary about working at the Cancer Center.

ZIERLER: Who were some of the key people you were working with at that point?

BALTIMORE: Outside of the Cancer Center?

ZIERLER: No, even within.

BALTIMORE: I had a big enough lab that I was working mostly with people in my own lab, my postdocs and graduate students. I didn't have a lot of papers, over my whole career, with other scientists, for better or worse. It's not that I was avoiding it; in fact I encouraged the Cancer Center to have as much communication from one lab to another as possible. We had meetings weekly. We had a famous meeting called the Fifth Floor Meeting, because it was the scientists on the fifth floor—my lab, Phil Sharp's lab, Nancy Hopkins, Bob Weinberg, David Housman who was more of a geneticist, human geneticist. We would share information, and we would share the latest experiments. There was a lot cross-discussion, but my people worked with me, and Phil's people worked with him, and Bob's people worked with him.

ZIERLER: What was the trajectory of the graduate students and the postdocs you had taken at that point? In other words, you came from a very different field, and here you were squarely in this field. Were your graduate students and postdocs already in the new field that you had joined in terms of where they had come from?

BALTIMORE: No, most of them actually came in from other kinds of backgrounds, and I had to acculture them to what we were interested in and what we were doing, and the kinds of parameters that we were working within, and the kinds of methods we were working with. What many of them did have, though, were skills that they had developed working on other systems, which were very useful in the cancer-oriented work that we were doing. Postdocs would often contribute technology that they had developed the skills with as a graduate student somewhere else.

ZIERLER: Would this include computers? I'm waiting for when computers make their entrance into your lab.

BALTIMORE: Oh! [laughs] Yes, it certainly would include computers. Like everybody else, computers first came into my lab and my life through word processing.

ZIERLER: Just typing, essentially?

BALTIMORE: Just typing.

ZIERLER: No data analysis, no memory, nothing.

BALTIMORE: Right. But then as experiments became more complicated, as computers became easier to manipulate so that they would store information, they would display pictures, display data, make graphs, we used them more and more.

ZIERLER: Did that allow you to take a more quantitative approach to the research?

BALTIMORE: It did. It did make things more quantitative, and it did make things more reproducible, and it helped the storage of results so that particularly the savvier students would keep their data on computers. By this time, everybody does. It took a while to get there. I don't know how to program. I was never a maven in that area at all. But I was glad to see that my trainees could manipulate the stuff. The first time somebody came in and said, "I wrote a program so that we can do that," I was overjoyed. [laughs]

ZIERLER: So 1973, 1974, what are the big questions at this point? You're in the new lab.

BALTIMORE: We're moving into the new lab. We're able to give Naomi Rosenberg a home in my lab. She moves over with her technology.

ZIERLER: She's one of how many women around now?

BALTIMORE: I don't know, a few. I always had maybe 20% women or something like that, but that was a lot more than a lot of other people. I've trained, oh, I don't know, 10 or 15 full professors now.

ZIERLER: They can thank your mother for that. [laughs]

BALTIMORE: Yeah, they can.

ZIERLER: All right, so the big questions. What's going on now?

BALTIMORE: The question for the Abelson system was what we've talked about: how does it transform cells, how does it cause tumors, and what is the nature of the tumor cells? You could put this virus into young baby mice and when they grew up, they had these florid cancers. But what cells were they? They were in the circulation, and we could identify them as lymphocytes, and they seemed more related to B cells. They turned out to be very young B cells. That led us to thinking about, can we use these cells to understand the sequence of events in the differentiation of B cells? That wasn't well known. Happens in the bone marrow, not easily accessible. All the different stages of maturation are mixed up with each other. The nice thing about a tumor cell population is it's relatively homogenous. You can imagine that what the virus was doing was freezing cells in different aspects of the differentiation pathway in the B cell. If that was true, we could analyze that differentiation path. Nobody had ever done that before.

The marker that we had—and this made it so easy to be precise about it—was the rearrangement of DNA. Tonegawa had shown that the way that B cells make this incredible range of antibodies is by rearranging their DNA so that a relatively small amount of DNA can encode a vast number of products, because it's constantly recombining itself and mutating itself, so there's a whole mutational spectrum. It wasn't clear at that time that that's true, but he showed that it involved the recombination of DNA. Once we knew that, then if we could develop markers for that recombination, we could tell what stage the cells were in. We did that, and it worked. We were interested, on on hand, in the nature of cancer, but on the other hand, the nature of b lymphocyte differentiation. We were still interested in polio, and in fact around that time, we did an experiment that revolutionized the research on polio and all RNA viruses, which was to show that if you made a DNA that represented the genome of poliovirus and copied that DNA into RNA, and put that RNA into cells, that RNA would take over the cell and you'd get out poliovirus. {I think this is wonng: the experiment was done by just putting the DNA onto cells and, sort of magically, the virus would reappear.]You could now chemically manipulate the genome of polio as DNA and then reconstruct the virus and study the nature of the mutations you made in the virus.

I started doing that, actually, also. The guy at my lab who did that, Vincent Racaniello—I was just trying to get him into the National Academy—we continued work on polio. We continued work on the molecular biology, and this was a big interest that I had a number of people involved in, in the details of reverse transcription. It was enough at the beginning to say you incubate the virus in the right way, it makes DNA, that DNA is a copy of the viral RNA, you can show it is, and so that was big news. But then if you get down to brass tacks, what part of the virus is being copied? Is it the whole thing or is it a piece? Is it all done at once, or is it done in pieces? All sorts of questions like that. What enables you to come out, when you're all done, with a new virus particle that has a new RNA in it, which is an intact representation of the whole genome of the virus? I'm simplifying things a little bit here because there's a lot of DNA and RNA mechanics involved in it. We wanted to understand that mechanics. I had people working on that from the time I made the discovery for the next ten years, probably, until—I published a paper with a guy named Eli Gilboa, an Israeli, which laid out that whole mechanics, and it integrated work that we had done and work that a lot of other people had done. He then added to that some very key observations that had put the whole thing together, and it has been verified ever since.

So, we did that. Worked some, still, I think, on vesicular stomatitis virus. Alice took that. She became a professor at Harvard in 1971, maybe? That's probably right. I didn't continue that work after that. I finished up a student or two on that. That's sort of the way things were going, until 1975. In 1975, I took a sabbatical. I went to New York. Actually I had thought about it for a while, and I said to myself, "I want to do a sabbatical that would enable me to better understand immunology." I saw this B cell work going into increased interest in immunology. I think we talked about this—I had always been intrigued by immunology.

The Nobel Buzz

ZIERLER: If I might suggest, that's a great place to pick up for next time. Last question for today, to get to 1975, when does the Nobel buzz start? When is that in the air, people are talking about it? Is that like right in 1970, it's there, right from the beginning?

BALTIMORE: Yeah.

ZIERLER: Even if you wanted to, it's in your mind. You can't help it. It's around.

BALTIMORE: It's around. Many people said to me, "You're going to win the Nobel Prize for that work." The only danger was—it wasn't exactly danger—the only thing that might have gotten in the way was that they might just give it to Howard. But that didn't happen.

ZIERLER: You were rewarded for being a mensch. [laughs]

BALTIMORE: Right in 1970, the next day, people said, "This is a Nobel Prize." But Nobel Prizes take years and years and years to be awarded.

ZIERLER: Yeah, but that's because you need the experimental verification. That's what Sweden is waiting for.

BALTIMORE: No, no, no.

ZIERLER: Look at LIGO.

BALTIMORE: First of all, LIGO is now. I'm talking about 1970 and earlier.

ZIERLER: Okay, fair.

BALTIMORE: Second of all, they are still giving prizes to work done in 1970.

ZIERLER: Sure, sure.

BALTIMORE: It's not because it wasn't verified; it's because it just was in a queue where it finally got to the top.

ZIERLER: Ask David Politzer.

BALTIMORE: Right, right. He thought it was all over. Come 1975, and I go on sabbatical, it never occurred to me that I'd get the Nobel Prize.

ZIERLER: Meaning 1971 had come and gone, and 1972, 1973.

BALTIMORE: Yeah, but I didn't think that I was in contention even at those times. I didn't feel like, "Uch, it hasn't happened." I just said, "That's for another time in my career." I didn't know when the Nobel Prize was announced. I really had no idea. I didn't pay any attention to it.

ZIERLER: On that note, we'll pick up in 1975 when you had no choice but to pay attention. [laughs]

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, February 1st, 2022. I'm delighted to be back with Professor David Baltimore. David, good to be with you again.

BALTIMORE: Hello, hello.

ZIERLER: We're going to go back to 1975, pick back up on your decision to take a sabbatical. Lots of reasons to do that; what were your motivations at that time? Why did you want to go back to your old stomping grounds?

BALTIMORE: I can give you actually a context. In 1974, there was a sort of earthquake that went off in biology with the discovery that tools that we had, that we had aggregated in the process of each one of our research programs. You put them all together and you've got an incredible ability to take apart DNA, to put it back together again, to determine its sequence, things that we had never imagined doing before. It's called the recombinant DNA revolution, because we could recombine molecules of DNA.

ZIERLER: Where is reverse transcriptase in this?

BALTIMORE: It's part of it. Reverse transcriptase was very important because it would allow you to capture, as what we called cDNA, the sequence of messenger RNAs. We could then manipulate those DNAs in any way we wished. We could make products from them. We could modify cells by their expression. We could study the proteins that were made. We could make mutations of basically any sort that we wanted. Reverse transcriptase was a key piece of this toolbox. Restriction enzymes were a key part of it that had been discovered by people interested in how bacteria fight off viruses. Enzymes that cut DNA—the restriction enzymes cut DNA at specific sites, but there were enzymes that could cut DNA at non-specific sites, enzymes that could chew up DNAs or RNAs, enzymes that could put them together, put molecules together. All of those were part of this toolbox. I looked at that and I said, "There is now a chance for me, a relatively young scientist"—I was less than 40, then—

ZIERLER: Thirty-six.

BALTIMORE: Yeah. That's right, I was 37 when I got the Nobel Prize. I could now work on systems of the mouse body. What I had always wanted to do, which was to work with mice, and to take advantage of the mouse genetics, but now added to it was all of this other capability. The decision that I made in 1960, which was to work on viruses, was now no longer necessary.

ZIERLER: 1960, way back in undergraduate days?

BALTIMORE: Yeah. Wait, no, as I went to graduate school. When I went to graduate school I decided to work on viruses, because you couldn't work on the fundamental properties of mice, because we didn't—

ZIERLER: There was no toolbox.

BALTIMORE: There was no toolbox. You had to access to it. Now, in those 15 years, there had been this total revolution. It was widely recognized. It was what led to the Asilomar meeting. The Asilomar process was started in 1974.

ZIERLER: Who was responsible for that? Who drove that?

BALTIMORE: I did, partly. Paul Berg did. Maxine Singer did.

ZIERLER: The idea was that this was a meeting of minds because all of these new tools were available?

BALTIMORE: Right. The question was, were we likely to cause adventitious harm in the process of trying to do experiments using all of the now available technology?

ZIERLER: Harm to what?

BALTIMORE: Harm to ourselves, harm to the population around us. Could we make Frankenstein monsters?

ZIERLER: Oh, I see, not just biosecurity concerns but like life going in crazy directions kind of concerns.

BALTIMORE: It was all of those things, but the Asilomar meeting actually focused down on the issue of making bacteria that were able to carry genes around with them and modify, and could they sort of infect the genes.

ZIERLER: Side question—was the U.S. Army, like Fort Detrick, biowarfare, were they aware of what you were doing? Did they see some potentials and some concerns?

BALTIMORE: Yes, they were aware. They were developing programs, most of them secret. We had signed a Biological Warfare Treaty, and so if you really believed that that was doing its job, then there was no reason to be concerned, because we should not have been making warfare agents. But there was a suspicion that we weren't being as careful about it as we might, and we knew much less about what other countries were doing.

ZIERLER: Careful with what you were making, or careful that you could have had a postdoc in from some adversary country?

BALTIMORE: It was more what we were making, although there was a worry about having Russians. There was a worry that the Russians might not be following the rules, and as it turns out, they weren't. There was really a major Russian biological warfare effort.

ZIERLER: The government didn't stand in your way; they just wanted an appreciation of what you were doing?

BALTIMORE: Right. They wanted to monitor what was going on and know what the possibilities were. But the major worry that led to the Asilomar meeting was that we would do something dangerous in the laboratory in the process of manipulating.

ZIERLER: Asilomar is a place name, it's an acronym? What is that?

BALTIMORE: Oh, you don't know about the Asilomar.

ZIERLER: I've heard of it, but I don't know what—

BALTIMORE: Oh, that's one of the most important things I ever did, was to work on Asilomar, and it reverberates to this day. Asilomar is a place in California, near Carmel and Monterey, where the state maintains a conference center on the ocean. It's a beautiful, beautiful place.

ZIERLER: Is it connected with the Monterey Institute at all?

BALTIMORE: No. It's entirely for academic use, although they may have corporate meetings there too. It's a little rustic, especially for corporate meetings. But for instance, the Stanford and UCSF departments, many of them have yearly retreats at Asilomar. There's a yearly immunology meeting at Asilomar where I spoke many times, and is one of the premiere immunology meetings in the world.

The Origins of the Biosecurity Regime

ZIERLER: Was the term "bioethics" in use at this point?

BALTIMORE: No, it became in use around that time, and we had ethicists at Asilomar. You need to know about Asilomar.

ZIERLER: Let's learn. The ideas that would go into Asilomar happened right around this time, 1974, 1975?

BALTIMORE: Right. In 1974, in Paul Berg's laboratory at Stanford, they decide to put together DNA molecules of disparate sources, for the first time.

ZIERLER: What are the sources?

BALTIMORE: The sources are from a virus, and from bacterial plasmids. Paul, who was a great biochemist and a good friend of mine over many years now, has plans of various sorts. There's a guy who writes a thesis at Stanford in which he proposes putting together DNA molecules. But it's really the work of two guys named Cohen and Boyer that gets there first. Cohen is at Stanford, and Boyer is at UCSF. They decide to put together molecules from bacterial plasmids. But it doesn't really matter because all DNA is the same. Once you put two molecules together, you can put any two molecules together. They announce at the nucleic acid Gordon Conference, which is a yearly conference in New England, that they have put together these molecules, to replicate.

ZIERLER: You were there for this?

BALTIMORE: No, I wasn't. That conference was run by Maxine Singer, who was a very thoughtful, ex-Swarthmore graduate, now very old, working at NIH, working in nucleic acids, very well known. Swarthmore just named a new building for her. Maxine and another guy who was her co-chair, whose name I'm going to block [Dieter Soll from Yale], were approached by the people at the meeting, who said, "This is terrific. This is a revolution." This is of course the beginnings of the recombinant DNA revolution. "But it's dangerous, and we don't know if it's too dangerous to go ahead. You're going to make things that are able to carry disease-causing genes around, or antibiotic resistance genes." That was something that we were really worried about.

ZIERLER: This is like a lab leak concern?

BALTIMORE: Right.

ZIERLER: Is the whole biosecurity one through five schema in place at this point?

BALTIMORE: No.

ZIERLER: There's nothing?

BALTIMORE: It's made as a consequence of this. The people at the meeting said, "We should send a letter somewhere warning people that this is happening, and calling perhaps for a moratorium on this kind of work." It's very dangerous. It goes to the heart of this revolution.

ZIERLER: What are the actual techniques in combining molecules that creates this concern that something might escape from the lab? Is it transmissibility? What is it?

BALTIMORE: We know about transmissibility already. We know that you can take a plasmid, a circular piece of DNA, and get it to go inside a bacterium where it will duplicate itself and be transmitted forever after in that bacterium. We know how to do that. What we didn't know was that you could insert any other gene you wanted into that plasmid. That's what the Cohen-Boyer experiment said, and it said it to this group of knowledgeable people at the Gordon Conference, who then asked Dieter Söll, who was the guy working with her, and Maxine, to write a letter. They decided to write that letter to Science magazine and to the National Academy of Sciences. I may have that wrong. I didn't know anything about it.

There's one other thing I have to say. Paul Berg had already run into difficulty because he was working with cancer-causing viruses, SV40 virus, and people were worried about the danger of that virus getting out, causing tumors in people. It did cause tumors in monkeys. This was in 1972 or 1973. He had organized a meeting at Asilomar to talk about this among the community. I had helped him organize that. He had talked to me about it. That was all in the background. That meeting was held, was successful, sort of allayed fears, but also started a tradition of biological scientists taking responsibility for their work.

ZIERLER: How were fears allayed? What were the assurances?

BALTIMORE: I don't remember. I'm only doing this to set a historic—

ZIERLER: But the idea was that the concerns about a lab leak or transmissibility were overblown, or that we had the facilities to prevent those things from happening?

BALTIMORE: No, I think it was more that the concerns were overblown, and that people were being careful. But out of that started coming levels of biocontainment.

ZIERLER: You were starting to practice this in your own lab with the new building?

BALTIMORE: In the Cancer Center?

ZIERLER: Right.

BALTIMORE: We were not working with viruses that we thought could cause tumors in humans, even if they got out of the lab.

ZIERLER: What about for you and the technicians working in the lab yourselves?

BALTIMORE: We became increasingly concerned about that and became more cautious, and more careful.

ZIERLER: What would have been the mode of transmission? Respiratory? An accidental injection? What would it have been?

BALTIMORE: I don't think it was that specific. It was just this feeling that—

ZIERLER: You're just working with this stuff, and "we've got to be careful"?

BALTIMORE: Yeah. That was just biologicals. But now you had this whole ability to treat DNA as a chemical, and to modify it and recombine it in whatever way you wanted, to isolate genes. That's 1974. This letter is sent, and Paul gets it, maybe Maxine. Maxine and Paul were very good friends. Maybe she sends it to him. He calls me, and said, "This is what has happened. There was the announcement of this revolution. We're also working along these lines. I said, "Paul, we've got to get together a small group of people and talk this through, how do we respond."

ZIERLER: All biologists, or you open it up to other experts?

BALTIMORE: At that point, all biologists. We called a meeting, I'm guessing for September? This is all written down somewhere. Something like September 1974. We invite James Watson, a variety of other people extremely well known in the general field of nucleic acids and of molecular biology, and some other people who had been involved in that first Asilomar meeting, and even though they weren't so right for this, had experience thinking about the issues. We all came together in my conference room at MIT and decided two very important things. First of all, that we would write a letter, to the National Academy, saying that there ought to be a moratorium on the most potentially dangerous experiments, which were experiments with tumor-causing viruses, experiments with genes that lead to antibiotic resistance, and toxin genes.

ZIERLER: This is germs and viruses that you're thinking about?

BALTIMORE: Right. And that there ought to be an international meeting that would talk this through and come out with some kind of framework for going forward.

ZIERLER: The National Academy has what authority to impose—?

BALTIMORE: None.

ZIERLER: They're a conduit to the government? Who oversees a moratorium? It's a gentleman's agreement?

BALTIMORE: A gentleman's agreement. The only authority, and this becomes very important, was the National Institutes of Health, which could announce regulations over people who got research support from them, and most of us did. That left industry free to do what it wanted. It left people who were supported by philanthropic organizations or people who were supported from industry with the ability to do whatever the hell they wanted.

ZIERLER: What about FDA, CDC, regulatory agencies?

BALTIMORE: FDA only covers drugs and devices. CDC doesn't make these kinds of regulations. There was no place. Worse than that, this was an international issue. There was absolutely nothing about U.S. borders, and we were all training people from abroad. Everything that happens in biology starts in the United States, for very good reason, but spreads to other countries very quickly.

ZIERLER: This gets back to the government. Where would the military, DARPA, the State Department, where would they get involved in this?

BALTIMORE: All these things. We called a meeting which was at Asilomar. I think it was in March of 1975.

ZIERLER: You were already on sabbatical at this point?

BALTIMORE: No. I go on sabbatical in the Fall of 1975.

ZIERLER: You're in New York when the Nobel is announced?

BALTIMORE: Yes.

ZIERLER: We'll come back to that.

BALTIMORE: But no, I'm still at MIT. Four hundred people came to Asilomar. They came from all over the world. We met for three days, and came out with a final statement that we wrote basically overnight on the last night. None of us slept. It was the organizing committee that took the responsibility to do that. That was me and Paul and Maxine and Sydney Brenner, a great British South African scientist, and Norton Zinder from Rockefeller, one or two other people. We wrote the statement and more or less established the idea that there should be high containment and medium containment and lower containment, that the moratorium should stay in place on the most dangerous kinds of experiments, but that the less dangerous experiments can go forward.

ZIERLER: What's the threshold? Tumor-causing viruses are all going to be verboten?

BALTIMORE: Yes, at the moment, they were. Viruses of any kind, we couldn't make. I mean, here I was working on polio. I wanted to turn it into DNA so I could really manipulate it. Couldn't do it. I was responsible for regulations that said I couldn't do it.

ZIERLER: Because it could become super polio, or something?

BALTIMORE: Because we didn't know what genes were in there, really.

ZIERLER: These are heebie-jeebies as much as anything else.

BALTIMORE: Right. There were some people, notably James Watson, who said, "You're all being sissies," basically. He said it publicly, at the meeting.

ZIERLER: Who was the letter addressed to? The president of the Academy? A committee?

BALTIMORE: That's what I don't remember exactly right now.

ZIERLER: Do you remember the response? What did they say?

BALTIMORE: This little committee that we had put together to think about it, they designated us a committee of the Academy.

ZIERLER: You were a member at this point?

BALTIMORE: I was a member. I was a member in 1974.

ZIERLER: Probably one of the youngest, ever.

BALTIMORE: Yeah, but they knew I was going to get the Nobel Prize and they wanted to get ahead of it.

ZIERLER: So you write the letter. What do they say in response, or what's the next step?

BALTIMORE: We made it a committee report, because we are now a committee of the Academy, and we said there should be a moratorium and there should be an Asilomar meeting, and we start preparing the Asilomar meeting, because we didn't give ourselves a whole lot of time.

ZIERLER: What's the funding for the meetings?

BALTIMORE: We don't know what the funding is going to be, but in the end, how did that get funded? I don't remember. Did the Academy put up the money? Maybe. I think the international travel was supported by the individual countries.

ZIERLER: The host institutions?

BALTIMORE: Well, no, just the countries.

ZIERLER: Russians were represented?

BALTIMORE: Russians were represented.

ZIERLER: How did the CIA feel about that?

BALTIMORE: I don't know. [laughs] We just invited them as scientists. We invited some ethicists. We invited lawyers. In fact, the lawyers spoke at the meeting and scared the shit out of everyone.

ZIERLER: Of course. That's what they do! [laughs] What were their concerns?

BALTIMORE: They said, "You're all going to be responsible, and people are going to sue you, personally, if there's any trouble." They said, "How's your liability insurance?"

ZIERLER: [laughs]

BALTIMORE: We asked, and they agreed, all the journalists who came, and we limited that to a small but significant number, to wait to write about this until it was over, so that it wasn't subject to the pressure of public discussion.

ZIERLER: How long was the conference?

BALTIMORE: Three days. They did that, and then they wrote really very responsible articles. Notably, the science writer for the San Francisco Chronicle whose name I'm going to forget, and The New York Times. Of course there was no Twitter and Facebook and any of that in those days, no internet, so there was no way to get sort of instant communication. If you tried to do that today, you can't control it. It was left in the lap of the NIH to write regulations.

ZIERLER: This was the conference's recommendation, that the NIH should write these regulations?

BALTIMORE: Right. That was then done.

ZIERLER: Where is Varmus in all of this?

BALTIMORE: He was there. Was he there, even? He was not well known at that point. The famous Varmus and Bishop experiments that won them the Nobel Prize were done in 1975.

ZIERLER: Is Tony Fauci around at this point? He's too young?

BALTIMORE: I think he's already head of NIAID, and there were people from NIAID who came, and they had come to the first Asilomar meeting, because they worked with these tumor viruses. But Fauci, I didn't even know him then, I think.

ZIERLER: What are the regulations that you want the NIH to write up?

BALTIMORE: We want there to be levels of regulation. We also agreed that the only plasmids that should be used in these experiments were ones that could not grow in the wild.

ZIERLER: All synthetic?

BALTIMORE: All synthetic, yeah. There was one in particular that we said should be used. It was a very finicky thing. It by itself slowed things up. But there's a lot more. The NIH sets up the NIH Recombinant DNA Advisory Committee, RAC. I sat on RAC later. RAC is the adjudicator. People who want to do experiments and want to have those experiments designated at the lowest containment level applied to RAC for that designation.

ZIERLER: The regulations that NIH puts out, this is the origins of the biosecurity levels one through five?

BALTIMORE: One through four.

ZIERLER: Isn't there a five, or that comes later?

BALTIMORE: I don't think there was a five.

ZIERLER: Wuhan is a four in that case.

BALTIMORE: No, Wuhan is a three. Four is very high containment.

ZIERLER: What's an example of a four?

BALTIMORE: There's a lab in Montana that's a four. There's a lab in Boston that's a four.

ZIERLER: They have to be government, or they can be university?

BALTIMORE: The one in Boston is run by BU. The one in Montana is government. It's part of NIH. There's one in Galveston, which I think is part of the University of Texas. But there are only a few in the whole world. There's one a friend of mine put together in Lyon, France. That's for really dangerous organisms—Ebola. Nobody works with Ebola. You can work with Ebola DNA, or you can work with Ebola genes; you just can't work on Ebola virus. If you want to study a vaccine for Ebola, you've got to do it in a level four.

ZIERLER: At the time the NIH creates these biosecurity levels, I assume scientists beyond biologists need to get involved, because it's now about fluid dynamics, now it's about materials science.

BALTIMORE: Yeah, and a lot of engineering. There's a lot of engineering that goes into it, yes.

ZIERLER: Is that what you wanted? You wanted the NIH to come up with these levels? That was the goal?

BALTIMORE: Right. Because we wanted to free up the low-level experiments so they could move ahead, because there was so much to be done, such important science. We didn't want the dangers to stop the easy things, because we didn't think they were dangerous.

ZIERLER: What were the discussions about what fit into each category? To go back to Watson—"you're all sissies"—there's obviously disagreement about what's dangerous and not. What were those discussions like to make those determinations?

BALTIMORE: Watson and Lederberg and a couple of other people felt that you didn't have to worry about these things because nature would take care of itself. It was never going to actually turn on us. It was just that kind of inchoate belief that there were mechanisms in the natural environment that would be protective.

ZIERLER: Faith-based science?

BALTIMORE: Yeah, it's a little bit that. [laughs] That was their feeling. I don't think they could prove it. We had stuff that could only be done at level three, and stuff that could be done at level two.

ZIERLER: Would the lawyers now be happy that if you were working under protocol, you were doing everything right according to the NIH regs, the liability issue would go away if heaven forbid something happened?

BALTIMORE: No, I don't think lawyers will ever give you that assurance.

ZIERLER: Right. [laughs]

BALTIMORE: That's not their job. They were just making sure that people took seriously their responsibilities. I'm sure that they were, from their point of view, happy to see that we were trying to do what we could to be responsible citizens. You've got to recognize that no meeting like this was ever held before, and that's why it has become an icon. People talk all the time about the Asilomar meeting, Asilomar process.

ZIERLER: Probably the closest analog would be the Manhattan Project.

BALTIMORE: Right, but physicists—partly because that was secret. There was never an open meeting held about whether it was dangerous. There were physicists who took seriously the dangers of atomic energy. When we first called for a moratorium and called for a meeting, we were aware of the analogy to the atomic scientists, and in a sense we were trying to get out there in front, get out into a position that they never got into because it was a secret and had government support.

ZIERLER: When the NIH put these regulations out, did that transfer to Congress in terms of legislation, appropriations of funds to support the creation of these facilities?

BALTIMORE: NIH as an agency of the government could do those things itself, without further legislation, and had that authority.

ZIERLER: Executive order?

BALTIMORE: No, regulations for people who are getting NIH grants. That was their authority.

ZIERLER: But again, this still doesn't cover other countries, industry.

BALTIMORE: No, it didn't cover lots of things, and interestingly, once the regulations were in place, industry voluntarily said, "We will follow." Once the U.S. had regulations, many other countries used that as a framework for making regulations.

ZIERLER: This would have been too early for Big Pharma to be thinking along the lines of therapies?

BALTIMORE: Yep.

ZIERLER: There wouldn't have even been at this point a financial incentive to skirt NIH regulations?

BALTIMORE: No, there was nothing they could do at that point. It took another, well—

ZIERLER: Late 1980s?

BALTIMORE: No, late 1970s, Genentech is formed. Biogen is formed.

ZIERLER: Where some of these techniques are relevant now?

BALTIMORE: Yeah, they're based on these techniques. The existing pharma industry is very slow to recognize how important this is and to pick it up, and it takes the venture capitalists to build new companies.

The Recombinant DNA Revolution

ZIERLER: That's the backdrop. You get this accomplished. It's the Spring of 1975. The sabbatical at Rockefeller is Fall of 1975. Let's rewind back to my original question—your motivations for taking the sabbatical.

BALTIMORE: Because of the recombinant DNA revolution, I had a feeling that I could be working at a different biological level—I didn't have to stay with viruses—and in particular, that I could work on mice. I had already had this itch to work on the immune system, and that itch went back to when I was first at the Salk Institute and was introduced to immunology and introduced by really brilliant people like Mel Cohn, who saw the nature of the problem of understanding how antibodies are made in particular. I think I said this already—Tonegawa had shown that at the heart of the B cell is a rearrangement of DNA, so the recombinant DNA methods are naturals for analyzing this process. How does it work? What does it do? Which DNAs are involved? How are the genes organized to fit into this? When I came back from sabbatical in 1976, I encouraged my laboratory to move into immunology. Now, what did I do over the year of the sabbatical?

ZIERLER: Let's talk first about the toolbox. What were the tools that were available to you where you now said, "Let's open this up, immunology, let's do this"?

BALTIMORE: They were the synthetic tools, the ability to make DNA molecules, to capture them, to replicate them up in bacteria, to analyze their structure using restriction enzymes. The DNA molecule now becomes a manipulable and characterizable entity.

ZIERLER: Including ability to sequence it?

BALTIMORE: Soon including ability to sequence it.

ZIERLER: Why Rockefeller? Why couldn't you just stay put? What was going on at Rockefeller at that point?

BALTIMORE: I wanted to get out of MIT for a while. I loved MIT. I wanted to come back.

ZIERLER: Just a breather?

BALTIMORE: Yeah, I wanted to take a sabbatical. I had been there seven years, and I thought taking a sabbatical was a good thing for an academic.

ZIERLER: Recharge the batteries?

BALTIMORE: Yeah. In particular, because I had been thinking about immunology, I wanted to go to a place which had good immunology.

ZIERLER: What was happening at Rockefeller at that point?

BALTIMORE: Actually probably left to my own devices, I might have gone to Australia, because the Hall Institute there was a major center in immunology—Sir Gustav Nossal. I thought about Australia. I thought about England. For some reason—and I don't remember exactly what, maybe Alice knows—I decided I just didn't want to be that far away from my lab. Because I had a big lab doing all these things; I wanted to keep tabs on it. And if I was just in New York—

ZIERLER: It's a train ride away.

BALTIMORE: Right. Phones weren't so good then, and we didn't have an internet. But it was a sort of chickening-out decision. I knew Rockefeller would be a good place to be, because it was just well set up. Jim Darnell was there, and I had worked with Jim before, and so I chose to go to his lab.

ZIERLER: He was doing immunology at that point?

BALTIMORE: No, he wasn't, but he was doing work on mammalian messenger RNAs and he was doing sort of the molecular biology of mammalian cells, so there were all sorts of things I could learn how to do. There turned out to be as senior postdoc in his lab who took me under his wing and taught me how to do all sorts of things, named Warren Jelinek. The Nobel Prize is announced in October; I arrived there in September.

ZIERLER: Put a kink in your plans, didn't it?

BALTIMORE: It made life much more complicated. Oh, and my parents were in New York. That was also important.

ZIERLER: That was nice. To go back to something you said earlier, the idea was the Nobel Prize was coming but it could take 10, 15, 20 years.

BALTIMORE: Probably more.

ZIERLER: Fall of 1979, that's not on your radar. This is not supposed to happen at this point.

BALTIMORE: Right. 1976.

ZIERLER: The announcement is?

BALTIMORE: You said 1979.

ZIERLER: 1975.

BALTIMORE: 1975. It was the Fall of 1975, right.

ZIERLER: Where were you when you got the call from Sweden?

BALTIMORE: That's a story in itself. In the first week of October of 1975, Alice is in Copenhagen for a meeting to talk about work that she has done. It's a leukemia meeting. I could have gone there, but I didn't. Also, we had a newborn, born in 1974, so she was one. We had a nanny living with us in New York but we didn't want to both be away. Alice is at this meeting, and she's at a session on—it turned out to be the day the Nobel Prize was announced—at noon at this meeting, and a very well-known Swedish virologist named George Klein, is chairing the session. George says to her, "Take all the time you want." Nobody ever says that. She and the other people in the session give their talks, and George gets up and does something which he does very eloquently and was well-known for, which was to summarize the session. George summarizes it—it must be getting to 11:30—and George says, "I don't have anything more to say"—to the audience—"but the Nobel Prize is going to be announced in half an hour in Sweden, and I know who's going to get it, and I think you all should know, because it relates to leukemia." He announces that Howard and I and Renato Dulbecco are going to get the prize.

ZIERLER: Violating all kinds of protocols in the process.

BALTIMORE: Yeah, right, jumping the gun by half an hour.

ZIERLER: But again, there's no Twitter so it's pretty self-contained at that point.

BALTIMORE: It doesn't matter a half an hour one way or the other. Alice runs out of the meeting to call me, and wakes me up.

ZIERLER: This is, what, 5:30 New York time?

BALTIMORE: Right. And first says, of course, "There's nothing wrong" because the only reason people called in those days was when there's a problem. Then she said, "I hope this isn't going to spoil you." It's the first words out of her mouth.

ZIERLER: [laughs]

BALTIMORE: And she tells me, so I'm the only person to ever be told by their wife they won the Nobel Prize.

ZIERLER: I've talked to many Nobel Prize winners, and they've all gotten the call from Sweden direct.

BALTIMORE: Right.

ZIERLER: Did you act surprised when Sweden called? What did you do?

BALTIMORE: Yeah, I guess I did. I didn't tell them I knew already. Well, no, I did tell them I knew already, because I did know already, but I knew already from the newspapers, because they were calling, and they had found me, but the Nobel Committee hadn't found me, because I was on sabbatical. I literally had just moved into this apartment in New York. It took them a little while to trace me down, and meanwhile the press was calling. When they discovered I was in New York, The New York Times came over as fast as they could, and they took all sorts of pictures of me. My daughter was wandering around on the floor, so they said, "Pick her up" and they took pictures with me and her. The next morning in The New York Times, there is a picture of me holding Teak on the front page of The New York Times, and it was the first time a baby had ever appeared on the front page of The New York Times.

ZIERLER: Wow! [laughs]

BALTIMORE: That's a great story. When my daughter was 18 or 21 or something, a friend of hers was working at The New York Times and went into the morgue and dug out the pictures this guy had taken and had a couple framed and sent to her as a gift. Is that picture here somewhere? No, it's not here.

ZIERLER: You have it somewhere though?

BALTIMORE: Oh, yeah. That disrupted my life.

ZIERLER: That was probably one of your first reactions—"This is going to mess up the research."

BALTIMORE: Oh, yeah. I didn't know what I was going to do. It turned out to be even useful that I was in New York, away from my lab, because there was just all sorts of stuff that I had to do.

ZIERLER: Did MIT want you to come back and give a conference?

BALTIMORE: Actually, what I did that morning—I'm alone in New York and I hop on the Eastern Airlines shuttle and go to Boston so that they could hold a press conference in Boston, and have a party, and—

ZIERLER: Who was the president of MIT at that point?

BALTIMORE: Jerry Wiesner was president, and Jerry met me at the airport. It was very important to him, I think, and I wanted to be at MIT.

ZIERLER: What do you remember from the press conference?

BALTIMORE: Oh, it was full of the usual questions. "Where were you when it happened? What are you going to do with the money?" It was nothing very deep. I was not ready for anything very deep. Then actually one of my friends on the faculty organized a party that night, and then I came back to New York on a shuttle the following morning, I think.

ZIERLER: When did you get in touch with your fellow recipients?

BALTIMORE: I don't remember. I don't even think that I talked to them right away.

ZIERLER: Those couple of days must have been a blur.

BALTIMORE: Exactly, and they are a blur in my memory, partly because I wasn't home, partly because Alice wasn't home. She gets on the next plane and comes, but that takes a day. She had a party in Copenhagen. People still remember being at it.

ZIERLER: When is the ceremony? When do you go to Sweden?

BALTIMORE: December 10th. It's a long time. That's why I say being in New York was not a bad idea because I could focus on, "I have to give a speech. I have to—"

ZIERLER: But it's quieter than at MIT.

BALTIMORE: Right.

ZIERLER: Did you get any research done between the announcement and Stockholm?

BALTIMORE: Not much in that time, but I did get some work done then the following spring.

Pomp in Stockholm

ZIERLER: Tell me about going to Stockholm. What was it like?

BALTIMORE: Oh, it is a fairy land. Because the Swedes have a functioning royalty, they basically lend the royalty to the Nobel Prize. One of the dinners is held in the palace, and the king and queen are there. He didn't have a wife, then. He was a very young new king. But he borrowed the queen of Denmark, I think. You get on a plane in New York, and land in Sweden.

ZIERLER: Were you able to bring your parents?

BALTIMORE: I was. My father was in the hospital when it was announced, and heard about it on television, because they closed down communications until 8:00 in the morning in the hospital, and they put him back in the ICU because they were worried about the effect on him.

ZIERLER: He was sick at that point?

BALTIMORE: Yeah, he had a heart problem and prostate problem. He was quite sick.

ZIERLER: But you were able to get him to Sweden?

BALTIMORE: Right. And whether he really remembered it all, we never knew.

ZIERLER: How much longer did he live?

BALTIMORE: He lived until I guess the following September, but very diminished.

ZIERLER: We didn't talk about this. We didn't do the early childhood. Your father, he was frum? He was religious growing up?

BALTIMORE: Yeah, and from the Lower East Side of New York.

ZIERLER: And then when did he go off the derech? As a child? When did he stop becoming religious? As a kid?

BALTIMORE: He wasn't Hasidic. He was Orthodox.

ZIERLER: No, but he was Shomer Shabbat, Kosher, right? And your mom was too, or no?

BALTIMORE: No, my mother was from a very areligious family, an almost anti-religious family, from the sort of socialist wing. Slightly wealthier than my father's family, and more stable. My mother's family, he was a tailor, but a moderately successful tailor, I guess, and had two daughters, and his wife. Although I never met my grandfather, on my mother's side, my grandmother lived with us for a long time. Both of my father's parents died when he was young, and so I never knew them. Famously his sisters—he had three sisters—left school and went to work, to support him so that he would graduate from high school, which he did. He was very smart and very effective, and interested in many things.

ZIERLER: He was secular by the time he married your mother, or that got him more secular?

BALTIMORE: I don't know the answer to that. He must have been pretty secular by the time they met, because otherwise they wouldn't have gotten together.

ZIERLER: You growing up, he didn't have tefillin, he didn't do any of that stuff by that point?

BALTIMORE: No, he didn't. But we did fast.

ZIERLER: You did the big stuff?

BALTIMORE: We did the big stuff. We walked to shul, which was a healthy walk.

ZIERLER: Sure. It's the suburbs; it's not the Lower East Side.

BALTIMORE: Right, exactly. There was a Conservative shul. I remember Herman Wouk was in that shul. I was much more on my mother's side in this, and so was my brother. We didn't really care very much.

ZIERLER: Back to Sweden. You've got your parents there. Who else was able to come?

BALTIMORE: We didn't have Teak come, because she was only one, and it wouldn't matter. She'd just be a nuisance. She wouldn't remember it. But we did invite my brother and his daughter, who does remember it. She was just talking to me about it.

ZIERLER: What about Alice's family? Anyone able to come?

BALTIMORE: No, I don't think anybody from Alice's family came. My brother, his first wife committed suicide, and then he was remarried, and I just can't remember who came, but the daughter is the daughter of his first wife. She may have come.

ZIERLER: When you sat down in New York to write the speech, it's an unparalleled opportunity to talk about your work. What did you want to convey? What was most important to you?

BALTIMORE: Basically the joy of working with viruses, and what you can learn from it.

ZIERLER: Did you want to convey the revolutions that were happening in biology that you were a part of?

BALTIMORE: No. The speech that you give is a speech to the scientists at the Karolinska Institutet, and the other Nobel laureates.

ZIERLER: They know that stuff.

BALTIMORE: Yeah, and it's basically a scientific talk, and it is meant to be, with the understanding that there are people there who are not versed in the particular science.

ZIERLER: Did you have any Nobel coaches at MIT who showed you the ropes?

BALTIMORE: No, I just did it myself. But the opening paragraph of that talk, I have quoted many times, quoting myself, because it talks about the pleasure of working with viruses. I can't quote it now.

ZIERLER: What's the pleasure in working with viruses? What did you want to say?

BALTIMORE: It allowed you to go down to the fundamental molecules of your pet organism and know it from the bottom up. I didn't say it that way.

ZIERLER: It's the most elemental level of biology, essentially?

BALTIMORE: Yeah, but if you treat viruses as an organism, and they are in a sense that, it was and still is the only organism where you can have a complete knowledge of everything about it, because it is simple enough. That means you can work at a very fundamental level in working with a virus. That was true and remains true.

ZIERLER: Like the quarks of biology, essentially? Like that?

BALTIMORE: Well, it's not like a quark, because it's not a building block.

ZIERLER: But in the way that a quark, we don't know if it's made up of any component parts.

BALTIMORE: Right, but we do know the component parts of a virus. We know them very well.

ZIERLER: Then what? It's the simplicity of a virus that allows us to know?

BALTIMORE: It's the simplicity that allows us to get down that far. Right.

ZIERLER: Did you talk at all about immunology, how you had just sort of moved into this field?

BALTIMORE: Well, because I hadn't yet. I hadn't even made the commitment to do it. My initial impetus of immunology was completely undercut by the Nobel Prize. Now I had to think about myself and about viruses, so it wasn't really until I left Rockefeller and got back that I could really think again about immunology.

ZIERLER: Going back to the late 1960s and early 1970s when you're very politically minded, did you recognize that the Nobel Prize offered a platform for you to take, if you wanted to, to elevate your political voice?

BALTIMORE: Yes. There was no question about it. In fact, you had to be careful, because you're now speaking not just for yourself but for your whole field, but the intense political involvement of the late 1960s and early 1970s had dissipated by that time, and so that wasn't uppermost in my mind. Uppermost in my mind was the position that I had within the field, and now I was not just an organizer of Asilomar, but sort of the royalty of the field.

ZIERLER: I wasn't thinking along the lines of Vietnam and foreign policy, but like bioethics, for example.

BALTIMORE: Yeah, I have had a role in that ever since, and there's no question that nobody ignores the fact that I'm a Nobel laureate. It's hard to avoid.

ZIERLER: Did you take the opportunity to hang out in Europe at all? Did you travel?

BALTIMORE: No. We talked to a number of people who had gone to Sweden before, and their advice was, "Just come back." Many of the research institutions in Europe would invite the Nobel laureates—"While you're in Sweden, would you come?" I turned all that down, and just simply got on SAS and came back. It really is like you're being transported out of a fairy tale back into ordinary life.

ZIERLER: Did that derail your plans at all for what you wanted to accomplish in the first place by taking the sabbatical at Rockefeller?

BALTIMORE: Yeah, it did, a lot, because really for that whole fall, I was involved in other things.

ZIERLER: The game plan, pre-Nobel announcement, Fall 1975, was to spend a year at Rockefeller immersing yourself in immunology, basically?

BALTIMORE: No, immersing myself in cell biology, because I had chosen to go to Darnell's lab and he didn't do immunology.

ZIERLER: That was a pathway to immunology, though? What was the connection?

BALTIMORE: It was a pathway, yeah.

ZIERLER: Explain that. How is cell biology the pathway to immunology at this point?

BALTIMORE: Immunology is about cells—B cells and T cells and macrophages and lots more—so you need to have the technical ability to manipulate cells, to put genes into cells, to get genes out of cells, to put genes together and take them apart. I wanted to develop those skills, but not focused on the immune system, because at Rockefeller at that time, there wasn't anybody who was moving in that direction. Had there been, I might have linked up with them. There was one guy [laughs], Gerry Edelman, and I actually approached him. Gerry was so insular, so unwilling to share what he was doing, how he was doing it.

ZIERLER: Which was what? What was his work?

BALTIMORE: He was working on the fundamental properties of the immune system. He was also by that time working on the brain. But he would have been a natural. And I knew Gerry, because he had been at Rockefeller when I was a student at Rockefeller. He was actually the dean, because he's considerably older than I am. But he was totally unapproachable and didn't offer me an opportunity to do anything. He would never have his people talk about what they were doing to anybody else. This was the worst sort of holding his cards to himself.

ZIERLER: Was that unique at a place like Rockefeller, or that was kind of how it was?

BALTIMORE: Rockefeller was that way more than most places, and the individual scientists were individuals. In fact, there were no departments.

ZIERLER: A faculty of Napoleons.

BALTIMORE: It really was. There were some people who were much more open. Darnell was very open. There were no independent young people. All the young people were in somebody else's lab, and if you were in Edelman's lab, you couldn't talk about what you did, even if you were an assistant professor or associate professor.

ZIERLER: After the rude interruption in Sweden, it's New Year's, January 1976. Do you go back to New York? What's the plan at that point?

BALTIMORE: Go back to New York. We were taking that year off.

ZIERLER: You still have eight months left on the year. The plan is to be back for fall semester 1976, like that?

BALTIMORE: I think so. I can't remember what I planned for the summer of 1976, whether I planned to go back in the spring, or in the fall. I don't remember.

ZIERLER: The plan is back to Darnell's lab in January?

BALTIMORE: Right.

ZIERLER: To basically pick up where you left off the previous fall? You did not change your focus, what you were after? It was the same mission, cell biology?

BALTIMORE: Right, and the kind of work that Darnell was doing, and Warren Jelinek, who was particularly helpful to me. It gave me a chance to do kinds of experiments I had never done before.

ZIERLER: What's the intellectual bridge to immunology at this point in your career? Why is this the next step for you? Are you thinking more translational at this point?

BALTIMORE: No, I'm thinking more about mammalian biology that's human biology, but it's in mice. Of all of the systems in the body, the immune system was the one that intrigued me, because it somehow could do this miraculous thing of making antibodies to things that it had never seen before.

ZIERLER: Like viruses?

BALTIMORE: Like viruses or chemicals. Any chemical made by Monsanto, when injected into a mouse, will yield an antibody that binds to that chemical, and yet the world has never seen that. Evolution has never seen it. It violates evolution. It turns out the answer is, it repeats evolution, and it's actually a form of evolution in the body. That was intriguing, and it was obvious that there was a lot of molecular biology in that, whereas if you wanted to work on the heart, for instance, there wasn't a lot of molecular biology in the heart. It was about electricity. It was about chemistry. It was about development. It wasn't about genetics so much. But the immune system did offer that challenge, and it was incomprehensible how it could possibly work, and we helped figure it all out.

ZIERLER: What was the foundation point of virology for you that you thought was an effective stepping stone to immunology? What had you learned up to that point that would be responsive to these foundational—?

BALTIMORE: We had learned how to manipulate the molecules—DNA, RNA. We had learned how to characterize them, how to cut them, how to—all of that. Now, a lot of that, I learned how to do in Darnell's lab. But in truth, when I left Rockefeller in the fall or whatever it was in 1976, I never did another experiment. I came back to MIT, and the combination of all the pressures that came from having won the Nobel Prize, people wanting me to do this, that, and the other thing, and my desire to do some of those things, the size of my lab which had gotten pretty big by that time, and the desire to move in new directions, just—I couldn't do it myself, and so I had to prevail upon my postdocs and graduate students to be the hands, and the heads in some ways, that would get us into this new field. Luckily, three or four of the people with me were absolutely enthralled by the idea of doing it. Fred Alt, who went on to be almost the premier molecular immunologist in the country. Al Bothwell, who I heard from recently, when my brother died. A guy named Enzo Enea, who I have lost track of. They became my immunology group. Then there were a few people I hired in to join that group.

ZIERLER: Did you do what you wanted to in Darnell's lab, even in that abbreviated time?

BALTIMORE: Yeah. I got the skills. I understood the methodologies.

ZIERLER: This was more learning techniques for you?

BALTIMORE: Yeah. I didn't want to do the kind of science he was doing. Not that there was anything wrong with it; it was just that's not what I wanted to do. But I did want to learn the methods.

ZIERLER: Were you managing the transition of your lab from afar? In other words, were you readying that when you got back to MIT, your lab would be doing new stuff?

BALTIMORE: No, we didn't start that until I came back. That's why I may have actually come back in the summer.

ZIERLER: What was the wrap-up research before this transition, at your lab at MIT?

BALTIMORE: I never wrapped anything up. I kept everything going.

ZIERLER: You just got bigger?

BALTIMORE: I just got bigger. In 1974, we had opened the Cancer Center.

ZIERLER: You had the space.

BALTIMORE: I had the space.

ZIERLER: New NIH grants to get bigger?

BALTIMORE: Yes. Actually, what I would do—I always did this—was to get grants to do something which I was in the process of doing, and so if I got a five-year grant, for the last three years of the grant, I had done everything I was going to do, and I would use the money to go in some new direction. Every time I moved in new directions, I basically used resources that I had gotten for doing other things. Don't tell anyone.

ZIERLER: [laughs]

BALTIMORE: It was the only way to fund yourself to do things.

ZIERLER: Not in reorienting your lab, but expanding it, what were the frontiers at this point, Fall 1976, immunology? What's there to do?

BALTIMORE: Everything. We don't know how the genes are organized. We don't know what mechanisms there are for rearranging DNA. We don't know anything about the biochemistry. I set about really in some ways doing the same things I did with viruses, but now in a much more complex, much newer and more difficult setting.

ZIERLER: Because immunology is inherently more complex than virology?

BALTIMORE: Right. In the end, we made three or four major discoveries.

ZIERLER: Let's take them in sequence. What's the first? Or at least what's the plan? What's the first big question?

BALTIMORE: The first question is—well, a question; I don't know if it's the first or not—is, how is the rearrangement of DNA accomplished? The mechanism. To do that, a graduate student of mine sets about to find out whether you can make genes move, rearrange, in a fibroblast cell, which is a cell which doesn't ordinarily rearrange its DNA at all, by transferring a capability from the immune system to a fibroblast. We set up a test of that, which involved a rearrangement of DNA that activated a gene which made the cell resistant to an antibiotic. You had a very precise selection, because you could treat with the antibiotic and kill every cell unless this had happened. Miraculously, he found a cell in which it happened. We published that, and it was a notable paper.

ZIERLER: What was so miraculous about the discovery? It was so unlikely? It was difficult?

BALTIMORE: It's just that it meant that the mechanism of rearrangement was something that was transferable.

ZIERLER: From what to what? What's the transfer?

BALTIMORE: From the immune system to this fibroblast. If it was transferable like that, you should be able to find out what it is. It meant that there was a discrete entity to be found, which was the gene that modified the fibroblast so that it could carry out this rearrangement, and we found it. It took this guy years of work, and he brought into it in a very wonderful way a new graduate student, and so in the end, the paper that really shows what goes on is written by both of them. Many people think I should have won a Nobel Prize for that, because it was so dramatic and completely set immunology on a firm basis.

ZIERLER: What's the timing of this? When does this paper come out?

BALTIMORE: I would have to look. It was probably around 1986.

ZIERLER: Oh, so really ten years?

BALTIMORE: Yeah. Maybe 1984? It's easy to find out. The other thing that was important—the antibodies are made from two proteins, really, what they call a light chain and a heavy chain. One is long; one is short. There are two genes that have to rearrange in order to make an antibody, the light-chain genes and the heavy-chain genes. What we discovered was it was the same enzyme was doing both of them. The RAG genes are what we called it—recombination activating genes. But how does that happen? Does it rearrange them both at the same time? Does it rearrange one and then rearrange another one? How do they fit together? All sorts of questions. We worked out almost all of that. A lot of it came from using cells transformed by Abelson virus. We talked about Abelson virus last time. That really opened up the biology of the immune system to investigation, to those kinds of cells, and they're still in use. That was a very important part of our work. How did we start out? We started out by just trying to clone the heavy-chain and light-chain genes. There are actually many of them.

ZIERLER: Why is that a logical starting place?

BALTIMORE: Because that gives you the material to ask about the rearrangement, to use them as probes for the structure of these genes in different kinds of immune cells. That's what we do to this day. But we needed these reagents and the one lab that was getting them wasn't giving them out to anybody, so I said, "Well, we're just going to make them ourselves, and we'll give them to anybody who wants them." Which we did.

ZIERLER: Was your lab an island at MIT? Were there other people doing immunology at that point?

BALTIMORE: No. Well, wait a minute now. When we opened the Cancer Center, which is 1974, there's a floor of immunology.

ZIERLER: Is that where your lab was?

BALTIMORE: No. I was in the virology section, and we had hired a senior immunologist, a guy who was very accomplished, sort of at the end of his career, and he then attracted a group of people. Herman Eisen. Herman was there, but he didn't do this kind of molecular immunology, and the people whom he attracted didn't except that we hired Tonegawa. Tonegawa was one of these very closed, controlling guys, and I made all the efforts in the world to work with him, but he just took advantage of me and never opened up. It was really sad.

ZIERLER: What was he working on that was of interest to you at that point?

BALTIMORE: Oh, everything, because he was working on the rearrangement process in T cells. I was working on B cells. When we set about trying to find the control regions for the genes, the promoters and enhancers, he was going after heavy chains, and I was going after light chains. You'd think we would have worked together, but I couldn't find out what was going on there.

ZIERLER: Where was he?

BALTIMORE: He was two floors down.

ZIERLER: What was that about? Culture?

BALTIMORE: Yeah, he was just a different sort of scientist. I told you about Edelman.

ZIERLER: Same thing?

BALTIMORE: There are those kinds of people.

ZIERLER: Like you were going to scoop him, or something like that?

BALTIMORE: Yeah, they're terrified that somebody is going to scoop them in some way.

ZIERLER: You'd think you had a reputation when you called Howard, that that's not who you are.

BALTIMORE: Yeah, you would think.

ZIERLER: What could you have gained had that been a more fruitful partnership?

BALTIMORE: Just the partnership, working together and we could have published together and whatever, helped each other with technology, but it was hard to. In the end, all of that work was done by people who were with me and then went off on their own. The next generation of people who came to work—Lou Staudt, Kees Murre, Fred Alt, a couple of other people—they all went off on their own and are today the strong people within molecular immunology.

ZIERLER: This was the breeding grounds for that?

BALTIMORE: Yeah.

ZIERLER: To go back to the fourth floor being dedicated to immunology in the Cancer Institute—

BALTIMORE: Actually, it was the first floor.

ZIERLER: Was that your foresight that you recognized that the Cancer Institute should have this dedication to immunology, even before you waded into it yourself?

BALTIMORE: Right. Because cancer—well, it's an interesting question. It was really because the kind of cancer that most people worked on at that time was leukemia, which is a blood cancer, and much of it involves the immune system. It really wasn't so much pure immunology as it was the immunological underpinnings of cancer. That's what Herman came to do. Herman had been actually a dermatologist, originally. That's how he was trained. He had gotten into the immune system because it's so involved in the skin, but he wanted to work in cancer, and so we were very happy to get him, because he was a well-known figure at that point, and turned out to be just fabulous to have, because he's very open, very nice, very thoughtful, very effective, trained good people.

ZIERLER: Let's talk about genetics at this point. 1976, 1977—where is the field? How is this relevant to what you are doing?

BALTIMORE: It's all genetics, in a sense, but it's now the genetics not just of organisms, but the genetics of cells. The immune system has its own genetics.

ZIERLER: That was understood at that point, or that's part of the evolution?

BALTIMORE: That's part of what we begin to understand, yes. It was only with Tonegawa's experiment do we start thinking that way.

ZIERLER: Why? What was it about his experiment?

BALTIMORE: Because he shows that there's DNA rearrangement in a cell of the immune system that he's working on. You just extrapolate from that, that that's going to be the future of immunology, and it was. Immunogenetics becomes a field, and is. Genetics overall is moving towards the sequencing of the human genome, and what breaks open human genetics in particular is the sequencing of the human genome. That happens over the 1990s.

ZIERLER: After the technology is available to do it?

BALTIMORE: Right.

ZIERLER: Is anybody talking in the 1970s about someday doing that? That's not even—?

BALTIMORE: It's not even on people's minds, no. It's not really until Lee Hood, working here at Caltech, automates DNA sequencing. He didn't discover how to sequence DNA.

ZIERLER: That was his advisor.

BALTIMORE: No, it wasn't his advisor. It was Wally Gilbert at Harvard and the guy's name I'm going to forget, in England [Fred Sanger]. The guy who discovered how to sequence proteins and then discovered how to sequence DNA. Got two Nobel Prizes for it. And Gilbert. They shared the Nobel Prize. It was a matter of chemistry that allowed you to sequence. It was clumsy and hard to do. I never did it. Lee took that clumsy system and made it sing. Now you could do lots of sequences, and you could imagine doing the whole sequence. That's in the late 1970s and 1980s that we're doing that. Renato Dulbecco actually writes to Science magazine, and in Science magazine there's a little article that says, "We have to sequence the human genome." He does it because he says that's the only way we're going to figure out cancer. Actually the guy who deserves the credit for setting the direction is probably Robert Sinsheimer, who was at Caltech. But Lee's technology changes everything. Lee deserves a Nobel Prize. As the technology became more and more doable, we started using it.

ZIERLER: Yeah, but again, this is all mid 1980s going forward.

BALTIMORE: Right.

ZIERLER: None of this is available—

BALTIMORE: No.

ZIERLER: You mentioned one big question for immunology. What were the others?

BALTIMORE: It was all the mechanics of the B cell, and what went on inside a B cell.

ZIERLER: Why is the B cell the linchpin?

BALTIMORE: Because it makes antibodies. It's the cell in the body that makes antibodies, and it first rearranges its heavy-chain genes, then rearranges light-chain genes, puts them together, tests very carefully whether they match and they make anything interesting, and then passes a quality control, and is sent out to do its job.

ZIERLER: Were there new instruments that you needed for immunology that you didn't have for virology?

BALTIMORE: No, it was the same instruments. Growing cells, extracting DNA, cutting DNA; it was all the same things.

ZIERLER: In terms of observation, what are you using?

BALTIMORE: Observation of?

ZIERLER: Like the microscopy.

BALTIMORE: Oh, we used better and better microscopes as they were available. All kinds of microscopes. Microscopes that see cells, electron microscopes that see molecules, basically anything that anybody comes up with. You don't really usually try to visualize molecules per se. You try to visualize some aspect of a molecule, like its size, and that, you can do wholesale. I've got the genome of a virus, and I cut it; it now gets smaller, and if I can size-separate the molecules, I can watch the cutting process by the loss of a big molecule and the gain of a smaller one. I can determine the kinetics of the enzyme that's doing that by freezing samples throughout the reaction and running them all in a size fractionation. Size fractionation is a very powerful tool. But we're not actually looking at the molecules. We're staining whole populations of molecules, just by the rate at which they move in an electric field, for instance, or the rate at which they move in a centrifugal field. We've done tens of thousands of size fractionations. It's a fundamental tool that I've used my whole career. We used microscopes, and in particular for the characterization of cancer cells, but I'm not much of a microscopist.

ZIERLER: To go back to the biosecurity stuff, was that relevant at all as you were moving into immunology?

BALTIMORE: No.

ZIERLER: Because none of this is dangerous?

BALTIMORE: Right.

ZIERLER: What about elsewhere in the Cancer Institute? Had that framework changed things, made people feel more comfortable?

BALTIMORE: It certainly did allay the fears of Maury Fox and other people in the department, because it got us out of their hair into a separate building. They didn't have to worry about us anymore.

ZIERLER: It's a counterfactual—you can't prove it negative—but retrospectively, is there anything obvious where you can point to and say, "Because of these regulations, because of what we did, we prevented such and such a thing from happening"? Or what did we learn about drug resistance or transmissibility that might have made those initial concerns overblown, or not?

BALTIMORE: We never found a situation in which there was real danger, where anybody was hurt or anything was released that caused a problem, in phase one, two, three experiments. Much of what was done by the Recombinant DNA Advisory Committee in advising on containment of experiments was probably unnecessary. We're now in a much more permissive regime. The only things that are really dangerous are things that are biologically dangerous, like Ebola virus.

ZIERLER: Or COVID?

BALTIMORE: Or COVID. COVID we don't actually contain very much, because it's everywhere, but Ebola we contain, even though there's places where it's a natural infection, but we certainly don't want it to be a natural infection in the United States, so we only work on the live virus in very high containment facilities. But they would not have been built, were it not for an understanding of where real danger is to be found and how you prevent it.

ZIERLER: Zooming out from your lab, mid 1970s, late 1970s, what else was happening in immunology around the country, around the world? What were some of the other major labs at that point?

BALTIMORE: There were a lot of people working in various aspects of immunology—T cells, B cells. There are two kinds of immune systems. There's the innate immune system and the adaptive immune system. The innate immune system is something that we all have, or all organisms have, but it doesn't differentiate one virus from another or one bacterium from another very well. The adaptive immune system is extremely precise, and it involves antibodies on the one hand which see individual molecular shapes, basically, and distinguishes one virus from another, one bacterium from another, one molecule from another.

There are two kinds of immune cells. There are B cells that are involved in making antibodies, and there are T cells that make the same distinctions as antibodies do, very precise distinctions between bacteria, for instance, or cells, but don't make a soluble, binding molecule like an antibody. They're all attached to cells, and they're really guiding cells in their behavior. But they involve rearrangement of DNA to make their specificity. There are two classes of specificity: there's T cell specificity and B cell specificity. Since it was discovered that there are T cells and B cells, which was only discovered in the 1960s, if I remember correctly, people have worked on either B cells or T cells or both. T cells are formed in the thymus, and so the thymus gland becomes a central focus of many people's interests.

B cells are made in the bone marrow. That's actually not where the "B" comes from, but it seems like it should be. There's a whole class of people working on that. The number of people working in immunology has just increased and increased and increased, over the period from when Tonegawa first did his experiments to today, because it has just become clearer and clearer what the power of the system is, what the different components of the system are, how they work. That just gives a scope for more and more scientists to find a niche for themselves.

ZIERLER: In your lab, was the focus on adaptive and innate?

BALTIMORE: No, almost entirely on the adaptive.

ZIERLER: More interesting stuff to work on there?

BALTIMORE: It's not that. It's that the DNA rearrangement doesn't relate to the innate immune system, and it was that kind of molecular gymnastics that drew me into the field.

ZIERLER: What's the better way to think of it? One immune system that has these two aspects, or it's two separate immune systems?

BALTIMORE: It's one immune system that has two aspects, because they are in many ways related to each other. They relate to each other in many ways.

ZIERLER: As the field matured, was there a convergence, or more of a divergence in research on the adaptive versus the innate aspects of the system? In other words, were people in the community detecting more differences or more similarities?

BALTIMORE: I don't really know. Well, no, the innate immune system involves fixed molecules. They don't rearrange. They don't change their specificity or nature. The people who work on it are different. They do different sorts of things, because they're working with a fixed system. There is one very key molecule, particularly in relation to defense against viruses, and there's interferon. Interferon is a whole biology of its own, but it's a central component of the innate immune system. But there are lots of others. There are literally hundreds of molecules.

ZIERLER: When did you start thinking about vaccines, perhaps the crossroads of virology and immunology? This was way too early for that?

BALTIMORE: Yeah, I started thinking about vaccines when the HIV epidemic hit, because it was instantly evident that the only way to put that genie back in the box was with a vaccine. We've never been able to make one. It has turned out for good structural biological reasons to be the most difficult vaccine that anybody ever set out to make.

ZIERLER: Did you see the recent alert that Moderna is doing an mRNA vaccine for HIV?

BALTIMORE: I wish them well.

ZIERLER: You're not hopeful?

BALTIMORE: It's not going to happen.

ZIERLER: Why not?

BALTIMORE: We don't know how to make a vaccine. We don't have the design work. If we knew how to design one, then it could be delivered by Moderna. I don't know what they're doing, but I—

ZIERLER: That's hype?

BALTIMORE: I think so. Or wishful thinking.

ZIERLER: COVID has not pushed along the research in a way that wasn't possible before? That's not a factor here, you don't think, just fundamental research in mRNAs?

BALTIMORE: You mean push along HIV?

ZIERLER: Right.

BALTIMORE: No, because the problem with making an HIV vaccine is intrinsic to the molecules that would make up the vaccine. Why don't we have an HIV vaccine? There are actually four or five reasons why, but fundamentally it's because the molecule that binds the virus to a cell has tremendous plasticity, and so it can keep mutating itself and avoiding antibodies in the process, and still be able to carry out the function of binding the virus to the cell.

ZIERLER: And for example, coronaviruses don't do that?

BALTIMORE: No, coronaviruses have this fixed spike that is much more rigid and much less plastic. In fact, there's no virus except flu which comes close—

ZIERLER: For which we do have a vaccine, obviously.

BALTIMORE: We do and we don't. We have a vaccine but you have to have a new one every year.

ZIERLER: That doesn't count as a real vaccine?

BALTIMORE: Right.

ZIERLER: A real vaccine should be like MMR, one and done?

BALTIMORE: Right.

ZIERLER: That's interesting. What does that tell us about immunology? What counts as a real vaccine and what is an arms race every year?

BALTIMORE: It's more about the organisms. It's because of the plasticity of flu or of HIV that they don't lend themselves to making a vaccine. It has nothing to do with the immune system. The amazing thing is something like polio is absolutely rigid and does not vary from one generation to the next, so the same vaccine works forever.

ZIERLER: We're very lucky that in the very early days of biology in the 1950s, we had a stable virus that we could figure out how to make a vaccine for?

BALTIMORE: Right, very lucky.

Early Impact of the HIV Epidemic

ZIERLER: Last topic for us to discuss today, let's figure out when the HIV epidemic hit, and what your reaction was then. The very early days, when it was whatever people thought it was, like a pneumonia of gay men, something like that, what are your early memories of news reports, hearing about this? What were your reactions?

BALTIMORE: From the time I heard about it, when we didn't know what caused it, I assumed it was an infectious agent.

ZIERLER: As in not a virus?

BALTIMORE: No, a virus or a bacterium, it could be, but a virus was the most likely cause of it. All of this stuff about poppers and gay life was all just so obviously prejudiced against gay men and gay life. It involved a world that I had absolutely no connection to.

ZIERLER: Sure, and it was a secretive world back then, as well.

BALTIMORE: Yeah. All I knew was that it turned up in artistic circles, and that famously there had been all these gay artists, but that's all I knew.

ZIERLER: What about intravenous drug use, people who shared needles? Did that register right away or that came later, in terms of people who were suffering from this?

BALTIMORE: Oh, no, that came very quickly, because if the virus was a bloodborne virus then people sharing needles were sure to share the virus.

ZIERLER: The lifestyle thing, was it immediately understood that risky sexual behaviors was what was causing this? In other words, if you saw intravenous drug users, connecting that to blood, what might be the biological basis for understanding why a particular group of people engaged in a particular kind of sexual activity would also be victims of this?

BALTIMORE: It was initially confusing, and I certainly didn't know enough about what went on in the gay world to know how the transmission was occurring.

ZIERLER: Did your lab get involved right away? Did you change gears at all?

BALTIMORE: No. I was doing other things. It didn't occur to me to change, until 1986. We first became aware of it in 1981, 1982, but in 1986, I was asked to co-chair a committee of the National Academy of Sciences on a study which ended up being called Confronting AIDS. I was chosen for a variety of reasons, but the fundamental reason was that I worked on retroviruses, and it was known to be a retrovirus by that time.

ZIERLER: Who was responsible for that discovery that it was a retrovirus?

BALTIMORE: It was famously either the French or Bob Gallo.

ZIERLER: There's some dispute there?

BALTIMORE: Oh! More than just dispute, but the French got the Nobel Prize for it, and Bob Gallo didn't, so take that for what it's worth. I think it's clear that the French first saw it.

ZIERLER: Were there any other retroviruses that destroyed the immune system in the way that HIV did?

BALTIMORE: No, not at all. It's a very different retrovirus from the ones that had been characterized as causing cancer.

ZIERLER: How useful of a classification is retrovirus, then, if HIV is doing something that has never been seen before?

BALTIMORE: Because from a molecular point of view, it does the same thing as a cancer-causing virus. That is, it's an RNA virus that copies itself into DNA, so that it can integrate into a cell. That's what makes it retro. The retroviruses that we associate with cancer, when they integrate themselves into a cell, the consequence is that the cell changes its growth habit and becomes a cancer cell. When HIV integrates itself, it actually in the end kills the cell, and so the integration is not a stable part of the cell's lineage; it's an intermediate in the growth of the virus.

ZIERLER: It's not a parasite; it's a destroyer.

BALTIMORE: Right.

ZIERLER: Was there any discussion that AIDS, or whatever was thought to be the disease caused by HIV, was actually a new form of cancer? Did people investigate that at all, or was it obvious that it couldn't be that?

BALTIMORE: It didn't look like it was a new form of cancer, except that there was a cancer associated with people suffering from AIDS called Kaposi's sarcoma, but pretty quickly it was shown that Kaposi's sarcoma was caused by a herpes-like virus.

ZIERLER: Which is also something from a lifestyle perspective that's going to be a—?

BALTIMORE: No, it's something that many of us harbor but can be activated by an HIV infection. HIV does cause the Kaposi's—your probability of getting it without that is negligible—but it's not the HIV virus that causes the cell to grow; it's the herpes virus.

ZIERLER: When do you meet Tony Fauci? When is he a player in this for you?

BALTIMORE: In the early stages of the HIV epidemic, I met Tony.

ZIERLER: Was he part of you joining this program in 1986?

BALTIMORE: No, that was the National Academy of Sciences. That was non-governmental. It was in fact a response to the government's very poor preparation for handling the HIV epidemic. If you remember, it was the period where Ronald Reagan was president.

ZIERLER: Yes. I wonder if you might comment on the historical parallels of Reagan and Trump, and HIV and COVID.

BALTIMORE: There are real parallels there, but Reagan simply didn't want to hear about gay men and didn't want anything to do with HIV, and never even talked about HIV. It was an embarrassment that it was clearly an American problem. It wasn't only an American problem, but it was an American problem, and rather than marshaling a research effort to understand it, we were just doing nothing. When I was asked to head this committee, it really was with an understanding that we needed to prod the government to take it seriously. And it worked.

ZIERLER: Obviously you were not in Los Angeles or New York at this point. Was there a gay community in Boston that got hit hard by this?

BALTIMORE: Absolutely.

ZIERLER: Was that close to home for you? You saw it, you experienced it?

BALTIMORE: Yes. In fact, a good friend of ours in Boston, a photographer, took pictures of AIDS patients as they were dying. I have a series of them somewhere that he gave to me. Nick Nixon, by name. Nick Nixon lived down the street. I taught a course at MIT using his pictures of AIDS patients. It was everywhere, but it was prominently in the Boston area.

ZIERLER: What was the impact of the National Academies group?

BALTIMORE: We did a very scholarly study of everything, and—

ZIERLER: And you remember, you chaired it? Where were you on the committee?

BALTIMORE: I co-chaired it, with a physician named Shelly Wolff, now deceased. Shelley was a bacteriologist, but was an MD, was on the medical side.

ZIERLER: Why a bacteriologist for this?

BALTIMORE: He was just a very good person to head a committee. He was an infectious disease doc, so the fact that he worked largely on bacteria was irrelevant. We put together the evidence about what was going on and wrote a scholarly report. As we were finishing it, I said to the committee, "There's one thing missing. We don't make a recommendation of how much money should be spent on it. In the political world, it's money that talks." I said, "I think we should recommend that we have a program spending a billion dollars a year." That was totally audacious.

ZIERLER: Which would put it on par with what? What is a billion dollars?

BALTIMORE: Nothing.

ZIERLER: Nothing like that?

BALTIMORE: I think the total NIH budget may have been $2 billion at that point. No disease had ever gotten anything like that.

ZIERLER: Let alone one that was perceived as a gay and drug user disease.

BALTIMORE: Right. We never wrote a budget that added up to a billion dollars; we just simply said, "A billion dollars."

ZIERLER: Was part of that rooted in the concern that HIV would branch out to affect more people than gays and drug users?

BALTIMORE: We never knew when that might happen. We didn't really understand why the virus was so associated with gay life. But, right, we were really terrified that the virus was going to—or that the virus might alter itself, mutations. You needed to take it seriously.

ZIERLER: Like, could it become airborne? Was that a concern?

BALTIMORE: It certainly was a concern. I don't think it was a terribly well-founded concern.

ZIERLER: But that would have been a Black Plague. That would have been the 1300s all over again.

BALTIMORE: Yeah, but it was so different than anything that we had ever seen before that you just didn't know how to put boundaries around it. We should have been treating it with that seriousness from the very beginning.

ZIERLER: Were there any heroes working behind the scenes in the Reagan administration that were moving the levers of power even if the president himself was not?

BALTIMORE: Tony was, but had to be very careful. Yeah, there were some others, but they were being very careful.

ZIERLER: Where were the activists at this point, with the National Academy? Did they influence the panel at all?

BALTIMORE: No, not a lot. They were in the streets and were putting their pressure on Tony in particular.

ZIERLER: Fairly? Effectively?

BALTIMORE: And Reagan.

ZIERLER: What would you say in terms of what they were directing at Fauci?

BALTIMORE: Tony really, yes, was sympathetic, and he was trying to not go too far but still take them seriously. He did a good job of walking that line. Then Clinton became president and changed everything.

ZIERLER: That's 1992. This is still a long way off. This is a full—

BALTIMORE: Oh, wait a minute now.

ZIERLER: 1986 is the middle of Reagan's second term, and then you have Bush I for four years.

BALTIMORE: Right. That's what I'm missing. Well, it really wasn't until Clinton got in that we had an understanding at the executive level, but the research program ramped up from the time of our report.

ZIERLER: The billion dollars.

BALTIMORE: Yeah, and within about four years, we were spending a billion dollars.

ZIERLER: Who was the ask for? For NIH?

BALTIMORE: For NIH, yeah.

ZIERLER: Was that approved?

BALTIMORE: Yeah. Tony ran that whole program, from the start.

ZIERLER: Who in Congress were the key allies to make sure the appropriations went through?

BALTIMORE: I don't remember. I know some of the people. There was a guy from Ohio, a congressman—I'd have to go back and look. I just don't remember. But there were a few. Now that I think about it, there were a few congressmen in the House I think mostly—no, in both the House and the Senate—and in particular the ones who chaired the committee that gives money to NIH.

ZIERLER: Did you testify, ever?

BALTIMORE: I did.

ZIERLER: What was that like?

BALTIMORE: Oh, it's a show, really, but it was actually a pretty dramatic show. There were a lot of cameras around. We released the report at the Academy with a press conference.

ZIERLER: How did you conceptualize allocating the $1 billion? What's fundamental research, what's therapies, clinical opportunities?

BALTIMORE: As I said, we never drew up a budget to spend a billion dollars.

ZIERLER: But in terms of tackling the problem, what needed to go into the fundamentals and what needed to go into the clinical opportunities? I mean, people are dying in a big way here, so there's an urgency.

BALTIMORE: Right. It was the drug companies that produced the drugs. The first drug, AZT, was a cancer drug that was reprogrammed and made by Burroughs Wellcome, I think. Then the drug companies saw there was money in it, and they all set about to make their own drugs, and it was wonderful.

ZIERLER: Can you draw a line from what you were working on to the development of AZT?

BALTIMORE: Well, as soon as we knew it was a retrovirus, the kind of drugs that you would make were drugs that interfered with DNA synthesis. AZT was one of those, so it was really the discovery of the link to reverse transcriptase that gave the idea of chain-terminating drugs, which is what AZT is.

ZIERLER: What about vaccines? Did people think about vaccines from the beginning? Did it become immediately obvious how difficult that would be?

BALTIMORE: Yes, to both things. When Margaret Heckler, who was then the head of HEW, announced that Gallo had found HIV, the virus that caused AIDS, she said, "And we should have a vaccine within two years." As soon as you know it's a virus, the first thing you think about is a vaccine. History says you can make a vaccine against every virus that comes along, and we had been able to do that, up to that point.

ZIERLER: That's still true today? HIV is the only one?

BALTIMORE: That we can't—? Oh, no, hepatitis C also now, it's very hard to make a vaccine against. She was not taking into account, however, that the virus grew in the immune system. That fact, which actually doesn't prevent it from being attacked by adaptive immunity, grows in T cells, so the T cell side of the immune system is not much use, but the B cell side is still there, and as it turns out, makes very good antibodies. It's just that it eludes those antibodies, and so as the immune system makes better and better antibodies, the virus makes better and better mutations, and it just stays ahead of the immune system. The fact that it grows in the immune system is not as bad as it seemed at that time. But if you asked me, or I must say anybody I knew, did we think we'd make a vaccine in two years, the answer was no, that this virus presented us with a problem we had never seen before.

ZIERLER: On that point, last question for today. Given the fact that your lab is operating at a foundational point of immunology at this stage—late 1970s, early 1980s—HIV hits. What bedrock assumptions about immunology in general might be challenged as a result of what HIV is and what we can and can't do about it?

BALTIMORE: The fundamental one is the one that I just said. It's that the immune system is a wonderful way of protecting us against all viruses except HIV. HIV has shown a chink in the armor that we didn't know was there. That's probably the fundamental fact that still drives labs to work on this. I was just talking to a friend of mine who started working on the HIV vaccine back when we were at MIT, and he's still working on it. New ideas. Actually, he may have gotten somewhere.

ZIERLER: Kind of like a question of is there life beyond Earth, there's got to be other viruses—we only know about HIV, but common sense would dictate there's others out there, right?

BALTIMORE: I guess? I don't know. HIV is close to unique in the way it gets into the body and grows. It's not as if there's any other virus that looks sort of like it. Not really.

ZIERLER: Let's hope that remains the case.

BALTIMORE: Yeah, let's hope. Right.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, February 9th, 2022. I'm delighted to be back with Professor David Baltimore. David, good to be with you again.

BALTIMORE: Hello, hello.

ZIERLER: Today I'd like to return to the Asilomar meeting, 1974. Last time, we discussed some of the biological concerns that fostered the need for this conference, but the larger political context, 1974 and 1975, there's Watergate, there's Church and Pike on the Hill. The sense of democratization is in the air. I wonder if you or your colleagues saw Asilomar either in real time or in retrospect in some ways as democratizing science or making what you were learning sort of more publicly accessible.

BALTIMORE: Not that I remember.

ZIERLER: In the literature, it did have that effect. That's one of the things that is regarded as a legacy of Asilomar.

BALTIMORE: I can see how it did have that effect, but in organizing it, I can't remember ever discussing that dimension.

ZIERLER: We did talk about the journalists who were present.

BALTIMORE: Yes, we certainly opened ourselves to some journalists, and were conscious that there was going to be public interest, that journalists were going to bring up some of that, but that it being the first time scientists had done anything like this, it was going to get broad coverage, not only in the science press but in the general press.

ZIERLER: Was one of the effects with journalists being there and getting the word out that potential industrial applications of recombinant DNA technology, did that hasten that process, do you think?

BALTIMORE: Oh, it did, because it sort of advertised what was going on, and in the interviews of people who had been at Asilomar or people who thought about it, the industrial applications certainly were beginning to be discussed. It was very much a beginning, because we didn't have any experience like this. Nobody had ever tried to build an industry based on biology.

ZIERLER: Again, biotechnology is not yet a term at this point.

BALTIMORE: I don't remember when that word came up, but it was certainly later. The pharmaceutical industry has been based largely in chemistry, and was a derivative of the German chemical industry, and so this was something brand-new. It was particularly new for America, because a lot of the pharmaceutical companies actually had their origins in Europe. Merck did. But we saw it. We saw it as a possibility. I can remember giving talks myself in which I said that commercial applications potentially were enormous.

ZIERLER: Just long horizon, what were you thinking? What possible applications?

BALTIMORE: First of all, new biologicals. Protein biologicals. The example of insulin was there. It dated back to the 1920s, but we didn't have an industry that could make it. It was extracted from the glands of pigs. Now we had an industry that could make it, and the recombinant DNA—it wasn't a huge jump from where we were in 1974 to an industry that made proteins in bacteria.

ZIERLER: Was industry represented at Asilomar? Were they invited, or they caught wind as a result of the journalistic accounts?

BALTIMORE: As I remember it, the pharmaceutical industry almost uniformly ignored it. They said, "When the time comes, we'll deign to take notice. But meanwhile, this isn't for us." It was amazing to those of us who came from basic science, and just assumed—I mean, "Here's an opportunity; isn't industry going to jump on it?" No, it didn't. It took Genentech and Biogen and Genzyme, the companies that were formed to exploit the new science.

ZIERLER: What were some of the academic connections from these companies that might have suggested that of course they would be the pioneers in this field? Meaning that Genentech, were there scientists coming from universities?

BALTIMORE: Into Genentech, yes. They formed Genentech. Famously, there's a statue of it on the Genentech campus, where Bob Swanson who was a venture capitalist, young guy, graduated from MIT, got involved with Brook Byers and Kleiner Perkins, and he had a beer with Herb Boyer. Herb Boyer was a professor at UCSF. The famous experiment that generated Asilomar and generated the whole industry was the Cohen-Boyer experiment in which Stan Cohen at Stanford and Boyer had gotten together. Boyer and Swanson talked, and I don't know—I remember hearing, I don't have personal knowledge of this—that it really was Swanson who had the vision, and they started Genentech. The idea was to make a couple of proteins and sell proteins.

ZIERLER: All because of recombinant DNA?

BALTIMORE: Yeah.

ZIERLER: What were the applications of these proteins? What were they thinking?

BALTIMORE: One was insulin, to make a truly human insulin.

ZIERLER: For diabetes, I assume?

BALTIMORE: For people with diabetes, right.

ZIERLER: It must have driven the cost down tremendously.

BALTIMORE: Yeah, although the cost of most drugs, the manufacturing cost is a small part of the overall cost.

ZIERLER: Research and marketing?

BALTIMORE: Yeah, research and marketing, and profit, regulatory, all that sort of stuff. Yes, it probably did cut down the cost of manufacturing, although they had to build plants de novo, because nobody had ever made proteins on that scale before. They tried to make a small protein first. I forgot; it was a hormone. They also got into growth hormone. Those were the early products. Actually Lilly bought the rights to insulin. Lilly had always been an insulin company, but it took too much imagination for Lilly to make it themselves.

Growing Involvement in Biotechnology

ZIERLER: Did you ever sit on any of these boards? Were you an advisor?

BALTIMORE: I'll tell you my own history in a minute. It's sort of orthogonal to all of that. Then on the East Coast it was really Biogen that was set up all by scientists working with some venture people in the Boston area, and actually it was international. They first started with labs in Europe and the United States. The European part of it really didn't go anywhere.

ZIERLER: Is this the origins of Boston's what would be biotech startup culture? Was there anything before that?

BALTIMORE: I was involved in something before that, but it never got anywhere, largely because the management didn't have enough imagination. But Biogen was—no, there was another company, the Genetics Institute, also set up by scientists, Harvard scientists. In the end, it ended up in a quite famous patent fight with Amgen, which Amgen won, and effectively drove it out of business. In terms of where the tradition of startups came from, yes, Biogen and Genetics Institute were I think the two biggest. Let me go back a step. It's also critical to remember that it happened around the universities. It was university scientists. It was the university atmosphere that provided the people not only who started but worked in those companies. When I discovered the reverse transcriptase, one of the first kinds of experiments that I did, that we did, and actually another guy in the lab did [Inder Verma} was to see if you could induce the enzyme to copy a messenger RNA, because all messenger RNAs end with a string of A residues. If you had a primer to start synthesis that was T residues, it would start copying the A residues, and then it would go into the body of the messenger RNA. What we called oligo(dT), a small stretch of T residues, was extremely valuable, because it could start copying, and that's what everybody did, and that's what everybody is still doing.

But where would you get a string of T's from? It turned out that a Brandeis chemistry professor named Orrie Friedman had started a company about two years earlier—this was 1970 or 1971, so he had started it in the late 1960s—to make, synthetically, stretches of DNA. The reason he did it is because the National Cancer Institute thought they would be valuable in the manufacture of drugs or something. I was never sure exactly what they thought they were doing with it. But Orrie saw that there was a market, and he came from a commercial family. He was a Canadian, came from a Montreal family, so he was itching to use his chemistry commercially, and quit Brandeis, and started what he called Collaborative Research, because the chemistry was collaborative with research, or I don't know why he called it that. He had an inkling that there were going to be other uses for oligonucleotides, particularly homopolymer oligonucleotides. His company was just sort of potchkeying along. It wasn't going anywhere. Then I discovered a use for oligo(dT). Salvador Luria somehow knew what Orrie Friedman had been doing.

ZIERLER: What year is this, that you made this discovery?

BALTIMORE: It was 1970 when I made the discovery, so this is 1971, almost certainly. He said, "Why don't you talk to Orrie Friedman about this?" I contacted Orrie, and he said, "You want to buy this stuff? I'm selling it." I bought a lot of it from him, and other oligonucleotides, and I sort of became an advisor to him. Now in 1974, recombinant DNA technology comes together, and I went to Orrie and I said, "You should really develop a subsidiary or an aspect of Collaborative Research using recombinant DNA methods. This is going to be the best thing since sliced bread." Orrie was a chemist. Orrie wanted to use chemistry. The idea of using biology, of moving ahead, was foreign to him. But, we convinced him. Actually I got together with two other professors at MIT—

ZIERLER: When you say that using biology was foreign to him, what does that mean? Methodologically, instrumentation, his approach?

BALTIMORE: Anything. All of the above. Making biological molecules. It was nothing he or almost anybody else had thought about. But David Botstein and me and Gerry Fink saw this opportunity.

ZIERLER: Where were Botstein and Fink?

BALTIMORE: They were both at MIT. Actually I had just brought Fink to the Whitehead Institute. No, no, no I take it back; that's later. Gerry was on sabbatical and was going back to Cornell. But the two of them, Botstein and Fink, had developed yeast as a sort of surrogate—not surrogate; as a eukaryotic model organism—and yeast was as good as bacteria in your ability to grow it up and to make lots and lots and lots of it in short order. But it has a nucleus; that's the definition of a eukaryote, and therefore it's much closer to human beings, to mammals, than a bacterium is, in evolutionary terms, and does things in ways that are more like what higher cells do than bacteria do.

They were trying to convince the world that this was the organism, and they taught courses about it. They really deserve a Nobel Prize for that, because yeast became the organism in which we worked out how cells divide and all sorts of fundamental processes of cells, and recombinant DNA methods were just made for studying yeast. We said, "We'll set up the yeast company." We convinced Orrie to get behind it, and somehow, and I can't now reconstruct how, a guy at Harvard Business School got wind of this—I guess we funded it just from the money being made by Collaborative Research. Anyway, we set up a subsidiary called Collaborative Genetics and I'm not exactly sure what the financial arrangements were. Somehow we started this subsidiary but I've forgotten exactly how. A year or two later—oh, I know—Mitch Maidique, who was a professor at Harvard Business School, heard about the company and developed a case study, because they taught by the case method at the Business School, around Collaborative Research, because it was a whole new venture. He got so interested in this he said, "I want to sit on the board, and I want to take this company public." And he did. He made the first money I ever made, aside from salary, because he started this.

ZIERLER: Was this real money, or this was just the very beginnings? It was play money?

BALTIMORE: For me, it was real money. I don't remember how much, but probably hundreds of thousands of dollars. In those days, we owned stock, and—

ZIERLER: Did MIT have an established IP program? Did they have protocols for these kinds of things?

BALTIMORE: We didn't do this through MIT, because we weren't really using our technology. We were advising the company about what it should do.

ZIERLER: MIT was not looking for a cut at this point?

BALTIMORE: Maybe they had some stock in the company? I just don't remember. We actually started the first biotech company, because this is before Biogen, before Genentech. Why didn't it flourish? The answer is because Orrie Friedman was more interested in running his little company and selling his little bits of stuff than he was in being a real entrepreneur. We tried to convince him. We actually sold a contract to Monsanto for the synthesis of rennet. Rennet is what allows cheese to be made from milk, and everybody extracted the protein from calves, and we said, "Well, you can make it." We actually did—and they never got in the business. Anyway, the business end of it didn't work very well, but we were all tied to Orrie, because he was the linchpin. None of us wanted to—well, we didn't even have the experience—to become businessmen, and he had done it, and so forth, so we allowed him to control what happened, and it just never grew to be what it should have been.

Actually the first identification of a gene for human disease was done largely by work there, which was the cystic fibrosis gene. We were doing human genetics, we were doing yeast genetics. The company was actually doing a lot of important stuff. We had some very good people there, but there wasn't anybody who was able to connect it to the larger world. It was a small town. A good town, but a small town.

ZIERLER: Did you enjoy that, the business side of things?

BALTIMORE: I enjoyed thinking about it a little, yes, but I had other things I wanted to do. It wasn't compelling enough that it occupied a significant fraction of my life.

ZIERLER: Did you have a merchant streak in your blood going back to the Lower East Side, maybe?

BALTIMORE: I guess I did. My father was in business, and he was actually quite successful. My parents had said outright they didn't want me to go into business. They wanted me to go into an intellectual endeavor.

ZIERLER: Education first?

BALTIMORE: Right. My father, being a little more conventional, really wanted me to be a doctor, but my mother, who had deep interest in the science of human development, was perfectly happy to see me in basic science.

ZIERLER: Could have been worse; they could have wanted you to go to law school!

BALTIMORE: Right. [laughs] They could have. No, that never came up. It was medical school or—

ZIERLER: Was there a second venture after this, or that was your one and only foray into that world?

BALTIMORE: Oh, no, no, no, no, I've done many companies since.

ZIERLER: I mean, in the early days, though.

BALTIMORE: In the early days, yes. It was just that. Right. Because it was a side activity.

ZIERLER: Was this really pioneering stuff? Was there other science faculty at MIT or really anywhere else who were dipping their toe into the business world?

BALTIMORE: Yes, lots. The people who started Biogen, the people who started Genentech, my good friend—I was just with him on the phone—Phil Sharp—was one of the people who started Biogen, made a fortune from it, and he started a number of other companies since then. It was almost a joke by the mid 1980s that every successful professor in MIT biology had a company.

ZIERLER: What was the institutional response? The dean, the president, were they supportive of this? Was this a welcome development? I'm thinking of the exchange that Lee Hood told me with him and Murph Goldberger. Famously, Murph Goldberger said, "This is not what we do in higher education."

BALTIMORE: It was demeaning.

ZIERLER: Similar vein at MIT or it was not like that?

BALTIMORE: No, it was not like that at MIT. There are two strains that are very important in that regard. One was Jay Forrester, who developed semiconductor memory.

The Forrester patent made MIT a lot of money and was the lead idea for the development of MIT's Technology Transfer Office.

We had a woman—I think she is still alive, Lita Nelsen—and Lita sort of regularized the writing of patents and the licensing, helping people get started in technology. Originally did that around electronics, but when biotechnology hit, they could move in that direction. Famously, Stanford, the same thing happened. Stanford had a patent office and there was a guy there who led it whose name I don't remember, and when Berg first developed the recombinant DNA idea, and he and a guy named Lubin, who was a student of Dave Hogness, wrote up this idea for his thesis exam, of bringing two molecules of DNA together, Stanford wanted them to apply for a patent, and Berg, my very good friend—I was just writing to him yesterday—didn't want to patent it. He said, "That's not what I'm in business for. I'm a biochemist."

ZIERLER: Open access ethos?

BALTIMORE: Yes, absolutely. They put more and more pressure on him, and famously—you know how you get one year after, or you did then, of grace after a discovery to put in a patent, otherwise you can't and you lose the rights? The last day of that year, they finally filed it. Of course that patent has brought Stanford a fortune, because every company that started had to take a license. They also did a very smart job. Instead of trying to charge a lot, they charged a nominal fee, and so nobody every fought it, and it never really got tested, whether the patent was valid or not, because it was cheaper to take the license than it was to fight the patent. But they made millions of dollars, and the people who did the science made millions of dollars. Anyway, that's the story of Collaborative Research. At that point, I ended up getting involved in the Whitehead Institute, so that's 1980.

Creating the Whitehead Institute

ZIERLER: Whitehead opens in 1982, right?

BALTIMORE: 1984, actually, but it had to be built. My first meeting with Jack Whitehead was late 1980. I'm just saying that my interests moved much more to academic development than they did to industry at that point.

ZIERLER: Post-Nobel, would you get pitched more often than might otherwise be the case?—"Join our board," "start with this venture"—or it's still too early in the game?

BALTIMORE: It's still too early. That doesn't really start happening until 1980. For the first ten years, for the 1970s, there were a few things that happened and I've talked about them, but there are only a few things.

ZIERLER: Bookending Asilomar, in 1978 there's the Ascot report. Were you involved in writing that?

BALTIMORE: No.

ZIERLER: The Ascot report was basically the initial concerns that compelled the creation, the biosecurity—it sort of threw cold water on that. You were not involved in that? But that was the general feeling by that time, in the late 1970s, that all of the biosecurity, all of that stuff, was to some extent overblown?

BALTIMORE: Right. I had gotten involved in probably the early 1970s in the movement to ban biological warfare. We did that through the American Society for Microbiology and other kinds of established societies.

ZIERLER: Were you involved in the Senate hearings on ratifying the Geneva Protocol?

BALTIMORE: No.

ZIERLER: If you remember, this was like Arthur Galston.

BALTIMORE: Right. But we in our smaller way were pushing for something like that, and it was successful, finally. By the late 1970s or early 1980s, we felt that we had done what we needed to do, and we had in place the Geneva Protocols and—

ZIERLER: That came through in 1975.

BALTIMORE: All right.

ZIERLER: I mean, it's amazing; it banned gas warfare from World War I and the United States finally got around to it, 60 years later.

BALTIMORE: Right. [laughs] Anyway, it was part of the reason why at Asilomar we didn't talk a lot about biological warfare. First of all, I wasn't convinced, partly because of conversations with Matt Meselson, that you really could make a good weapon, and it's not clear anybody ever has.

ZIERLER: But the pursuit in trying to can create one hell of a problem.

BALTIMORE: Oh, yeah, right. The Russians certainly went after it big-time.

ZIERLER: They were doing fungal spores to kill off agriculture, that kind of stuff.

BALTIMORE: Yeah. We mentioned it at Asilomar and consciously said, "We're not going to try to deal with this here." There were Galston and others. There was a whole movement behind that. And there was no connection. They didn't see the recombinant DNA methods that suddenly made it so much easier to make biological weapons because luckily they were banned. Now, we believed that; the Russians didn't believe it.

ZIERLER: We talked last time about your centralizing interest in immunology, post-Nobel, post the sabbatical. We didn't talk so much about your work on oncogenes at this point, late 1970s and early 1980s. What was happening in that line of research?

BALTIMORE: I started the work on the Abelson virus in 1971, 1972. Abelson virus clearly had an ability to transform cells and turn them into cancer cells, and really no other virus was as potent as that. Then Varmus and Bishop isolated the SRC gene and showed that it was a cellular gene that had been picked up by the virus. They did this in 1975, roughly. We, then, taking their model, looked to see whether the Abelson virus protein could phosphorylate another protein, which was the hallmark of the SRC gene, and showed that it did, much to our amazement. Then we showed that it actually made a new kind of phosphate linkage. That was the oncogene that I focused attention on. We studied it. We made mutants of it. We showed how important its phosphorylation was, and we looked for phosphotyrosine elsewhere. That was the major thing I had to do with oncogenes. By the late 1970s, we were getting into immunology. Other people who worked with oncogenes sort of ramified their work to other oncogenes, and other organisms, and I never did that, I think because I was focused more on basic immunology.

ZIERLER: When does Vincent Racaniello enter the scene?

BALTIMORE: Aha! I'm not sure. I could look it up but I'm not sure.

ZIERLER: What was he interested in? What was the point of connection?

BALTIMORE: I kept a polio virus group.

ZIERLER: You stayed with poliovirus the whole time.

BALTIMORE: I stayed with polio until I went to California. I always accepted a small number of people into the polio group and kept it at a large enough size so that it was a serious scientific enterprise. Vincent came whenever he came, and just then, the restrictions on what you could do with recombinant DNA were liberalized so that we could make a cDNA from poliovirus. If you could make a cDNA from poliovirus, you could sequence that, so you could get the whole sequence of polio RNA. Vinnie set out to—he loves to be called "Vincent" now, but he was Vinnie then.

ZIERLER: He's a bigshot now. [laughs]

BALTIMORE: Right, right. He set out to sequence polio RNA and was successful, and we published that. Then we said, "I wonder if you could make a full-length cDNA, a single molecule, and put that into a cell, and it would somehow be copied into RNA and give you a plaque." I said, "Vinnie, it's one of those experiments that is enormously important if it works, and which you'll forget about if it doesn't work, because it's not going to take a lot of work to do it." We didn't know how to do it, because nobody had ever done anything like this before. He did it, and he brought it in my office and he said, "Look, there's a plaque." We recovered it and showed that it was actually coming from this DNA, and we published that. That was very dramatic because that changed the whole history of RNA virology.

ZIERLER: What was the impact? What did it do?

BALTIMORE: Everybody started doing it, with their own virus. Polio is easier than some of the others, but ultimately all the RNA viruses were copied into DNA, they were all sequenced, they were all recovered. That's how you do genetics now of any RNA virus, is you make a DNA, you make a mutation in the DNA—because the chemistry of doing that is much better than working with RNA—and then you recover the infectivity by putting it into cells.

ZIERLER: This was the game plan for COVID in early 2020.

BALTIMORE: Yes, right. That's one of my favorite experiments, actually.

ZIERLER: This is all mice research at this point, still?

BALTIMORE: No, polio doesn't grow in mice, although there is a mouse-adapted strain. Basically it doesn't grow in mice, and so it was all in cells in culture. We didn't do anything in animals with polio, and polio was too dangerous then to sling around in monkeys. It grows in monkeys, and all of the virulence tests of the vaccine are done in monkeys.

ZIERLER: Let's move to the origins of Whitehead. First, who approached whom? Did Whitehead come to you or vice versa?

BALTIMORE: Whitehead came to me.

ZIERLER: What was his original interest in this?

BALTIMORE: We have to go back a ways, to the 1970s. I don't even know what the exact dates are. Jack Whitehead had built a company that was very successful, he and his father.

ZIERLER: What was his business?

BALTIMORE: You'll be amused: he and his father, Whitehead and Weisskopf, because his father kept his original name but his parents were divorced, and he was really brought up by his mother, and his mother took the English translation—Whitehead.

ZIERLER: Weisskopf, Whitehead—there you go. [laughs] It's a Yiddishe kop, [Ed. literally meaning a Jewish head, figuratively it means to be clever], right there! [laughs]

BALTIMORE: That's right. And literally so! Jack never went to college. He enjoyed tinkering. He enjoyed science, but he never had an education in basic anything. His father started a machine shop to make instruments and in particular they were making instruments—I don't know how the connection was made—for the chemistry labs at the Rockefeller Institute. Their company, Technicon, was outside New York; Tarrytown, New York. Jack actually knew the great biochemists of Rockefeller, because he made their toys. I actually at one point very early in my scientific career used a fraction collector which was from Technicon.

The Whiteheads were friendly with scientists. One of the connections they had was with a guy at the Cleveland Clinic, I think, or at Case Western Reserve in Cleveland. This guy was a physiologist and he used machines to measure blood levels of hormones that he'd inject into animals. It was interesting. He was a good physiologist, Leonard Skeggs by name. Leonard had a lot of samples to analyze and was frustrated that whenever he did duplicates, they came out with tremendous disparities. The process of pipetting and centrifuging and whatever it took to get an answer had enough squoosh in that that by the time you were done, you didn't get a very precise answer. He was frustrated; he wanted better answers.

Leonard had an idea. He said, "Maybe we can just separate tranches of chemicals or of samples in a Teflon tube with an air bubble on either side, and as the air bubble goes down, it will clean off the edges and nothing will stick to it, and so you can put large numbers of samples down a tube, and you can have very precise amounts of them, and then mix them in a mixing chamber of some kind with the reagents for testing." Jack saw this. Leonard had patented it, patented an air bubble, for all intents and purposes.

Jack bought the patent rights from Case and set about to adapt this to automatic analysis of human samples—blood work—successfully, and he built his little machine company into a powerhouse of clinical analysis equipment. At a certain point, all clinical analysis in the world was done on Technicon machines.

ZIERLER: Wow.

BALTIMORE: It was all the air bubble that allowed it to happen. Teflon tubing and air bubble.

ZIERLER: What was he worth by the time you connected?

BALTIMORE: He in the end sold his company to Revlon. When he sold it, it was hundreds of millions of dollars [nearly $400M]. I don't think it was in billions. This is a long time ago. It's like billions today. When Jack still owned it, Howard Hughes got the U.S. Congress to pass a bill saying that if you had a medical research organization, allied with a hospital, it could own your company. He did that so that he could keep control of his company and still monetize it. He did that, and that's the origin of the Howard Hughes Medical Institute.

ZIERLER: Oh, wow.

BALTIMORE: Then when he died all of his wealth went to the Medical Institute. They had very strange rules around it, because they all conformed to this paradigm that was established by Congress. Jack heard about that. He said, "I'm going to do that, because I don't want to lose control of my company, and I want to monetize it."

ZIERLER: Was he also interested in supporting fundamental research?

BALTIMORE: Well, so that's now the story. No. He was interested in clinical research at a medical school in association with a hospital, because that's the requirements of the bill, so he got himself a group of advisors, graybeards of the time—Lederberg, and Gus Nossal from Australia, and some others. The money that was made by the company had to go into medical research. Profits would have to go to medical research.

ZIERLER: Basic science, not applications?

BALTIMORE: No, no, medical research, ill-defined.

ZIERLER: Either way.

BALTIMORE: Since it was a medical school, and medical schools weren't doing much basic research in those days, it was mostly for clinical work. Jack goes around and looks at different medical schools, to decide which one he wants to give the prize to. He is afraid of Cambridge, because the institutions—Harvard Medical School—are so powerful they will over—

ZIERLER: He wants to be a big fish in a small pond?

BALTIMORE: Right, thank you. Simple answer. Right. It certainly doesn't have to be a small pond, but he doesn't want to be overwhelmed by being with one of the really top medical schools.

ZIERLER: Mass General, what influence would that have in this thinking? That's separate?

BALTIMORE: That's the hospital for Harvard. Harvard doesn't have its own hospitals. It's all the various Harvard hospitals. So, no. But he goes around and he announces to these institutions that he is coming, and he wants a seminar by their top scientists so he can get an idea of what they are doing and where would be the best place.

ZIERLER: What about closer to home like Columbia Presbyterian? Was he looking in New York?

BALTIMORE: I don't know.

ZIERLER: Cornell Medical?

BALTIMORE: I had nothing to do with him then. I don't know where he went, but I do know that he came to Cambridge. I was one of the people who presented to him, because I had done—this was the early 1970s—I had recently done the reverse transcriptase.

ZIERLER: Presenting means you're pitching him, essentially?

BALTIMORE: Well, I'm telling him what science I'm doing.

ZIERLER: Let's pause for a second there. You have the Cancer Institute, so what's the new thing that you might be looking for?

BALTIMORE: He is coming with literally hundreds of millions of dollars to start a research institute. We had the Cancer Institute by that time.

ZIERLER: Had you outgrown it? Is that a factor also?

BALTIMORE: No.

ZIERLER: How big is your group at this point?

BALTIMORE: No, this wasn't for me. I was being trotted out.

ZIERLER: I see. You're the shiny object.

BALTIMORE: I'm the shiny object, that's right, and there were others. There wasn't any idea that we would be the recipients of this, and I was a young squirt at the time. But the odd thing is I met Jack Whitehead then. He and his advisors were there. The end result was he said, "No, I don't want to do it here. I want to do it at Duke." He set it up at Duke.

ZIERLER: Did you not click? Was that part of it?

BALTIMORE: No, no. He didn't want to be overshadowed by Harvard.

ZIERLER: I'm just saying interpersonally, one to one, you got along well with him from the beginning?

BALTIMORE: I'm not sure I even met him, one on one. He was sitting there.

ZIERLER: What was going on at Duke? What was the winning pitch there?

BALTIMORE: They had a good medical school. They had some very good research people. It was a good place. It still is a good place. But they didn't do their homework. They didn't look at all the documents and figure out what it is he was doing. He was keeping total control of this thing, and it was going to be at Duke, but it wasn't going to be of Duke. He got his own director, a guy from Mass General actually, to come down—Ed Haber—and run it at Duke, and hiring his own people. Duke realized that they had made a huge mistake. Took them a couple of years, I think, to realize that.

ZIERLER: They broke ground, already?

BALTIMORE: I don't know about buildings, whether they used space they had.

ZIERLER: How clearly did Whitehead articulate his vision? Was he hands-on? Did he say, "This is what I want to accomplish"? Or it's just, "Here's a chunk of money. Do great medical research."

BALTIMORE: Right. Because this was not about him. He just wanted the money and the control of the company.

ZIERLER: Sometimes, though, there's a very personal connection.

BALTIMORE: Sometimes there is, but as I said, he was not a terribly educated man, and he certainly didn't know what goes on in research labs, except that he had seen them and admired them. He really did admire the people at Rockefeller. Duke cut bait, and Jack realized that what he was setting up wasn't going to work, that the academic world can't be bought that way. He actually gave Duke a large endowment, which there are still Whitehead professors at Duke. He gave them $10 million or something, real money, at the time. Then he set out to do it over again, but it was different the second time. First of all, he had sold his company to Revlon, so now he had money, and he didn't need to have a hospital associated with it. He didn't need to do it in a medical school. He could do it anywhere. He still had his advisors. They were still helping him. He probably paid them well. He starts looking for where to do this. Now he decides, "I'm going to the top."

ZIERLER: He probably learned a few things along the way.

BALTIMORE: Right, he learned a lot. He learned an enormous amount. He now is looking for basic research, because he's no longer tied to medicine, and he has been convinced by the likes of Lederberg and Nossal, who were great—Lederberg was a Nobel laurate and Nossal almost a Nobel laureate; he just turned 90, I think—they had convinced him that the bang for the buck was bigger in basic research than it was in clinical research, and there's no question that that is true. I get a call one day from Josh Lederberg.

ZIERLER: This is out of the blue? You're not following the developments?

BALTIMORE: No, I don't know anything about it. He said, "Would you come down"—I was in Boston—"to New York and meet with Jack Whitehead and his advisors? They're trying to set up a research institute. They have"—as it turned out—"$100 million, and $35 million to build and equip the building, and they want to ally this with an existing institution." That's all I knew. The question was if you have an idea of how to structure this thing to make it work. Now, I was not known to be an institution builder at that point. [I looked up the NY Times article on the sale of Technicon and they say that Jack got $335M from the sale. He put up $135M of that for the Whitehead Institute. That is amazing: philanthropists generally give gifts that are maybe 5% of their wealth. To give about 25% of his wealth (neglecting whatever else he had) is remarkable.]

ZIERLER: The Cancer Institute doesn't count?

BALTIMORE: The Cancer Institute was really done by Luria, although I had worked with it. I had a little experience from that.

ZIERLER: You were not PI, so to speak, on anything?

BALTIMORE: No, and I was not known for that. It's just that I was known to be I guess an effective scientist, might have some good ideas. I thought it through and said, "Look, we're on the cusp of the applications of recombinant DNA. The big question in biology is development. We're going to crack development through this. It's at the forefront of everybody's thinking. You build an institute of developmental biology, with strong structural biology and strong molecular biology."

ZIERLER: Where did your particular interest in immunology and virology slot in?

BALTIMORE: No, they don't.

ZIERLER: And that's okay with you?

BALTIMORE: Yeah. By that time, I was convinced—this is 1980—that what we knew about the Abelson transformed cells enabled us to look at B cell development, but when most people talk about development, they don't talk about B cells. They talk about drosophila, they talk about mice, they talk about—so yeah, I had a little interest in development, and a belief that I knew how to get at development, but it wasn't my thing. That turned out to be critical. I went down and I told Jack and this group what I was thinking. Jack told me later that of all the people he had come to give him advice, I was the only one who didn't pitch his own science.

ZIERLER: Ah! That's the key.

BALTIMORE: That's the key. I hadn't done it strategically; I had done it because—

ZIERLER: You just saw the bigger game.

BALTIMORE: They asked me a question; that was my answer.

ZIERLER: In terms of your own strategy, would you keep up the group at the Cancer Institute?

BALTIMORE: Wait, wait, wait; I was giving them advice. Nobody's—

ZIERLER: That's too far afield. Right.

BALTIMORE: But the next day, Jack calls me and said, "It was wonderful. Would you head up this institute?"

ZIERLER: You were not prepared for that call?

BALTIMORE: I was slightly prepared for it. I knew that that was one possible outcome from it, but I didn't really expect it to happen, certainly not that way. I was smart enough, and I had thought enough about it, to know I didn't know the particulars very well, and the story of working with Jack Whitehead around the community was terrible, because he reneged on Duke.

ZIERLER: Did you appreciate, though, that he reneged for the right reasons?

BALTIMORE: I don't think I fully understood what was going on, but he had a little red flag on him, or a big red flag on him. I said, "Look, I'm willing to be an advisor to you, a paid advisor. I'm willing to try to put together the elements of an institution, a direction for the institution. If I can do that with a university that was responsive, someplace where it would work, and I want to be there, I'm willing to be the director. But at this point I'm not promising anything." He said, "Fine." We set out to talk to five or six different universities in America. I was at MIT. It was clear that I loved MIT. The likelihood was it would end up at MIT. But MIT had nothing like this.

ZIERLER: Why is the Cancer Institute not an analog?

BALTIMORE: Ah. It is. Slightly. Jack had certain things that had to be part of this deal. One was it had to be an independent research institute, with its own board, making its own decisions. As Jack likes to say—I just quoted this yesterday to somebody else—"I want to make my own mistakes." So, "I don't want to inherit the mistakes of MIT or anybody else." MIT had nothing like that, and the Cancer Center was not a model at all, because the Cancer Center was a center of MIT and was built into the Biology Department.

ZIERLER: But it had its own internal administrative structure? Who directed the Cancer Institute?

BALTIMORE: Luria.

ZIERLER: And Luria reported to—?

BALTIMORE: To the chairman of Biology and to the provost.

ZIERLER: It was really just a sort of big group within Biology?

BALTIMORE: Yeah, right, administratively.

ZIERLER: Jack wanted something entirely out of that reporting structure.

BALTIMORE: Right.

ZIERLER: What makes it part of MIT, then?

BALTIMORE: It took me about a year and a half to answer that question.

ZIERLER: [laughs] Was one of the possibilities just not making it part of MIT, or Jack was insistent that you needed to square the circle?

BALTIMORE: No. I said, "My bottom line is it has to be allied to a large institution." Because it wasn't going to be big enough to be totally freestanding.

ZIERLER: It wasn't going to be big enough because as much as Jack was giving, that wasn't enough?

BALTIMORE: Right.

ZIERLER: What does that look like? How many faculty?

BALTIMORE: The agreement that we wrote with MIT was 20 faculty.

ZIERLER: With joint appointments in Biology?

BALTIMORE: Wait a minute, wait.

ZIERLER: That's granular, okay.

BALTIMORE: Because the first thing we had to do was decide where it was going to be. I went to Harvard, to the Medical School, and talked to them. They knew exactly how to do it, because all Harvard hospitals are like that. They're all independent organizations allied together in the Harvard Medical School.

ZIERLER: This would have been a turnkey operation at Harvard.

BALTIMORE: Right, so the dean was very excited.

ZIERLER: What problems does that pose for you as an MIT professor, though?

BALTIMORE: Well, I would go to Harvard, I guess.

ZIERLER: You would move the whole operation to Harvard?

BALTIMORE: Right. We'd build a building there. I went to Rockefeller, because Jack loved Rockefeller. The Rockefeller faculty whom I talked to were split. Some of them said, "Jeez, this sounds great, to bring something new here." But some of the really important people there said, "No way. We're too small. We'll be overshadowed by Whitehead. Can't do it."

ZIERLER: Also can you build in Manhattan?

BALTIMORE: Oh, Rockefeller had lots of space, and since that time, they have built a number of buildings. In fact, they built out over the East River. You've never seen the recent Rockefeller building?

ZIERLER: Is that the underpass on the FDR Drive? That's them?

BALTIMORE: Yeah, Rockefeller, interested but difficulties, and I thought the difficulties were right.

ZIERLER: Just to foreshadow, it sounds like it's the faculty that is making this decision and not the administration at Rockefeller.

BALTIMORE: At Rockefeller, yes.

ZIERLER: And there's a lesson there. [laughs]

BALTIMORE: Right. Stanford I talked to at some length, and they were just a little frightened of it. They didn't know how to do it. They had never done anything like it. It might have been possible. They had only maybe 15 years earlier brought the hospital down from San Francisco to the Stanford campus, and that wasn't going well, and never went well, just financially.

ZIERLER: What about UCLA?

BALTIMORE: No, no. I only talked to four or five places, and I talked to MIT. I talked to MIT, Harvard, Stanford, Rockefeller, someplace else. I'm sure Alice will know. Jack later said, "You said it could be anywhere, as long as it was MIT."

ZIERLER: [laughs]

BALTIMORE: That's not wrong. I felt I could deal with MIT. But when I saw the level of concern at these other places—

ZIERLER: That was useful?

BALTIMORE: Oh, yeah. Then I saw a level of concern at MIT, and a real uncertainty about whether the faculty wanted it. I began to understand why people say the academic world is so conservative. Here was a gift! I said I didn't see anything better than MIT. I would rather work with MIT. Harvard was a possibility but I didn't know how to do it.

ZIERLER: The fact that you were shopping this around elsewhere, did that move things along at MIT?

BALTIMORE: Oh, yeah, it meant that there was a reality to it. That's right. And they were going to lose me, and it.

ZIERLER: But that was legitimate, when you were looking around. You were not leveraging.

BALTIMORE: No, you're right, and I was following Jack's wishes in this. He knew all those other places; he didn't know MIT at all, because he had come from a medical device environment. I said, "I want to try to make it happen at MIT." But from the initial reading that I got, I knew it wasn't going to be easy. And it wasn't.

ZIERLER: Who were you talking to, in concentric circles?

BALTIMORE: I was talking to the whole administration.

ZIERLER: What about faculty? Did you start with faculty?

BALTIMORE: My initial discussions were with the administration and faculty—the head of Biology, the previous head of Biology, who was savvier than the head of Biology at the time. Boris Magasanik, by name.

ZIERLER: Was the previous, or the current, at that point?

BALTIMORE: He was the previous. The current was Maury Fox, who was just not as savvy and not as sort of sure of himself as Magasanik was. And the president, who was Paul Gray, and the chairman of the board, Howard Johnson, ex-president at that point. He was my greatest supporter. He was an entrepreneur at heart. He said, "This is a great opportunity. How can anybody not want it? Now, the devil is in the details, but assuming you could work out the details in a way that was consistent with MIT, we should want this." The president was scared. He was scared of his faculty, and having been president of Caltech, I now know what it means to be scared of your faculty. When you have a group of faculty, any one of whom is somebody you have to admire for their scientific prowess, it becomes hard to try to tell them what to do.

ZIERLER: The concerns from the faculty, or at least what the president was imagining, was that the Whitehead Institute would sap power from the department, that it would just be too powerful an institution within the administrative structure?

BALTIMORE: That was one of the concerns. One of the concerns was that if we set it up so that all of the faculty at Whitehead were faculty at MIT, which seemed like the right thing to do, then it would be a significant fraction of the total Biology Department.

ZIERLER: And it would give you all kinds of hiring power?

BALTIMORE: Right, and there were plenty of people who were afraid of me, because I was known to be pretty sure of myself, and they didn't know what I wanted from it, and they thought I was going to try to make it in my image in some way.

ZIERLER: Did you do a listening tour, a hearts and minds campaign?

BALTIMORE: Oh yeah, I did everything. I talked to everybody.

ZIERLER: What were you getting from some of those discussions? What were some recurring themes?

BALTIMORE: "Will they teach?" The answer was yes. "Will the faculty be chosen by MIT along with Whitehead?" The answer was yes.

ZIERLER: Why not without Whitehead? Why not just chosen by MIT?

BALTIMORE: Because then it wouldn't be Whitehead's decisions. Remember we still have Jack to worry about. What you're talking about is a piece of MIT. But I agreed. Actually, I wanted MIT to be strong in this, because I believed that MIT was the quality control, particularly over the long run, to make sure that Whitehead stays at the forefront of its science. And it worked.

ZIERLER: Funding was not a concern; it was not going to sap resources, obviously?

BALTIMORE: No, it was not going to take any resources, and the way we actually set it up, all of the students who work in the labs at Whitehead are paid for by Whitehead, out of Whitehead funds. We had a lot of money. A hundred million dollars was a lot of money.

ZIERLER: No need for grant-writing every year, that kind of thing?

BALTIMORE: No, there still was. All the faculty still had to write grants, but they had a cushion under them that nobody in the Biology Department had. The Biology Department was entirely on soft money, so this was a much better arrangement. As I went around and talked to people, they were all concerned about these kinds of questions. A concern developed, which The Boston Globe—I'm just now terrified of what The Boston Globe is going to do to Eric Lander.

ZIERLER: Oh, yeah.

BALTIMORE: The Boston Globe is vicious. The Boston Globe decided that Jack was doing this because he was going to profit from it. Now, this was totally philanthropic. There was no way that could be true.

ZIERLER: I don't even see what the angle is. What are you doing there? Maybe in 20 years, something would come online.

BALTIMORE: They just said, "Is he going to—?" Well, we had it set up so that Whitehead would patent its own intellectual property, and they mixed that up with Jack profiting.

ZIERLER: Was this like lefty corporatizing education?

BALTIMORE: Yes. In fact, there was an avowed socialist in the Political Science Department at MIT who led the charge.

ZIERLER: Chomsky?

BALTIMORE: No, no, no. He's somebody you never heard of, a kid.

ZIERLER: When you say avowed leftist and MIT Political Science—

BALTIMORE: Yeah, I know. But Chomsky had more important things to worry about. He didn't get in my way. And anyway, he was Luria's very good friend, and Luria was very much behind all this.

ZIERLER: Luria did not want to see this happen?

BALTIMORE: No, he did want to see this happen. I was his prodigy.

ZIERLER: Any idea who was feeding the journalists details?

BALTIMORE: Or they were creating them themselves. I've never understood. But this leftist guy whose name I don't remember was certainly part of the problem, and he produced quotes and just awful things. A total lack of understanding. I started out to try to build this thing at MIT, with The Boston Globe on my back, with groups of faculty uncertain in various ways, basically general conservatism of the academic world, so there were a whole lot of people who just said, "We don't do this sort of thing."

ZIERLER: Howard Johnson is a force for pushing through all of this?

BALTIMORE: He is, but he's also smart enough to know that you can't steamroll the faculty, so he was doing it with a gentle hand. He was the best. There were a number of faculty meetings. It was the first time there had been a faculty meeting that anybody went to since the Vietnam War. There was finally a vote taken, and the vote was in favor.

ZIERLER: Do you remember what the number was?

BALTIMORE: No, I don't.

ZIERLER: Was it close, though?

BALTIMORE: There was a strong opposition.

ZIERLER: This is only science faculty who is voting, or everyone?

BALTIMORE: No, it was the whole faculty.

ZIERLER: Wow, so you have English professors weighing in on whether there should be a Whitehead—

BALTIMORE: Well, we don't have that many English professors.

ZIERLER: But still.

BALTIMORE: Yeah. And mostly engineers. The engineers were the most conservative.

ZIERLER: Oh, interesting.

BALTIMORE: They historically are. Somebody gave a speech—it may have been Jerry Lettvin—at the last faculty meeting, in which he said, "This is the kind of thing MIT has to do. We have to take chances. I don't know exactly how this is all going to work out, but if we don't do it, we're ridiculous." That carried the day.

ZIERLER: When a professor thinks to themselves at an elemental level, "How is this going to affect me?" was there any basis for a concern that anyone's research agenda or career would be negatively affected by the creation of the Whitehead, in any way that you might define that?

BALTIMORE: There was such a concern in the Biology Department, because—

ZIERLER: People would get eclipsed?

BALTIMORE: Yeah. I don't know how many of them were smart enough to understand it, but they were right, and they were right because I was going to be able to hire a brand-new faculty, and the existing faculty, by just the way time goes by, had a whole bunch of older people in it whose time had passed.

ZIERLER: And you can hire the best anywhere, who are in their prime.

BALTIMORE: Right. Now, a big person will say, "This is the greatest thing that can happen, to get a center of strength in new biology." But a weaker ego will be frightened of it.

ZIERLER: There were weaker egos at MIT? [laughs]

BALTIMORE: Yes. [laughs] Just by age. Yeah, there were. I had to deal with a whole lot.

ZIERLER: Must have been very stressful.

BALTIMORE: Oh, yeah. This was a year of great uncertainty.

ZIERLER: Your postdocs probably weren't getting the best of your attention either during this time.

BALTIMORE: No, they weren't. They probably did the best work of their life!

ZIERLER: [laughs]

BALTIMORE: Yeah, this is the time when I'm building immunology, but I was always able to do a lot of different things in a day. I still am. The last day, the faculty votes, and I went out in the hall and I found a phone, and I called Jack Whitehead, and I told him. His response was, "Democracy is wonderful when you win."

ZIERLER: [laughs] That's great.

BALTIMORE: There's a real truth in that, which is that the process that we had been through meant that the Whitehead Institute was born in complete knowledge of what it was.

ZIERLER: You were as transparent as you possibly could have been.

BALTIMORE: Yes. You had to be.

ZIERLER: What was the arrangement with Jack? You get the agreement by MIT and he writes a big check, or you already have the money?

BALTIMORE: No, as I said, I hadn't agreed to be director, but once I put it in place at MIT, I said, "I'm willing to be director." At that point, I got a check.

ZIERLER: What's your administrative experience at this point? Anything?

BALTIMORE: No.

ZIERLER: Never department chair?

BALTIMORE: No. Never wanted to be.

ZIERLER: No special title at the Cancer Institute?

BALTIMORE: Right. And we have to build a building. We have to negotiate with the city to get land.

ZIERLER: Oh, land wasn't even secured at that point?

BALTIMORE: No.

ZIERLER: I assume you wanted it to be close to campus, close to the Cancer Institute, even?

BALTIMORE: Right. I can talk about this for as many hours as you want to sit and listen [laughs], because there are elements that keep coming up. I haven't even really told you all the details of the affiliation agreement that I wrote with the provost at MIT.

ZIERLER: What does that mean, affiliation agreement?

BALTIMORE: We wrote a formal affiliation agreement that affiliated the Whitehead Institute with MIT, that it had in it all these things that we were talking about—that all faculty of Biology had to be chosen by joint searches, that they had to teach. [laughs] The provost, bless his heart, he was a theoretical physicist—

ZIERLER: Who was the provost?

BALTIMORE: Francis Low.

ZIERLER: Low was a good guy?

BALTIMORE: Francis Low was a wonderful human being, but he had the failings of a physicist.

ZIERLER: Smarter than everyone?

BALTIMORE: Smarter than everyone, and it didn't happen unless it was quantified. [laughs] So in this affiliation agreement, there is a long section about what happens if it's necessary to unravel the affiliation agreement.

ZIERLER: A prenup, essentially?

BALTIMORE: Right, but in particular, about how many courses will have to be taught, how much money goes this way and that way, and everything. The way Francis had written it, it was like a law of physics, with lemmas at the bottom. It's hysterical. It is just absolutely hysterical. Luckily, we have never had to put it to the test. But that meant I had the provost on my side, because we had all that in there. There's lots of other stuff in there. I'd have to dig it out to remind myself of it all. But I get nothing at this point. Money, I get; a hunting license, I get, within the affiliation agreement; but I have to find land, I have to build a building, and I have to build trust.

ZIERLER: You have to do what you said you were going to do.

BALTIMORE: Right, or more. Because it really was a national issue. It was everywhere. It was in The New York Times.

ZIERLER: There was nothing like this anywhere at this point.

BALTIMORE: No, and The Globe kept stirring it up. But we did it. In 19…I don't remember the year—well, I roughly can—this is in the 1960s—oh, Kennedy was president, right—Kennedy said, "I'm going to build a NASA electronics facility." Because NASA wanted to—actually, I don't know the history of it, but it was sort of the beginning of the computer era, and they understood that NASA needed this kind of strength. MIT convinced Kennedy that it should be in Cambridge. Cambridge City cleared out a huge tract of land, razed buildings, housing as well as these old three-story things, three-decker things, which I used to live in, and old factories. It was actually a major center of rubber. They made rubber belts and things, these circular belts.

ZIERLER: Industrial Cambridge.

BALTIMORE: Industrial Cambridge, that's right. This is the heart of industrial Cambridge, and they cleared it. Then Kennedy was assassinated and Johnson became president, and everything went to Texas. The community in Cambridge was livid that they had torn the heart out of it, and now it was just empty. It sat there for many years, because the politicians wouldn't touch it.

ZIERLER: I'm sure it has filled up nicely, since. [laughs]

BALTIMORE: When you talk about Kendall Square, you're talking about that land. It was many, many years later that finally Boston Properties got the development rights for it. What's his name, the head of Boston Properties? Also Jewish. Mort Zuckerman. Mort built this Boston Properties, which is a development firm, and made himself into a billionaire. He's actually one of the great characters of all time. He's so funny. He had built a few buildings, or they had built—a guy named Linde was really the guy who did it all. From the time I started thinking about this, I had an eye on that land for the Whitehead Institute, but MIT had agreed it would not touch the land, so I had to be very careful that this was totally not MIT.

ZIERLER: What was the issue? Why wouldn't they touch the land?

BALTIMORE: Because the land was originally for NASA development purposes and then for commercial development, and the city would have gone bonkers if MIT had tried to take over any of the land. One day, I sat down with one of the great negotiators of the world, Mort Zuckerman, to get a piece of land from his development. It turned out Mort Zuckerman cared as much about basic science as anybody. We paid him for it, but he was very glad to see it happen.

ZIERLER: What were you looking for, like a city block?

BALTIMORE: A piece of a city block, not the whole block. I got this land. It sits at the corner of Main and—I can't remember what the cross street is. It doesn't matter. But I love that corner, because the Whitehead Institute is here, the MIT Cancer Center is here. All the things I've had to do with are sitting around this corner in Kendall Square. Biogen was there already, and they had a piece of the NASA property, in fact maybe even two pieces. Genzyme wasn't there and Amgen wasn't there. They're all there now. And we built Whitehead. It was a tremendous thing for the developers to have this Institute there.

ZIERLER: You're hiring this whole time during the building process?

BALTIMORE: Yeah, we're looking for the best people.

ZIERLER: What's the number of new people, 20?

BALTIMORE: No, we didn't start out with 20. It was really eight or ten.

ZIERLER: Who were you looking for? What were the skill sets?

BALTIMORE: I was looking for strength in structural biology, strength in developmental biology, strength in model systems. I wasn't looking for anything human. I wasn't looking for standard biochemistry. I found Gerry Fink in yeast, who was at Cornell and had been at MIT on sabbatical for that year when he and Botstein and I had been starting up Collaborative Research. Gerry was glad to come. Gerry later became the director when I left. Rudolf Jaenisch. Rudolf, I had known at the Salk Institute. I used to go there in summers, after I had been there as a faculty member. Rudolf is a little younger than I am. He had come there to do a postdoctoral fellowship and then had stayed in the United States for a while, then had gone back to Germany—he's German—to Hamburg. I just thought he was the best person in organismal biology, using molecular biology in organisms, mainly mice. He needed fantastic numbers of mice, and I had the money to buy him his mice, keep his mice. I convinced Rudolf to come.

When I moved to MIT, shortly thereafter, they hired Harvey Lodish, who was a little younger than I am—he has just retired—actually he was my next-door neighbor at Rockefeller when I was a student, so I had known Harvey. Harvey is really smart, a cell biologist. I got Harvey. Harvey came and we shared a laboratory until I moved to the Cancer Center. Then I couldn't convince Luria to take Harvey to the Cancer Center because he didn't do cancer research. Luria said, "This is seriously cancer research. Harvey won't do." I was annoyed by that, because we had worked so well together. I got Harvey to come to Whitehead. The Department said I could take two people, but not their favorite people, and Harvey was not one of their favorite people. The other person who was not one of their favorite people was Bob Weinberg. Nobody has done more for MIT than Bob Weinberg. Bob had been a postdoc with me for a year. He had wanted to break into cancer research and I had shown him how, and then had moved to the Cancer Center, and so I got Bob to move to Whitehead. Those were full professors. Then we hired some young people whom we heard about in various places. I started the fellows program there, and that brought also young people.

ZIERLER: As postdocs?

BALTIMORE: They were roughly the age of postdocs.

ZIERLER: But these were staff scientist positions?

BALTIMORE: It was a staff scientist, but it was an alternative to going for a postdoc, or an opportunity for somebody to change. Like Eric Lander came there as a fellow, changing from a mathematician to a geneticist. David Page came as a fellow, and then we hired him on to the faculty, because he was great. He later became the head of Whitehead, one of the great geneticists of sex chromosomes in the world. Peter Kim, who was a fellow and then stayed on at Whitehead and then left to become the director of research at Merck Pharmaceutical, did that for ten years, and then took a position at Stanford and is there now, happy as a clam that he's no longer in industry. I was just talking with Peter the other day. I keep track of these people. It's not that I keep track of them; I keep intersecting with them. Who else? Who am I forgetting? I'm forgetting wonderful people, I know.

ZIERLER: Who is making the decisions on hiring with you, within MIT?

BALTIMORE: The young people were all hired from search committees that included MIT faculty and Whitehead faculty. They were all people who the Department of Biology thought were a catch and fit into the world we were building at Whitehead. One of the things that I found very important in choosing these people was that they seemed to be people who would get along with each other and be collaborative, and that worked out. They have been.

There was another reason that we were able to make it a very collaborative environment, and that was that Jack Whitehead loved to ski. He had a house in Vail. When he first was sort of courting me, he took us out to Vail and taught me how to ski. I knew slightly how to ski. And Alice. Jack wanted to know the faculty as people, so he invited the whole faculty to come out and ski every year, with their children, and their wives, husbands—mostly wives. He fostered in that way a community feeling among the faculty at Whitehead that almost no other academic institution has ever created. I swear the reason is because we knew each other's children. You could follow them year by year, and they grew up. It just gave a humanity that almost no—people don't do things like that.

And it was the money, because he put a lot of money into that, to stay in Vail. He had enough space for the group for the first year, but by the second year, we had to hire space and have dinners. It was really an expensive operation. He bought ski lift tickets for everybody. He had instructors skiing with us all the time, so we all learned to ski, some better than others. Rick Young was a guy we hired from Stanford, a very smart guy. He's still there, still doing brilliant work, but a really good skier, one of these big guys who dominates the slope. Jaenisch turned out to be crazy, and he and Rick go hiking and skiing all over the world. They come close to killing themselves every year; it's amazing.

ZIERLER: You kept your group at the Cancer Institute?

BALTIMORE: No.

ZIERLER: You switched everything over?

BALTIMORE: Right.

ZIERLER: Did that change the kinds of postdocs and graduate students you had or even the work that you were doing?

BALTIMORE: You mean, it was less cancer-oriented?

ZIERLER: The whole name of the game, the origin story with Whitehead, is that you were advocating a vision that wasn't your science, right? What were the ramifications in terms of where your group was?

BALTIMORE: Oh, but I could have my own group. My science was no different than Harvey's science or Bob's science, Rudy's science.

ZIERLER: The thrust of your group didn't really change as a result of the Whitehead move?

BALTIMORE: Right. It came at a time when I was just maturing the immunologic focus, and so the really important work that we did in immunology, a lot of it was done at Whitehead.

ZIERLER: I think questions from some of your postdocs, and that will get us through the 1980s, and then we'll pick up on Rockefeller next time. We talked a little bit about it, but just because it's so important, Ranjan Sen. Tell me about the research with Sen. What was that?

BALTIMORE: [laughs] At what length would you like to go forward?

ZIERLER: [laughs]

BALTIMORE: I have to go back a step. A very interesting guy whose name I'm not going to be able to remember for the moment, came to work with me [his name is Cary Queen]. He was very computational in his thinking. This was early for anybody to be computational. A guy who came from NIH. Well, whatever his name was, he started doing experiments and all that, to define the region of DNA that controls the expression of the light chain of immunoglobulin, light chain of antibodies. We knew that in the developmental sequence of the B cell, you first rearrange the heavy-chain gene, then you rearrange the light-chain gene, then you've your two rearranged genes, they make their products, they come together and they form an antibody. There's a lot of control mechanisms built into all that. That's what I was really interested in doing. He set out to do this by cutting out segments of DNA and seeing when you cut out—when it no longer expressed itself as a gene, finding the regions that were important, because there was no way to know where they would be. They were at one end of the gene, they were at another end of the gene, they were in the middle of the gene. Because with introns, they can be right in the middle of the gene, and they were. He finds where the sequences are that control the light chain.

Now, we know from drosophila work that transcription factors are the key proteins that determine when genes turn on and off. In drosophila development, first one gene turns on, one protein turns on, and it gets transcribed, and then—sorry, the transcription factor transcribes the gene, and the product that is made helps that stage of development, so this thing is staged all the way through, and there's transcription factors at every stage. It was beginning to be clear that that was true. But in mammalian cells, no one knew anything about this, because we didn't know where the genes would act. We didn't know the transcription factors. This region sounded like a region that transcription factors would bind to. It was in the middle of the gene, it was nearby where the gene started, could be. How do you find it? Ranjan Sen comes to the lab as an organic chemist trained at Columbia with a legendary organic chemist, Nakanishi. He said, "I want to break into biology." It was just a tremendous chance on my part to take him, because he knew nothing. He didn't know anything about immunology. He didn't know anything about biology.

ZIERLER: Bright guy, blank slate.

BALTIMORE: Right, and a good chemist. Well, I believe in chemists, for one thing. Actually my undergraduate degree is in chemistry. He's in the lab trying to figure out how are you going to find the proteins that bind to this region of DNA. We knew what regions were interesting, but how do you find a protein that binds? Actually I didn't even realize what they were doing—he starts working with a postdoc in Phil Sharp's lab, who is also interested in this question, who goes on to become actually an even better known immunologist than Ranjan, also Indian by background, whose name I'm blocking for the moment [his name is Harindar Singh].

They become—and I don't know how they did this—they become aware of a technique that has been developed by a guy named Don [his name was Don Crothers from Yale University], in which Crothers showed that when a protein binds to a piece of DNA, if you have the protein, if you have the piece of DNA labeled, it now migrates in an electric field through a gel more slowly, because the protein is bound to it. That allows you to say that there's a protein that binds to that DNA. It identifies that protein even though you can't see the protein, what you're seeing is the DNA. They said, "Maybe we can make this work for transcription factors, and we're going to focus on this region of the light-chain enhancer." We called it an enhancer for reasons I can explain, and cut up the enhancer in different pieces and get the proteins that bind to it, and those are going to be the proteins that control the expression of light chain, and this is going to be the first step to understanding the differentiation of B cells. It turned out to be largely true, actually.

Ranjan starts cutting up the DNA in different ways and running it in gels with protein extracts to see what protein extract would cause it—change the migration of the DNA, indicating binding, and finds that there's all sorts of binding going on. We write a paper about all the things that bind to the light-chain enhancer, the most important of which turned out to be NF kappa B, and that is the one that has gone down in history. But there were four or five others, and they started the careers of four or five different other people.

ZIERLER: Why was this one so important?

BALTIMORE: Because it was linked to inflammation, a central mediator of inflammation.

ZIERLER: That gets to the heart of all kinds of maladies.

BALTIMORE: Right. But initially, that's not what we thought was going on. We thought it was a gene that controlled, or a protein that controlled a step in differentiation. It didn't at all.

ZIERLER: What was the theory or hypothesis that led you down that road initially?

BALTIMORE: We could show that that protein would turn on in cells where light chain turned on, so it had a correlation. I could make that protein turn on, and I could make the light chain turn on, so it really looked like it controlled that step. It can do that, but it doesn't do it because of differentiation. It had nothing to do with differentiation; it has to do with inflammation, because in inflammation, you turn on the light chain because you turn on B cells. Right idea, but wrong interpretation. Fine. Actually, as it turned out, nobody complained, and Ranjan got famous, turning on NF kappa B.

ZIERLER: During this time, you're heading up Whitehead. When did the original concerns start to go away, all of the misgivings that faculty and the administration had?

BALTIMORE: As fast as you can imagine. First of all, it stopped being headline news. A decision had been made. Everybody moved on, and it was all left in my lap, and I was perfectly happy to have it there.

ZIERLER: Any bruised egos, as far as you knew?

BALTIMORE: I guess, but—

ZIERLER: Minor stuff though?

BALTIMORE: There wasn't a lot of recrimination. There weren't people going out after me. Once the vote was taken, basically everybody said, "Show me." And I showed them.

ZIERLER: Once you had everything up and running, how much of your time was spent on administrative stuff?

BALTIMORE: In those days, every minute was double-marked. [laughs] There wasn't enough time in a day to do everything. I got a lot of help. Bob Weinberg, it turned out, loved buildings, and he loved architecture, so he was an enormous help in the choice of the architects and in guiding the architect, but I was there. I followed every turn of the building.

ZIERLER: What kind of a presence was Jack? On a daily basis, monthly basis?

BALTIMORE: It was more monthly, but he was there, and he came, famously, for the topping off—when they put up a steel frame and it gets to the top, there's a topping-off ceremony. The workmen took a big doll up to the top, and nobody saw them do it, and then when we were just having the ceremony, they dropped it off, as it somebody had fallen off the building, and scared the shit out of us, including Jack. Actually, I was afraid Jack would have a heart attack on the spot.

ZIERLER: [laughs] Oh, god!

BALTIMORE: But he was there. No, he was very good about it. He was glad to know the people, he was glad to help develop the camaraderie, but he didn't try to second-guess, because he didn't understand what we were doing.

ZIERLER: There were no benchmarks that he was providing to make sure that you were hitting? That was not the level of interface that he had.

BALTIMORE: No.

ZIERLER: There's really a lot of trust on his part, here.

BALTIMORE: I'm sure he was keeping track of the milestones, and they were happening—hiring an architect, and this and that.

ZIERLER: No, but I mean in terms of he had no independent means of keeping tabs on the science.

BALTIMORE: Oh, not on the science, not at all.

ZIERLER: With the funds at your disposal, what kind of technology was available? What was some fun new stuff—instrumentation, computation? What was some really fun stuff that was accessible?

BALTIMORE: It wasn't yet computation. It was instrumentation. It was ways of separating molecules, centrifuges. We had structural biologists so I was able to get them good x-ray crystallographic machinery. We bought some good microscopes. We basically could get anything that we needed, but biology wasn't yet as technologic as it has become. The heart of the laboratory was still hoods, laminar flow hoods, where the air is kept sterile, so we could grow cells and we could take cells off of one plate and put them on another plate, infect it with viruses, and show how all of that happens. Very, very rudimentary stuff was still very, very important.

DNA Sequencing and Trout Fishing

ZIERLER: Last question for today—were you following what Lee Hood was doing here at Caltech, in real time? DNA sequencing, protein sequencing? That was not registering with you yet?

BALTIMORE: It was registering with me, because I knew Lee, because Lee grew up in Montana. When we bought a house in Montana in the end of 1979—is that right?

ZIERLER: The draw there is fly fishing?

BALTIMORE: For me it was fly fishing. Lee didn't fly fish, but Lee loves Montana and loves having a place to go in Montana. The first house that we bought there, Lee and we and Irv Weissman bought together. Then Irv kept having children and grandchildren, and we had this one nice young daughter, and she was going to have to inherit this thing, with all these other kids. I said, "No way." I had Irv buy me out of that property, and we built another one. We built our own house up there, just up the street. I've seen Lee on and off for years and years and years. I was aware of what Lee was doing, but I wasn't aware how important it was. I've always been very—it's partly why I'm able to do a lot of what I do—very supportive of people who want to do something that I may not understand, but I admire the person and I want to see it happen. Lee was in that category. I was glad he was doing what he was doing, but I wasn't sure that it was going to revolutionize the world. Which it did.

ZIERLER: On that note, we'll pick up for next time.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Monday, February 14th, 2022. I am delighted to be back with Professor David Baltimore. Once again, David, great to be with you.

BALTIMORE: Happy Valentine's Day.

ZIERLER: Happy Valentine's Day to you. Today, before we get to the main topic, some other issues that we have not really covered yet from the 1980s. I want to return to the AIDS crisis, particularly in the early years, and if you connected, before anyone knew what this was, if you had at least some very preliminary concerns that the fears that prompted the Asilomar conference might be related to whatever this new illness was that was affecting gay men in metropolitan areas in the United States.

BALTIMORE: No, it never occurred to me that this was something consciously developed, or even accidentally developed, because—well, it depends on how early you want to go.

ZIERLER: I'm thinking David Ho in UCLA, 1981, 1982, the very first cases.

BALTIMORE: No, it just seemed like an infectious disease. I was always very skeptical that anybody could actually make a virus-like entity using recombinant DNA methods. Now, let's see, this was 1980.

ZIERLER: The very first cases.

BALTIMORE: By that time, we had the ability to use certain recombinant DNA methods, but they were pretty rudimentary. That somebody could make something that really would transmit and would cause disease just didn't seem possible.

ZIERLER: If not for what would later be identified as HIV, theoretically what would an illness look like that would have borne out the worst fears that prompted Asilomar early in the decade? Just to use your imagination, what might that look like?

BALTIMORE: You could have an organism being transmitted that would cause a disease—it would be very hard to imagine something that would cause AIDS, because AIDS was an immunodeficiency, and we really had no example of an immunodeficiency like that. If you tried to make a lethal organism, I don't know what gene you'd use. We didn't really know of any.

ZIERLER: This had to come from nature, is what you're saying.

BALTIMORE: I think it pretty well had to come from—it had to involve things that we didn't yet understand, and therefore it had to come from nature.

Activating a National Response to HIV

ZIERLER: Was your lab involved at all in HIV research in the early years?

BALTIMORE: No, not until 1986. We worked on reverse transcription, and I followed the work on HIV, but I never initiated anything in my own lab, because I didn't feel there was anything that I could do at that point. Once it was sequenced, because I wasn't going to sit down and sequence it—there were people much more capable than I to do that, and they did very quickly sequence it—then it offered us all sorts of puzzles. I suppose we could have worked on it, but I was just sort of digging into immunology there, and getting involved in lots of other things, so I wasn't going to do that. But then when I was involved in the Confronting AIDS book from the Academy—

ZIERLER: When did that work start at the Academy?

BALTIMORE: In 1986, I guess.

ZIERLER: Who was the driving force behind that?

BALTIMORE: I don't know exactly. I was asked by Walter Rosenblith, who was provost at MIT and a member of the Academy; foreign secretary, I think, of the Academy. He approached me first to be co-chair of this committee that produced Confronting Aids. Walter was a physical scientist. I don't actually remember what his specialty was. If it was his idea to do this, then it was on a policy ground; it wasn't on a scientific ground.

ZIERLER: Advocacy for more federal funding, that kind of stuff?

BALTIMORE: No, just national need. The scientific community was actually embarrassed by the fact that it hadn't been marshaled to confront AIDS, because the political world saw it as a taboo. The Academy, somebody like Walter who was a responsible member of the Academy, I can imagine deciding himself or with a group around him that the Academy ought to be involved and suggesting that there be a committee report. The way the Academy works, it generally delves into an area deeply through experts to make a recommendation.

ZIERLER: What were your contributions to the report?

BALTIMORE: I co-chaired it, but I chaired the scientific side of it, so I brought together the experts, many of whom I knew personally, in virology. My co-chair, Shelly Wolf, brought in the more medical people and the people who were actually taking care of the patients. I can't remember whether we brought in industry or not. I'd have to look back. I haven't looked at the report in years.

ZIERLER: Were people talking about vaccines that early?

BALTIMORE: Yes. When the virus was identified, in roughly 1983, in the United States, building partly on the French work, building on the work that Gallo had done in his lab, it was announced by Margaret Heckler, who was then the secretary of I think it was called Health, Education and Welfare, HEW—in a press conference, a lot of hoopla—"We found the virus, we know it's a virus." It was very important that it be identified as a virus. She said then, "We should have a vaccine in two years." She said it because we had this great history of making vaccines when there was a viral disease, and we had made lots of different vaccines. She said, "This should be like other—we have people who make vaccines who are wonderful, so why shouldn't this generate a vaccine in short order?"

ZIERLER: Did that strike you at the time as pie in the sky, or did that seem reasonable?

BALTIMORE: It struck me as pie in the sky, struck a lot of people in pie in the sky, immunologists in particular, because it was clear that the virus was attacking the immune system. If the virus is attacking the immune system, it could well be that you couldn't really make a vaccine against it.

ZIERLER: What does that tell us about the virus itself that makes it evasive to vaccines?

BALTIMORE: We didn't know what that would mean, and in the end, the fact that it affected the immune system was not the reason that the vaccine was so hard to make. We might have gotten around that. The problem is in the virus itself. The virus is very structurally flexible, meaning that it can maintain its nature as a virus in the face of many mutations, and that's the core of the problem making a vaccine. It's why we still don't have a vaccine. We have now discovered in the last decade that there are great antibodies that if we could make them, would protect us. The problem is that we can't design something which will artificially induce those antibodies. In fact, the way we make vaccines, we never worry about inducing a specific antibody; we just assume the immune system in its generalized coverage of immunity will have a segment that works against the virus. That turns out to be true for most viruses, but it's not true for HIV. HIV always finds a way around whatever the immune system makes.

ZIERLER: What contributions did the Academy report make in the public health realm, education and that kind of thing?

BALTIMORE: They provided a lot of resources for public health, for getting people to protect themselves, condoms. Spreading of condoms and clean needles were two very important aspects. Public health was a very important part of the report.

ZIERLER: What was the response, in industry, academy, government?

BALTIMORE: There was a response everywhere. The research community responded. Industry, I don't know that we take any credit for industry developing the drugs that it did. I don't even remember whether we had AZT or not. I could go get the report and look at it.

ZIERLER: People were talking about a cocktail approach at that point?

BALTIMORE: I don't think so. I think we had AZT, and it worked, but it was very easy for the virus to mutate around it, so we needed much better drugs and we knew it. It wasn't a cocktail approach yet. The history of that is interesting, because the cancer people had developed the notion that the way to make drugs against cancer was to make multiple drugs so that the cancer couldn't mutate against all of them at the same time. There was no question that multiple drugs were better than single drugs, so that idea was well developed. It was also well developed from a theoretical point of view. You can go back to the Luria-Delbrück experiment. But we weren't ready for that yet. We needed drugs that were better. And once industry learned that there was one drug, it rose to the occasion and started making many drugs, and some of them much better, and harder to mutate around. Then as combinations they could provide a really durable immunity. That took another 20 years.

ZIERLER: Do you think the Academy had a role in changing the tone in the Reagan administration that wouldn't even touch this for the first six years?

BALTIMORE: I think it helped liberate the people at NIAID to mount a serious response, even in the face of Reagan's reticence about using the word.

ZIERLER: What did you think about the ACT-UP protesters?

BALTIMORE: That's interesting. I was sort of horrified by them, particularly because they were attacking Tony Fauci. I had a lot of respect for Tony and I knew that Tony had given his life over.

ZIERLER: He was the wrong guy to be angry at.

BALTIMORE: He seemed like totally the wrong guy. He, in the end, invited them into his office, and he was wonderful about it. He today says that they changed the way he saw the issues, so I was probably being too conservative, and the activism really was a worthy and appropriate approach. It had never happened before that patients rose up against the research people who were trying to help them. But it does now, and it has activated people to work on all sorts of diseases they might not have had any intention of working on.

The Origins of the Human Genome Project

ZIERLER: New topic. The Human Genome Project, were you involved at the earliest discussions that would lead to this collaboration?

BALTIMORE: Yes, I was. I helped run one of the meetings.

ZIERLER: How far back does that go? What year are we talking about? Like if we could orient your involvement with the Whitehead Institute, for example. Early 1980s, around that timeframe? Or would it have to be after automated sequencing, 1986 or 1987?

BALTIMORE: It's certainly after 1986 or 1987, because of automated sequencing, but the discussions started right then. Again, I'd have to go back and look, but there was a letter that Dulbecco wrote, and I don't know when that was published. Then there were meetings being held. I wasn't deeply involved in that—I was doing other things—but my good friend of that time, David Botstein, was deeply involved in it, and helped run the meetings and develop the commitment to sequencing. The mantra of the time was, "Map first, sequence later" because we all felt that you needed to lay out the framework in order to then go down to the next level of sequence and fill in within that framework. Actually the contribution of Venter was very much to question that and to say, "If we just get lots and lots of sequence and give it to a computer, it should be able to put it together." The problem with that, the reason that many of us were skeptical about that, was the vast amount of repeat sequence that we knew existed and that made it very hard to figure out what the overlaps were. Up until recently, there were still gaps in the sequence. Even though we said we had sequenced the genome, there in fact were gaps, because of all this redundancy.

ZIERLER: Was it conceptualized to be an international collaboration from the beginning?

BALTIMORE: Yes, it was.

ZIERLER: Just because the scope of the project is that big?

BALTIMORE: Right, and because there was a very real feeling that this didn't want to be owned by one company, and that's where there was tremendous opposition to Venter, because he started a company to do this, or any one country. It was the genome of the whole world, and the world should have been involved in making it visible.

ZIERLER: The supercomputers that DOE had, was this always a factor, that there was the recognition that we needed that level of computational power for this?

BALTIMORE: Yes, there was no question about that. DOE actually played a very important role in establishing the commitment to sequence the genome. They've been sort of left behind.

ZIERLER: That's right, everyone thinks it's an NIH story.

BALTIMORE: That's right. They were actually there earlier than NIH.

ZIERLER: The impetus to do this, what aspects were motivations of fundamental research, and what were specifically translational motivations, as in, if we map the genome, we'll be able to do x, y, and z?

BALTIMORE: It was both. The community of people interested in inherited diseases saw it very much from the second point of view. If we can sequence the genome, then we can sequence people who have inherited disease and find out what gene it is. Now, we already had some genes—cystic fibrosis, a couple of others—but there were 8,000—I can't remember an exact number—inherited diseases. We weren't ever going to find most of those without some kind of organized approach to the issue. There was a serious community of people who saw it as laying bare the underpinnings of genetic disease. But people who had been involved in genetics, particularly in the genetics of other organisms not humans, often model organisms—drosophila, yeast—they wanted the genome sequence because it would make their work so much simpler, to know what the whole sequence was. I viewed it myself during that time as providing closure, because we were then isolating genes that caused cancer, oncogenes. For instance, my own work had shown that enzymes that phosphorylate tyrosine were often oncogenes. The question was, how many were there in the genome? We didn't know that. There was no simple way of finding out. If we had a sequence of the entire human genome, we could count them, and we could know if there were 100, that there were only 100, that there weren't 1,000. It had to be that the human genome was sequenced, because there's no model organism that would have the same number of these things. Every organism has evolved separately, and that turns out to be true in spades. Some organisms have many, many tyrosine phosphorylated genes, others have many fewer. In a sense, everyone had their own lens to look at this, and their own reason to want to see it happen. But it was such a break from the way we had done science in biology that there was a strong opposition and there was a lot of uncertainty. I put myself in the category of people who were skeptical that we might first of all change the nature of biological research, that we would put in an enormous amount of effort, spend a lot of money, and not get the value for that spend, because it was just going to be a lot of A's, G's, C's, and T's. That turned out to be short-sighted, because once we had the genome, it did change our science, but it changed it for the better, and I and everybody else used this catalog of information as the basis for future research.

ZIERLER: That's from the fundamental perspective. What about the exuberance in the early years that once we've mapped the genome, disease will be conquered, designer drugs and all the rest. What has aged well and what has not?

BALTIMORE: That didn't come from the research community; that came from the popular community. And I understand why.

ZIERLER: From a layman's perspective, it does seem to make sense.

BALTIMORE: It does seem to make sense. But we knew that we were going to see a lot of A's, G's, C's, and T's, and to make science out of those was going to take a long time. We knew there were three billion base pairs. That's a huge number. That will keep a lot of people busy for a long time. And we're still busy. We didn't expect miracles to just drop out into our lap, but we did expect and it was true, that it would change the nature of research. It would simplify a lot, because you looked it up; you didn't have to isolate it, sequence it yourself. We had been doing that for years—isolating what we wanted to look at, characterizing what we cared about—but that was all in the past. That was no longer necessary.

ZIERLER: Are there clinical applications like cancer immunotherapies where you can draw a clear line between what we have today and what the Human Genome Project was able to accomplish?

BALTIMORE: Not cancer immunotherapy. Some of the aspects of the genome sequence were used in that—the particular genes involved, the manipulations of vectors. Lots of things were made possible by the technology that came out of the genome. But the sequence of the genome was not really the key there. Other aspects of immunology were the key. But I'll tell you, the advances in cancer research, not so much immunotherapy but the understand of the genes involved in cancer—today we look at cancer virtually as a personal disease. My cancer is different than your cancer. That's because the genes involved, mutations involved, the interactions that are involved, are complex enough that for each one of us, it's a little different than the other. Therefore, when you treat those diseases, you treat my cancer and your cancer differently, even though they may have the same name, look roughly the same, but we can get down to the underlying genetics of the situation and show that they're not the same and that I'm going to respond to one set of drugs and you're going to respond to a different set of drugs. To that extent, the genome really opened up the complexity of cancer in a way that simply would not have happened. That goes back to the insight that Renato Dulbecco had in starting the discussion about sequencing the genome by pointing out the need for this range of knowledge to understand cancer.

ZIERLER: Is there a long game to play here? That in x number of years, we will see an outcome?

BALTIMORE: Well, yeah, we are seeing an outcome from it, slowly emerging, but it's not embedded in our research, so almost everything that goes on in biology is richer and deeper in understanding, because of the genomic data that we have.

ZIERLER: These are not headline news generating developments.

BALTIMORE: No, they're not.

ZIERLER: This is more gradual. This is just the way we approach the problem.

BALTIMORE: Right. And the sequence of experimental animals has been equally important, maybe in some ways more important. We understand tumors in mice today extremely well because of the background of having the mouse genome. And on and on it goes like that. But it has also opened up regions of science that were moving much more slowly, in particular evolution. Today, evolutionary biology is all based in genome sequence. When we talk about everything from fossils to the nature of particular organisms, the forces at work that lead to selection of certain organisms in certain situations, that's all genomically based now.

ZIERLER: Moving back to your lab in the 1980s, what was some of the work that you and the postdocs and graduate students were doing on leukemia at this point?

BALTIMORE: We had been interested in leukemia for a long time.

ZIERLER: You transferred this over from the Cancer Center, I imagine?

BALTIMORE: Yeah, but there's a wonderful story. A guy named Ronald McCaffrey came to my lab from Children's Hospital in Boston. I was still at MIT. This would be 1971, 1972, very soon after I discovered the reverse transcriptase. Ron, lovely man that he was, had no background in science. He just had a feeling that if you wanted to understand leukemia, you had to begin to use molecular methods. Maybe viruses actually caused leukemias in humans? We didn't know at that time. He saw the reverse transcriptase as a real lead to studying human leukemia.

ZIERLER: This is pretty deep thinking for a non-scientist?

BALTIMORE: Well, it was pretty shallow thinking, actually. Look, he was an MD. He had made his way to Boston and only the best—he was a smart guy. It's just that he had no real training in biochemistry, and biochemistry was the issue. I was excited to get a real MD, somebody who knew disease, to come to the lab. We had developed an assay for the reverse transcriptase that was very sensitive, very easy to do, and so you could search in tumors to see if they had a virus in them. There were lots of people doing that, not just us. But I felt that our handling of the biochemistry gave us a particularly sensitive way of doing this. Here was a guy who wanted to do that. That was his dream experiment, to look for reverse transcriptase in human tumors, as a measure that they were being caused by viruses. He came over, continued seeing patients. He wasn't 100% in the lab, but he was a lot. He learned how to do the manipulations to do the assays, because he really had never seen anything like that before. Then he got some samples from children's tumors. No, that's not even true. From tumors, from leukemias. Leukemic cells. Broke them open and started assaying them. A very dangerous thing to do, in the sense that you're looking at a gemish [Yiddish: mixture] of everything in the cell, and hoping to get a signal of a very specific enzyme. It usually doesn't work, but I was happy to see him give it a try. It was a good start for him. I'm sitting at home one evening, and the phone rings, and it's Ron. He said, "I found it!" I said, "Wait, what have you found?" He said, "I've got this sample. It produces an enormous signal. I said, "Tell me what controls you've done. Have you left out this? Have you left out that? Have you shown what's required?" In particular I said, "Have you left out the other—" I have to explain this.

What he was looking for was incorporation of radioactivity into an acid precipitable product, and the radioactivity was being added to the reaction mixture as part of one nucleotide, probably T, of the four nucleotides in DNA. But you add the other three non-radioactive, and so if you're making DNA, you can add all four. If you leave out any of the others, then this one won't be incorporated, because it's copying DNA. It's copying DNA that has all four. I said, "Have you left out the other three nucleotides?" He said, "Well, no, I haven't done that control" and he hadn't done some other things. I said, "Go home, go to sleep, tomorrow come in, set up the controls." Tomorrow comes and Ron gets in touch with me. I can't remember whether he walked into my office or called me or something. Absolutely the most dejected human being. He said, "If you leave out the other triphosphates, it still works just as well." [unrelated call with Rick Klausner]

BALTIMORE: My latest venture.

ZIERLER: We'll talk about that too, at some later date!

BALTIMORE: [laughs] Yes.

ZIERLER: So he went home, he got up in the morning, he was crestfallen.

BALTIMORE: He went into the lab, did the experiment, and was crestfallen, because in those days, you got the result right away.

ZIERLER: What did he miss, or what did you see?

BALTIMORE: I knew that there was an enzyme that could make homopolymers called terminal transferase. It had been discovered by a guy named Fred Bollum, been worked on by him and people working with him. Wasn't well known. I knew that it was in the thymus, which is where leukemia comes from. When he told me that the incorporation was independent of the other triphosphates—you could take them out and still continue—it had to make a homopolymer in that case, all T's, because that was the only thing it could make. And that it would be that enzyme. Ron knew nothing about that, and so he then tested a whole bunch of samples and a few of them were positive, and a lot of the others were negative, and it correlated with a tumor that came from the thymus, and my instincts were in fact exactly right to what he had. For the rest of his career, he worked on this as a marker of the origins of leukemia, so it in fact gave him exactly what he wanted which was a handle on leukemia that was coming out of molecular analysis, but it had nothing to do with a virus. He stayed in my lab for a couple of years and built that whole thing up and continued on to this day.

Sustained Interest in Leukemia

ZIERLER: In the 1980s, the ongoing work about leukemia, what were you and your students doing at that point in the Whitehead?

BALTIMORE: The major thing that we were doing was working on the Abelson leukemia, the Abelson virus-induced leukemia. That was actually thymus-independent, so it was a different kind of leukemia. What we wanted to know really was what was the relationship between leukemic cells and normal cells, and could we use leukemic cells as a probe for normal differentiation. That was an old question in cancer analysis, of how close were cancer cells to normal cells. But we could do that in the context of DNA rearrangements, so we could use DNA rearrangements as a marker of the differentiated state of the cell. One thing that we showed was that all of the leukemic cells had their heavy chains rearranged, but many of them didn't have their light chains rearranged. We postulated—and it turns out to be very general and very true—that in the differentiation of normal B lymphocytes—these were all B lymphocyte precursors—that the first thing to rearrange is the heavy chain; the second thing to rearrange is the light chain, and many tumor cells have not yet gotten to the point of rearranging the light chain. Today, everybody characterizes tumors by whether the heavy chain is rearranged, the light chain is rearranged, whether they are making different proteins. But at that time, it was a major discovery, that there was an ordered process of rearrangement. The next question of course is what orders the process of rearrangement. Although I stopped working on that question many years ago, my students have continued to study that, and the maven of that line of research is Fred Alt who came from my lab and worked with me in the early stages of this.

ZIERLER: Later in the decade, the postdocs David Schatz and Marjorie Oettinger, what were they doing?

BALTIMORE: Didn't we talk about their work?

ZIERLER: I don't think so. We talked about Ranjan.

BALTIMORE: They were interested, in particular David Schatz, in the enzymes that caused rearrangement of DNA, what we ended up calling the RAG genes. David started working on whether you could transfer into a fibroblast the ability to rearrange a gene. He showed that you could. That then led him to search for the gene that was involved, and be brought Margie Oettinger into that as a new student. He was a student; she was a somewhat younger student. Together they found that there were two genes that had to be put into a fibroblast to get it to rearrange immunoglobulin genes. It has nothing to do with heavy chain and light chain. Two RAG genes—RAG 1, RAG 2—which are located next to each other on a chromosome. Had they not been located next to each other on a chromosome, we never would have found them using the methods that we were using. That was when we published it big news.

ZIERLER: What was the significant? Why was it big news?

BALTIMORE: Suddenly you went from knowing that DNA was rearranged to knowing what genes were involved in making the proteins that allowed for rearrangement. That meant you could study mechanistically how the rearrangement occurs. What are the signals for it? How do these proteins attack DNA? They're bringing together two disparate pieces of DNA to join them together. How do they do that? That has been a whole subfield of immunology since we discovered that, and David made his whole career doing that.

ZIERLER: More broadly, of course, the name of the game for the Whitehead is translational breakthroughs. How did the Institute interface with industry? How did that work to get these things ultimately into clinical applications?

BALTIMORE: We wanted two things. We wanted Whitehead to be an institution of basic science where the role of translation was to take advantage of what the basic science had uncovered and to allow society to have the fruits of that, without becoming so involved in it that it was the driving force of research at the Institute. We didn't want it to be a driving force. We wanted the driving force to be basic science and the spinoff to be the applications.

ZIERLER: Jack Whitehead was on board with his approach? He understood the way to do it?

BALTIMORE: He wouldn't have understood that at the beginning, but yes, he became fully understanding of this approach.

ZIERLER: Was there a management of expectations component to this, at least in the early years, to get him to understand what the process was, how this would look long term?

BALTIMORE: He had been around. It didn't require teaching him a lot. It required changing a sense of priorities. When he had approached Duke, it was very much with an idea that translation was the key. But that hadn't worked, and one thing he had learned from that was that clinical work is very expensive. It's much cheaper to do basic research, and so it's much more efficient in terms of your money, to spend the money on basic research and let the applications flow from the science, not the other way around, the science flow from the applications. It meant that you weren't necessarily working on cancer; you might be working on heart disease, you might be working on just basic DNA mechanics, and it then would have a consequence for leukemia, or for whatever else it might. He became perfectly comfortable with that.

ZIERLER: When venture capital started to get interested in biotech—Paine Webber, 1986 and 1987 investing in Amgen, Genentech—did this register with you? Was this significant for what you were accomplishing at that point?

BALTIMORE: Certainly yes. It meant that the volume of the industry was just growing and growing and that therefore the opportunity for translation was larger and larger, and we were very aware of that—the startup of Amgen, of Genentech, of Biogen, and of just a myriad of smaller companies.

ZIERLER: We'll get to Rockefeller in due time, but just to foreshadow to that, by the end of the 1980s, was Whitehead in a secure and smooth enough operating position where it was going well on its own and you did not feel a burden or a need to stick around longer than you did?

BALTIMORE: Yes. And in particular, when I had started Whitehead, I said to myself, and maybe I said it to other people, that the measure of success will be, "Can I leave it?" By the end of the 1980s, it was clear I could leave it. I had a group of people each one of whom independently was doing magnificent work, and interacting with each other in a very collegial and effective manner. They didn't need me at that point, and it turned out they didn't.

ZIERLER: You mentioned previously all of the initial concerns at MIT administratively, those had fallen by the wayside?

BALTIMORE: All of those had fallen. By 1988—we opened in 1984, and after four or five years of functioning, it was all—because it was a pretty simple place. There were only at that point probably 12 faculty, and five or six fellows.

ZIERLER: Roughly speaking, was it a five-year plan that you had put yourself on? Did you have any conception of what kind of a time commitment this would have been? Purely open-ended?

BALTIMORE: Yeah, it was purely open-ended. I must say I didn't think I was going to leave it.

ZIERLER: You mean that could have been a capstone career position?

BALTIMORE: Yeah, because at that time, I had a lot of freedom to do my own work. In fact, I was very productive through that whole period, or my lab was, and I was just sort of looking ahead to more of the same.

ZIERLER: The smoother the thing ran, the easier your administrative burdens would be.

BALTIMORE: That's right. And since I really believed in small, and I was very glad to have this thing not grow, but be a steady state organization. I was a little horrified when Gerry Fink took over and the first thing he did was build another building on it.

ZIERLER: [laughs] That's what happens when you leave. You don't have a say in those things anymore.

BALTIMORE: A, I had no say, and B, it makes sense. The next person wants to show that they were a real leader.

ZIERLER: David, now for today's main event, The Baltimore Case.

The Baltimore Case and Laboratory Science

BALTIMORE: Yeah, right. Right.

ZIERLER: Maybe it came from Dan Kevles' book, but does the phrase "The Baltimore Case" rankle because it might suggest to somebody who doesn't know anything about the specifics that somehow you yourself were implicated in wrongdoing?

BALTIMORE: Sure. But the other side of it is that it wouldn't have been a case at all if I weren't involved, and I know that. If it was just poor Thereza on her own.

ZIERLER: This thing would not have metastasized.

BALTIMORE: No, and it would never have made it to the halls of Congress.

ZIERLER: Let's start with the science. What was the experiment that you initially conceptualized?

BALTIMORE: In the very early times that I started in immunology, there was a new technology that was developed. It was developed at Columbia. I don't remember everybody who was involved. What that allowed to be done was to put a new gene into the mouse genome. It wasn't easy. There were very few people who could do it. I guess it was developed first by—won the Nobel Prize, was in Utah, came from Harvard originally. What's his name? [Mario Capecchi]

ZIERLER: We'll come back.

BALTIMORE: Easily found. This would be a powerful way of examining the immune system. In principle, it would allow you to put a rearranged immunoglobulin gene into a mouse and get the mouse to make a very particular antibody that you wanted. But as a probe of how the immune system works, this organized rearrangement that we were beginning to understand how that comes about and how it works, this probe would be absolutely phenomenal. I got in touch with the guy at Columbia who was doing this, whose name I am also going to forget—Frank—something Italian [his name was Frank Costantini]. I said, "Can we put in an antibody gene into the mouse?" He said, "Well, you can put any gene in." I said, "Look, I'll get all the stuff organized in my lab, and then will you put the gene in for us?" He said, "Sure." It was one of the very first applications of this technology. He was successful, and we had a mouse with a rearranged gene in it. And we had put in a gene for a known antibody that had been characterized—that's right, I have to go back a step. There was an immunologist in Germany who had been working on this particular antibody for a long time, and had shown a lot about it. The antibody bound to a small molecular structure which you could characterize very precisely. It was a very nice experimental system. Klaus Rajewsky by name. I had gotten in touch with Klaus, actually, earlier even, and said, "This system really ought to be analyzed in molecular detail. He said, "Yeah, but I can't do that." I said, "Well, I can do that."

ZIERLER: What did you have that he didn't?

BALTIMORE: I had all the molecular techniques. When I set out to go into immunology, I developed those techniques in my lab. He was a much more biological guy. Later he became much more chemical. I was working on that system, so that was the thing we wanted to put in the mouse. We were successful, and we published that. Oh, and Thereza—ah!—and Thereza was at MIT and she had been working on that system, she actually initiated it when working in Finland. She had been in Germany with Rajewsky, and then on her own, and then we had hired her at MIT. She was collaborating with us on this project. I think she was an author on the first paper. We published that you could put in this gene and it would make antibody. Then we looked at the consequences of making this antibody, and there were some amazing things going on. It was being followed by everybody in the community, because it was sort of a lead to how to use molecular techniques to analyze a physiological question in the immune system. All of that was going along fine when Thereza, in analyzing these mice, found that they had a global alteration in the immune system that nobody had ever seen anything the likes of. She interpreted this in terms of a network concept that had been developed by Niels Jerne. Niels Jerne was a legendary immunologist, Nobel Prize winner ultimately, but also had a very sort of philosophical way of looking at things and really enjoying thinking about this network concept. But we published this, and we talked about in the discussion the possibility that there was some network interaction. Because Thereza wanted to say that. I didn't really want to say that, because I didn't believe it, and I thought that the Jerne concept had not found core experimental verification that the network even existed, never mind that we had perturbed it. But I couldn't say it didn't happen, and Thereza was wedded to this notion, so we commented on it in the paper. Actually it doesn't involve the experiments at all; it involves an interpretation of the experiment.

ZIERLER: When did you first meet Thereza?

BALTIMORE: Well, when she gave to give a seminar at MIT. I don't remember whether I had anything to do with hiring her or not. I might have?

ZIERLER: What was she working on before and how closely was it related to this?

BALTIMORE: She was working on this gene system that made—it's called an ideotype, and it made these ideotype-specific antibodies. That was her whole program, and she was one of the world's absolute experts in this area.

ZIERLER: You were impressed with her?

BALTIMORE: Oh, yeah. And she was not the usual postdoc coming into her assistant professorship, because she had a more responsible position in Europe before she came to the United States.

ZIERLER: So she was like a quasi-assistant professor at this stage in her career?

BALTIMORE: We hired her as an assistant professor. But in Germany, or actually in Finland where she ended up—after her training with Rajewsky she went to somebody's lab in Finland, and had been there for a number of years, so she was somewhat older than the average, and more mature, in a sense, than the average assistant professor. [That history is wrong. TIK was a student in Finland, married there and then moved to Germany where she was a post-doctoral fellow for a few years.]She started a laboratory, and she got some younger people working with her quite quickly after she arrived. She probably arrived around 1975, something like that.

ZIERLER: In your personal interactions with her, anything strike you as odd about her personality?

BALTIMORE: First of all, she had significant difficulty with English. That was now her, I don't know, fourth language. She's actually from Brazil. She grew up speaking Portuguese. She then had been trained I guess in Europe, so she spoke German, and then she ended up in Finland and spoke Finnish. But everybody in science speaks English, so she did speak English, but with this complicated background. That was one characteristic of her, that she had a very odd way of phrasing things sometimes. You just had to get through it and understand what she was saying. She would sometimes say things that were really hard to understand, because she just couldn't formulate them in a way that translated what she was thinking into what she was saying.

ZIERLER: At her career stage, obviously she's not a graduate student, would you ever have been in a position to look at her notes or to see how her work process was going?

BALTIMORE: Not in an intrusive way. I'm trying to figure out what the best way to say this is. I saw a lot of her work. I saw the notebooks and such when we talked about specific experiments, and the information was all in the notebooks, but I never examined them for what they might contain.

ZIERLER: You would never have been in a position to reproduce any of her experiments?

BALTIMORE: Right. To a very large extent, what she could do and what she did do involved utilization of reagents that I had no experience with, and that she was a master of. I had my contributions to this, and she had hers, hers being the characterization of the antibodies that were being made.

ZIERLER: So there was really no way for you to independently get a sense that something might have been off, major or minor?

BALTIMORE: Yeah, but I also had no reason to think anything was off.

ZIERLER: Sure, this is a trusting environment. These are people who are doing good work. That's not the culture in the lab.

BALTIMORE: Right.

ZIERLER: When does Margaret O'Toole enter the picture?

BALTIMORE: Thereza in getting her laboratory going had gotten people from wherever she could get them, and it's true of all of us when we start out—you're looking to build a group, but you're not known very well in the community, and so you want the very best people, but the very best people don't necessarily want you.

ZIERLER: Especially if somebody like David Baltimore is around also.

BALTIMORE: Yeah, but lots of other people. The kinds of things she did, I was not any competition for, but there were lots of other people who were. And students don't really know necessarily what it is they want to do; they go on the basis of reputation and what they hear in discussion with other students, so it's hard to get started. She had some good people; she had some marginal people. I think Margot came from a laboratory at Tufts that was doing the kind of serology and ideotype analysis that Thereza did, but Margot—she said this—was looking to make a bigger splash than she could out of Tufts in the lab that she was in.

ZIERLER: Why would she have been looking specifically to reproduce this experiment? Was that something that would happen normally in the course of events at a lab?

BALTIMORE: No. I've never been able to understand what drove Margot.

ZIERLER: Is it possible that she was out to get Thereza even before?

BALTIMORE: No, I don't think so.

ZIERLER: What justifies reproducing another person's work? Why do it? Is this common? Do you hear of this kind of thing?

BALTIMORE: No. First of all, I've generally avoided characterizing Margot in any way at all, because it's a no-win situation for me.

ZIERLER: But it's fair to say just at an objective level, one person going about specifically trying to reproduce another person's work is an out-of-the-ordinary kind of endeavor?

BALTIMORE: This is the kind of thing you can say, and particularly years ago, if I had said it, it would seem like I'm attacking her, and so I just have never characterized what she was doing, and I just make the assumption that she was in Thereza's lab and that anything going on in Thereza's lab was hers to become involved in or not.

ZIERLER: When you say she's looking to make a bigger splash, in what field? Exactly the field that Thereza is working in?

BALTIMORE: Yes, right, that's why she came to Thereza's lab.

ZIERLER: So she reproduces the experiment. When do you first hear about the fact that she's doing this? Is this happening in real time, or are you hearing second or third hand?

BALTIMORE: I was not hearing anything about her. I didn't know she existed until I began to hear that she was having difficulty repeating something that—it wasn't that she did repeat those experiments.

ZIERLER: She couldn't.

BALTIMORE: She couldn't. There are a thousand reasons why somebody can't repeat an experiment, so in general, you don't take tremendous notice of somebody who hasn't been able to repeat something.

ZIERLER: You don't think anything about malfeasance?

BALTIMORE: No.

ZIERLER: It's about technique, it's about lack of perspective, it's those kinds of things?

BALTIMORE: Right, and these are hard experiments. As I said, Thereza had very special knowledge of how to handle these reagents, and I didn't know whether Margot did or didn't.

ZIERLER: Do you have a specific memory of when you started hearing about this, that there was a problem brewing?

BALTIMORE: No, I don't. You see, it was not from Thereza.

ZIERLER: She would not have been the person to report these things to you?

BALTIMORE: No, she wasn't. Because it was about her lab; it was nothing to do with our—I didn't think it had anything to do with our collaboration. I'm very vague about that.

ZIERLER: When did it start to be a problem?

BALTIMORE: When Margot took it out of the lab. She complained to some people at Tufts, because she had come from Tufts. And I don't know, it just built up over time.

ZIERLER: But you're the director. The reporting structure should be that if she sees problems, don't you handle that internally? Was that a red flag for you?

BALTIMORE: Wait a minute. I wasn't in any administrative capacity relative to either Thereza or Margot.

ZIERLER: But you're director of the Whitehead Institute?

BALTIMORE: Yeah, but they weren't at the Whitehead Institute. She was in the Department of Biology; she wasn't at Whitehead.

ZIERLER: Ohhh. I thought this was all internal to Whitehead.

BALTIMORE: No, no. She was in the Cancer Center, and she was a professor at MIT, but I had no authority over her at all. We were just two faculty members who were—

ZIERLER: Same question but different person. Don't you bring this up to the department chair or the provost?

BALTIMORE: Well, ultimately, yes.

ZIERLER: But I'm saying best practices, why go to Tufts first?

BALTIMORE: Oh, no, I didn't go to Tufts.

ZIERLER: No, Margot, why does she go to Tufts first?

BALTIMORE: Oh, because she's not getting a sympathetic reaction from Thereza. Thereza began to feel, I know, that Margot was not the greatest postdoc she had ever had. And Margot, who had come over, as I said, to make a splash of some kind, because she wanted to advance her career, was finding that her career was going down the drain, and lashed out. Again, I really don't want to get into characterizing her. I mean, I've got my own beliefs.

ZIERLER: So she starts making noise at Tufts, and then what happens?

BALTIMORE: I think actually the guy she worked for at Tufts may have been the first person to really sort of call me up and say, "There's a problem." Then I talked to Thereza about it, and Thereza just felt that Margot had been unable to reproduce the experiments. She didn't know exactly why Margot was trying to do that in the first place.

ZIERLER: What was the problem that the researcher from Tufts conveyed to you? How did you understand what you were hearing?

BALTIMORE: That she had been unable to repeat experiments which we had jointly published in the analysis of these mice.

ZIERLER: But again, as you said earlier, there's all kinds of reasons why one person cannot reproduce. Were you already thinking that this was something beyond a technical inability?

BALTIMORE: The answer is no. I had no idea why she was doing this, why she was raising questions about the published paper.

ZIERLER: This is much ado about nothing, so far.

BALTIMORE: Right.

ZIERLER: And you communicated this to Thereza, what you had heard from this person at Tufts?

BALTIMORE: Yeah, I think that's right.

ZIERLER: Any recollection of that exchange with Thereza, what her response was?

BALTIMORE: No, all I remember is that she did not think this was a serious challenge to the science of that paper.

ZIERLER: Did you ever talk to her about sitting down with Margot in the lab and let's reproduce this together, let me show you what I did?

BALTIMORE: Wait. I had never tried to reproduce it.

ZIERLER: No, in you talking to Thereza, you're hearing that there's this problem, and you don't know what it's about. Thereza doesn't think it's a serious challenge. Did you and Thereza talk about maybe Thereza just sitting down with Margot and saying, "Here, let me show you what I did"?

BALTIMORE: I think she had done that, or at least tried to help Margot get results.

ZIERLER: So there's no defensiveness at this point; there's "Sure, let me show you what I did."

BALTIMORE: Right. Well, no, I just don't remember anymore.

ZIERLER: We have to get from here to the NIH investigation team getting involved. How do we get to that level? What are the steps in between?

BALTIMORE: Yeah, that's what I was going to read the book, and I never did, because I think all of that is in Dan's book.

ZIERLER: Well, it's important, just your memory. Not what he recreated; your memory of this. Did this hit you like out of nowhere that the NIH was involved and they were investigating?

BALTIMORE: Oh yeah, absolutely, it hit me out of nowhere.

ZIERLER: Okay, so there's no problem, this is much ado about nothing, and then the next thing you know, NIH is sending investigators to figure out what's going on?

BALTIMORE: No, it wasn't like that. No, there were many steps in between. What I wanted to do and I haven't done it is to get straight the chronology, because it went right to Congress. It didn't go through NIH.

ZIERLER: You mean Congress authorized NIH to do the investigation?

BALTIMORE: No, no. John Dingell heard that there was an experiment done by a Nobel laureate that can't be reproduced and that this shows that scientists can't be trusted.

ZIERLER: Big news.

BALTIMORE: Right.

ZIERLER: He wasn't bothered by the fact that it wasn't the Nobel laureate who did this experiment?

BALTIMORE: He never understood, at first, who actually did what. I was involved, because I was an author on the paper. If I'm not mistaken, yeah, his investigators—do you know much about John Dingell?

ZIERLER: Sure.

BALTIMORE: Dingell had a huge power in the Congress, and he had his investigators were the most ruthless, disgusting human beings, and would browbeat people, would threaten people, and they dug this up and came to him with it, because he didn't do things like that. He thought he had an open-and-shut case. It is my understanding that what John Dingell wanted out of it was what he got in lots of other realms, which was power, the power of a budget. He wanted power over the NIH budget. He wanted people to come to him. He actually cared about NIH in a very honest way. His father had been involved with NIH. He thought he had a very simple situation that he could exploit, and that his dogs would make sure that he wasn't tarred with this in any way. They'll keep everybody in line. And they would do that. They would do that with the CEOs of big companies. They loved to do it, actually. And these guys would come crawling to his committee because they couldn't afford not to. When I stood up to his committee and didn't bend to his investigators, he was just horrified, insulted. And that was the origins of this whole thing. Now, it got to NIH because Dingell said, "I'm not getting the cooperation that I want" and so it came over to NIH.

ZIERLER: I'm still not getting how this got to Dingell in the first place.

BALTIMORE: Well, do I know the answer to that?

ZIERLER: Without trying to understand Margot's motivations—

BALTIMORE: Wait a minute now. I'm going to go look at the book, but I think it is possible that Margot brought it to the Dingell committee. Now, how did Margot know about the Dingell committee? That I don't know. But I believe she brought it to them, and her interests and their interests aligned. Because he loved this attractive Irish woman as his foil for attacking fraud in science. This all goes under the heading of fraud in science.

[What I had completely forgotten was the role of 2 people at NIH, Walter Stewart and Ned Feder. They had made a profession of uncovering what they considered to be fraud in biological science. They heard about Margo's difficulty repeating work in TIK's laboratory and they took the issue to the Congressional Committee.]

[I should note that there were results in the challenged paper that were very hard to understand and led to somewhat fanciful interpretations. While looking back at this material, I found a paper that explained the whole controversy. It is by Richard Hodes who worked at NIH and published it is 1992. Given Hodes' work, the results in Weaver et al are easy to understand using ordinary concepts of immunology.]

ZIERLER: More broadly at this time, was fraud in science in the zeitgeist? Were people primed for this kind of thinking?

BALTIMORE: Yes.

ZIERLER: What was there? What were the issues?

BALTIMORE: Oh, there's always a little bit. There were cases. I don't remember the details.

ZIERLER: Fraud in science was something that could get people worked up, at this point?

BALTIMORE: Right. It was also relevant that the NIH budget had grown and grown and grown over those years, and so it was a tremendous target for him [Dingell]. It wasn't the Defense Department, which was the other thing he kept control over.

ZIERLER: Looking back, could you have nipped this in the bud earlier?

BALTIMORE: No way. I never saw a way out.

ZIERLER: Because you were blindsided?

BALTIMORE: Right.

ZIERLER: Before you had a chance, maybe, to talk with Margot directly about this, or whatever, this was already in D.C., before you could do anything about it locally?

BALTIMORE: Yeah. That's true.

ZIERLER: You could see why I thought this all happened in the Whitehead, because I'm still not seeing where you actually slot into this besides being a famous biologist at MIT.

BALTIMORE: I was a coauthor of this paper—that's why—so people came to me. It's probably also relevant that Thereza was so incomprehensible.

ZIERLER: She couldn't speak for herself as well as you could speak for her.

BALTIMORE: I could speak for the paper. And people at that point loved to point out that if you were an author on a paper, you should take full responsibility for everything in the paper. It's still an open question exactly how you do that, when you have a collaboration in which there are two different expertise coming together.

ZIERLER: That must be particularly difficult for somebody with your name recognition who everybody wants to put your name on their paper.

BALTIMORE: Oh, no, no, no. I've tried my best to avoid being honorary author. No, this was work I cared about. I had contributed. The first author on the paper was a postdoc in my lab, David Weaver. [However, I was not the last author, the one who is considered the senior author of the laboratory. That was TIK.]

ZIERLER: Whatever the merits of your name being on the paper or not, you were not in a position to know exactly what Thereza had done.

BALTIMORE: That's true.

ZIERLER: Obviously you make a decision at some point that you're going to defend the hell out of Thereza. Did you do that knowing fully that her science was solid?

BALTIMORE: I knew that her science was honest. I didn't know, and I don't know to this day, whether there is somewhere in it a misinterpretation or a mistake or something else. Because it was very idiosyncratic to her, this area of science. [The Hodes paper removes any concern that the there was a seriously wrong result in the paper.]

ZIERLER: Before we even get to malfeasance, what about simple sloppiness? Do you accept that she might have been sloppy with her notetaking?

BALTIMORE: Oh, absolutely. Well, she was—many people in those days were very sloppy in the way they kept notes. The idea that your notebook is a record of everything you've done and open to audit was not widely appreciated. I know scientists of enormous skill and reputation who kept the messiest—literally who had their notes on a paper towel and who would put in their notebooks—they'd paste in a paper towel. My view of a notebook was actually something quite precise, because I did biochemistry. When you do biochemistry, you've got to have a very precise knowledge of just what you added in that test tube, how much you did, what the pH was, what the magnesium concentration was, all those things. The next time you do the experiment, you have to be able to go back to the previous time and check to make sure, did I actually look at this variable? Remember I was talking about control. Did I do that control? Did I do this control? Nobody can keep all that stuff in their head, so the notebooks are very important to a biochemist. But to a cell biologist who is doing things that are more visual, a notebook is a reminder of what you did. It's helpful, and you write down your things that are important, but it's not an auditable record of exactly what you did at every step. You look in a microscope and you see cells that look this way, and you see mitochondria, and you remember that that's what you saw. You may not write down in detail what it was you saw. You may even remember faultily; I understand that. Today, nobody would make the kind of argument I'm making as being the appropriate way to act, but science was not as organized an enterprise in 1970 as it is today.

ZIERLER: You knew her notebooks were sloppy, but you were convinced that her science was honest.

BALTIMORE: Yeah.

ZIERLER: Why were you convinced that her science was honest?

BALTIMORE: Because she had been a contributing member of the scientific community for many years, and lots and lots of her work was well known to be the basis of other people's work. Fundamentally, it's the ability for people to build upon each other's work that is the validation of science. Because the experiments, particularly in the fields in which I work, are often very hard to literally reproduce, a much better test of whether they're honest, if they're the right result, is can you build upon it.

ZIERLER: So her reputation was relevant. She was a known entity.

BALTIMORE: Right.

ZIERLER: It was not conceivable for you that all of a sudden, this respected, trusted member of the community could have done something crazy like fudge the numbers intentionally. Didn't register.

BALTIMORE: Yeah, and the kind of thing we're talking about wasn't even central to what the paper had been about.

ZIERLER: Some peripheral thing that Margot had become worked up about?

BALTIMORE: Right.

ZIERLER: When you made the decision that you were going to defend Thereza, did you talk to her about that?

BALTIMORE: Oh, yes. And I looked over more of her research work. I was very open about it. Because I was taking a big chance.

ZIERLER: Did she ask you to come to her defense? Did she need to ask you?

BALTIMORE: No, I don't think she ever did. I think she would have handled it alone, if I hadn't taken the responsibility on myself.

ZIERLER: What about the fact that you were a coauthor on the paper? How much of this was about your reputation?

BALTIMORE: To that extent. But I could have said, "Look, this was her work. I don't know about it." And although I was on author on the paper, there was no question that it was not work that we had actually done in my lab.

ZIERLER: If you so-called let her fend for herself, that would have been justifiable?

BALTIMORE: I don't know if it would have been morally justifiable—

ZIERLER: Not for you. Obviously you didn't make that call. But other people could have looked at this and said, "That's not David; that's her."

BALTIMORE: Right. Oh, they wanted me to do that.

ZIERLER: When you go to Washington, how much is it about defending Thereza's reputation, and by extension your own, and how much of it was just refusing to kiss the ring?

BALTIMORE: Oh, a lot of it was [laughs] that.

ZIERLER: Had you known about Dingell and what he was all about before you got there?

BALTIMORE: Just a little peripherally. By the time I got to Washington, I knew a lot about him. I had, by this time, a legal staff working with me.

ZIERLER: Outside counsel, or it was MIT?

BALTIMORE: It was outside counsel. It was Akin Gump.

ZIERLER: The big boys. [laughs]

BALTIMORE: That's right. No, I worked with Akin Gump people, and what's his name, he died recently. The big black lawyer, Democratic lawyer, who was an Akin Gump lawyer, and I used to see him in the offices in Washington. He was very nice to me. He followed the case. [Vernon Jordon].

ZIERLER: Who retained the firm? Was it MIT? Was it you personally?

BALTIMORE: I had a personal lawyer, Normand Smith, in Boston, who worked with me very closely and helped me enormously.

ZIERLER: He knew your work as a scientist.

BALTIMORE: No, he was as much a friend. All right, how did I know Normand Smith? When I was a young scientist, I ended up on a review panel in Washington for cancer centers. For a couple of years there, I spent a lot of time going back and forth to Washington. There was on that panel a guy who came from Boston, also, from Tufts, BU, somewhere, and who did a lot of financial work on these. Because these were huge grants, these center grants, and they required financial analysis as well as scientific analysis. Russ de Burlo, this guy, was the guy on the panel who handled the audit side of it. He was an accountant but worked for the universities and knew that whole world. We were sitting next to each other on a plane one day and I said, "Russ, I need some advice." I'd gotten a little bit of money just partly through biotechnology, partly through salary. Our family had some money at this point. "I don't know how to invest it. I don't know what to do. I want to invest responsibly, not in armaments and not in cigarettes. Do you know anybody who could advise me?"

It turns out Russ was a [Quaker]—not a Mormon, I'm forgetting—but Russ had a friend who was a broker, but who cared a lot about social responsibility named Bill Jose. He introduced me to Bill Jose; I wrote it down on the plane. Jose set up an account for me and invested and was quite responsible about it, turned out to be a good friend for years. As time progressed a little, I said to Bill, "I don't have a lawyer. Do you know a good lawyer who would be compatible?" Because he knew me pretty well by then. He said, "Yeah, I do, Normand Smith. Normand is a personal lawyer, works at a firm in Boston." So I got in contact with Normand, and Normand became my legal advisor on all sorts of matters, financial and personal, and in the end became the go-to scientific misconduct lawyer in Boston because he got involved in this case. Normand was my legal help, and when the Thereza events occurred, I turned to him and said, "I need help." And boy, did I need help; I had no idea. When I was called before the Dingell committee, we assembled a team.

ZIERLER: What does it mean to be called? It was a request? You were subpoenaed? What was it?

BALTIMORE: It used to be called "getting a Dingell-gram."

ZIERLER: [laughs]

BALTIMORE: You got a letter from the committee, signed by these investigators, asking for all papers that are relevant to this, or all notebooks, everything. Ultimately, they called me in front of the committee. But did it involve a literal subpoena? I don't know. But it didn't involve any choice. To prepare my testimony and my position, I was introduced to the Akin Gump firm and had a specific guy there whose name escapes me [Daniel Joseph]. We drew up a whole book of references, so when I was in front of the committee I had at my fingertips every piece of information I could possibly have.

ZIERLER: What contact did you have with MIT's trustees, the president, the provost, the people who would have been concerned about this from a strategic reputational level?

BALTIMORE: I had a lot of contact with them. MIT's board—the MIT Corporation—involves many CEOs of major corporations, many of whom had been called in front of the Dingell committee over the years, all of whom were very aware of Dingell's style and nature, so they were all on my side.

ZIERLER: You were just the latest victim here?

BALTIMORE: I was the latest victim. I presented to the Corporation, the Executive Committee, I guess, at one point, and found this wellspring of support. I was stunned.

ZIERLER: "Welcome to the club."

BALTIMORE: Yes! "Welcome to the club." I think that phrase was used directly! Explicitly. The rest of the people at MIT were very supportive. I don't know that they helped cover costs, but as I said, I think the Akin Gump representation was pro bono, because they hated Dingell. They had this problem, which was that Dingell was a Democrat, and Akin Gump is a—

ZIERLER: Boston law firm?

BALTIMORE: No, they're a Washington firm. They didn't have a Boston office. The Boston firms were not notably liberal. Akin Gump was liberal, very much a Democrat's side. They knew Dingell very well, and they hated Dingell. They just thought he was the lowest form of human being. The fact that I was willing to stand up to him meant that I was the rare person that they saw who wasn't looking to hide. Almost all the CEOs that they dealt with in their practice in front of Dingell were simply looking to kowtow to him and get out from under him, and did. They had never prepared anybody to counter him. But I wasn't going to let him tell me what to do. [unrelated phone call with Teak]

ZIERLER: Where's your daughter?

BALTIMORE: She's in New York. Her firm is in New York.

ZIERLER: She's a lawyer?

BALTIMORE: No, she's a businesswoman, I guess. The firm she works for is headquartered in New York. She comes down from Boston where they live to New York occasionally, so she's down there.

ZIERLER: So the game plan is, you're going to challenge Dingell. Does he know this going in?

BALTIMORE: Yes, I think so, or at least he could have known it.

ZIERLER: At this point, the NIH is not yet involved? This is after this confrontation? There aren't NIH investigators around the lab before you go to Washington?

BALTIMORE: There never were. But the NIH investigations are all later. This is now about 1987. It's before I go to New York, but it's after—yeah. Wait a minute now; there's something wrong somewhere. The papers were written in 1984, 1985, 1986, in there. Right. I went down to Washington, prepped up with these guys, but I'm called, and I'm sitting by myself. One guy, the one lawyer, was with me. And I faced down Dingell. I hadn't planned to. I had written a statement. I gave my statement. But then he accused me of something—I've forgotten what—and I just got furious.

ZIERLER: What did you want to convey in your statement? If you don't remember the specifics, what was the purpose of the statement?

BALTIMORE: The statement that I read was just to say we hadn't done anything wrong, and that there was no scientific misconduct.

ZIERLER: It was a direct refutation of whatever charges Margot had brought?

BALTIMORE: Right. But it wasn't an attack on Dingell, until he attacked me.

ZIERLER: What did he do? What did he say? Or what rubbed you the wrong way, as you reconstruct the memory?

BALTIMORE: I'm trying to remember what it was. I can't actually do it. I can find out the answer, but I've forgotten.

ZIERLER: Was it his arrogance? Were you surprised that he didn't simply accept what you had to say, that he challenged you?

BALTIMORE: No.

ZIERLER: You expected to be challenged?

BALTIMORE: Right. It was something deeper than that. I don't know, I've blocked it out of my memory.

ZIERLER: Cheap political point scoring, maybe.

BALTIMORE: I would like to find out. I'll find out. He basically walked out on me. He was so furious. I've heard from people that nothing like this had ever happened to him. That was the end of my contact with the Dingell committee, and I was a hero at Akin Gump. [This is described in Dan Kevles' book on "the Baltimore case", page 190. It is corrected below. Dingell said that he had not charged me with fraud and had not raised comparisons with the Holocaust. His staff had quite clearly done that and I was furious that he was denying it. He tried to close the hearing but I asked for an opportunity to rebut what he had said and he gave me that opportunity. I then sent up to him on the dais copies of articles in which his staff was quoted directly changing fraud and other issues. Dingell then closed the hearing.]

ZIERLER: What was your reaction leaving the hearings? "My god, what have I done?" Do you feel good about yourself?

BALTIMORE: I had reacted viscerally. It wasn't logical. No, I was terrified.

ZIERLER: That he was going to go after you, big time?

BALTIMORE: Yeah, because I didn't know what the sequelae would be.

ZIERLER: How long do you hang around D.C. for?

BALTIMORE: Oh, I don't know, hours.

ZIERLER: You were right back home.

BALTIMORE: Alice was with me. But the important thing is that it wasn't the end of the story by any means. It was taken over by NIH. Even if I hadn't gone to Rockefeller and it hadn't exploded in the press, it was now going to go on at a different level.

ZIERLER: The explosion in the press happened as a result of you standing up to Dingell, or this is later?

BALTIMORE: No, it was later.

ZIERLER: This particular confrontation doesn't really register in the news so much?

BALTIMORE: That's right. It wasn't big news. And the news wasn't necessarily supporting me. They also didn't attack Dingell. Nobody attacked Dingell. The New York Times wasn't going to touch it. When it was all over, and Thereza had been exonerated, The New York Times actually apologized. If you find the right place in The New York Times, there's an apology.

ZIERLER: To who? To you?

BALTIMORE: To me.

ZIERLER: What's the next step? You get back to Boston. Did you talk to Thereza?

BALTIMORE: Oh, yeah. She also had been called, and Margot had been called. They had all—

ZIERLER: Is Margo still at MIT at this point?

BALTIMORE: Yes.

ZIERLER: That's an awkward work environment.

BALTIMORE: She's not working anymore. She's not in the lab anymore, but I think they were forced to keep her for quite a while. They can't fire her, right? She's the golden girl.

ZIERLER: When does the Secret Service get involved?

BALTIMORE: I don't remember whether it was before I was in front of the committee. [The Secret Service was actually asked by Dingell's committee to get involved and they spent much of the time of the hearing describing their work.

ZIERLER: What's the reaction at MIT to the way that you stood up to Dingell? Were they concerned—president, provost, trustees? Was this a bigger problem on their hands, now?

BALTIMORE: No, because it wasn't followed up.

ZIERLER: There were no obvious retaliatory measures?

BALTIMORE: That's right. But when did the Secret Service—? I think that's afterwards. [Wrong.]

ZIERLER: Homework for next time—what got you so upset, what did Dingell say, and then when did the Secret Service get involved. Because that's what makes this—I mean, the Secret Service?

BALTIMORE: Oh, yeah. It's hard to believe.

ZIERLER: We'll pick up next time.

BALTIMORE: It's hard to believe how bad they were, too.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, February 22, 2022. Once again, it is great to be back with Professor David Baltimore. David, good to be with you again.

BALTIMORE: Hello.

ZIERLER: Today we are going to tie up some loose ends from the 1980s. We'll go back to the so-called "Baltimore Case." On the specific topic to revisit it, what was it that rankled you specifically in the hearings with Dingell? What was it about his demeanor that set you off?

BALTIMORE: He denied that he had attacked me, and he denied that his staff had made an analogy with Nazism and the Holocaust, and I was infuriated by that, because he had done all those things, and his staff had, and the press had picked it up. I had with me, prepared by my legal associates, a notebook with all of that information in it. I just turned to the relevant page and pulled it out and sent it up to him, because he was on a dais above me, to show what it was. I said unequivocally that it was not true what he had said. He actually looked at it and even conferred about it, but he didn't really respond.

ZIERLER: Not to get in his head, but what do you think he was expecting would be the outcome of this confrontation with you or however he saw this playing out?

BALTIMORE: He summarized it. At the moment when he was about to put down the gavel and say this was the end of the hearing, and it was his style to end a hearing with a summary that supported everything he believed before he went into it actually, I stopped him and I asked him for permission to respond to him. He was a very courtly gentleman and wouldn't deny something like that.

ZIERLER: If you played by the rules, so to speak.

BALTIMORE: Right. He said, "Yes, you may." That's when I sort of exploded and showed him the things that he was denying. Then he closed the hearing without responding.

ZIERLER: The basic point of contention at that point was, you had not been given the opportunity to clear your name, and that's what you were looking to do.

BALTIMORE: That's right, and to clear Thereza Imanishi-Kari's name. He was determined to continue, and did continue. He had already contacted the Secret Service and gotten them involved. They did an atrocious job.

ZIERLER: Was the Secret Service involved before you went to Washington for this hearing?

BALTIMORE: Yes, it was.

ZIERLER: Were they interviewing you? Were they rifling through files? What was their investigative status?

BALTIMORE: They were doing entirely investigations of mainly Thereza's notebooks and were not talking to us at all, were not trying to understand how people worked or anything else. It was all looking at the notebooks. You could see in them that there were dates overwritten. There were changes in notes. There were things taped into the notebooks. There was an explanation of all that, but they didn't want to hear it. They just wanted to use it as evidence of fraud.

ZIERLER: Was there anybody in the investigation that was scientifically qualified to assess the notebooks and what they might have said?

BALTIMORE: They did bring in some people.

ZIERLER: Is this where the NIH gets involved?

BALTIMORE: Yeah, the NIH had a committee at one point. Finally, when there was an adjudication of it, they threw it all out as not indicative of anything, that whole analysis.

ZIERLER: What's the chronology of when you felt finally this was over, it was behind you?

BALTIMORE: That was only when this committee of lawyers came back with a report. That report totally exonerated Thereza. It didn't say that she didn't do anything wrong, because you can't prove a negative, but it did say that there was no strong evidence that she had done anything wrong, and that everything that she had done and that the notebooks showed was understandable in the context of her being a somewhat sloppy note-keeper.

ZIERLER: Did you talk to her about this at that point?

BALTIMORE: Oh, I had talked to her about it, and it was clear that she was sloppy, but it was hardly unique. At that time, a scientist's view of a notebook was, for some people, a record of exactly what had happened, and they'd fill it out every evening, at the end of a day, and they'd sign it off. In pharmaceutical companies, you literally would sign your name to it. But for many other people, it was a reminder of what had been done but basically everything was in their head, not on the paper.

ZIERLER: It's more like a diary as opposed to an Excel spreadsheet.

BALTIMORE: Well, not even a diary. A series of notes, of things that were done, often with the particular values of a parameter because you might not remember those, but not a literal diary of daily record of activities. I as a biochemist, kept pretty detailed notes of everything. I can go back today and look at those notebooks and reconstruct exactly what I did. She could never do that, because it was in her head, not in the notes. The idea for many people, I think, was that you maintained enough knowledge of what you had done and what you had found to write a paper, and that once you wrote the paper and the paper was published, that was it. That was done. That was the evidence of it. And you went on to other things. The notebooks were not something that were detailed records of daily activity.

ZIERLER: On the interpersonal level, did you ever feel like Thereza owed you an apology for taking sloppy notes and making this whole big mess that didn't need to be?

BALTIMORE: She did apologize, and she did recognize that I didn't need this, and that she had gotten me involved in something that shouldn't have happened. But on the other hand, she was being treated miserably, and for her particularly, without a lot of experience with American politics, with somebody like John Dingle, she was furious.

ZIERLER: On the other hand, did she ever express gratitude that you were instrumental in clearing her name?

BALTIMORE: Oh, absolutely.

ZIERLER: It's an interesting thing, because if we take you out of the equation, does this ever rise to the level where anybody is questioning her career in the first place, do you think?

BALTIMORE: No, I don't think so.

ZIERLER: On the other hand, only because of her involvement was her name cleared and she could continue on with her career. What a funny thing.

BALTIMORE: Yes.

ZIERLER: Did Margot ever put out a statement after this whole thing had ended?

BALTIMORE: No.

ZIERLER: No regret, no recantation, nothing like that?

BALTIMORE: No.

ZIERLER: And you won't surmise as to what that might be about?

BALTIMORE: No, I don't want to.

The Decision to Lead Rockefeller University

ZIERLER: At what point in the narrative do you start thinking about the opportunity at Rockefeller? Are you still deep within the Baltimore Case, or that's mostly behind you at this point?

BALTIMORE: The Baltimore Case was nowhere near over at the time I took the Rockefeller position. I thought it was.

ZIERLER: The hearing was over, though? That was from MIT.

BALTIMORE: Yeah, that particular hearing was over, and we had not heard much from the investigators of what was going on. I of course warned the Rockefeller people that this might not be over. They looked into it whatever way they did, and said they thought it was completely behind me and that we could move forward, and so they offered me the job. I was not thrilled with the idea of taking it at first.

ZIERLER: This was an offer out of the blue? You were not thinking about leaving MIT, Whitehead? That was not in the cards at that point?

BALTIMORE: That's right.

ZIERLER: Who was driving the recruitment at Rockefeller?

BALTIMORE: The board, the way it is at most institutions. The board chairman was David Rockefeller. Well, I'm not even positive he was the board chairman. There was a guy named Dick Furlaud who came from the financial world, I forget exactly where—actually, he may have come from the pharmaceutical industry—who was very close to David Rockefeller, and who led, I think, the recruitment. But I really said I just didn't want to do it, and I didn't want to do it because I didn't want to take the chance that this thing would explode again, because it hadn't resolved completely, and because I didn't particularly want to leave Whitehead and MIT at that point.

ZIERLER: The group was doing fabulous work at this point. You had postdocs who were doing—

BALTIMORE: I had a great laboratory. We were doing wonderful work.

ZIERLER: Is Jack still in the picture at this point, circa 1989, 1990?

BALTIMORE: Did Jack die? I believe Jack was still alive.

ZIERLER: You come up upon this test that you said last time, which is, you'll know if it's succeeding if you're able to leave. Obviously the answer presented itself.

BALTIMORE: It did. But I didn't leave in order to test it.

ZIERLER: It forced the question, though.

BALTIMORE: I had discovered in myself the ability to be a chief administrator of an organization. It wasn't something that I knew I could do. I don't know that anybody ever knows they can do it until they do it. It had its rewards. I was thinking about the rest of my career. I was still a relatively young person. Among the things I didn't want to do was to be the president of a large university.

ZIERLER: Like Caltech.

BALTIMORE: No, Caltech is small.

ZIERLER: Compared to Rockefeller, though?

BALTIMORE: Oh, but no, I didn't want to, for instance, be the president of MIT, and that had been suggested. I just felt that the distance between the president and the organization at a big place is enormous with a lot of buffer—deans, vice presidents, and whatever else—and that the joy of heading Whitehead was that I was a colleague of the faculty. I was in close contact with the faculty. I could be the leader of the faculty.

ZIERLER: There's a flatness to the Whitehead that you thought might work at Rockefeller, also?

BALTIMORE: So, in thinking about what other institutions I might want to head, Rockefeller fit the bill. And I had been a graduate of Rockefeller, so I had the sort of alumni connection. And I had always felt that Rockefeller could be a much greater institution than it was if it would get out from under its very European organizational style.

ZIERLER: Greater in what way? More impact?

BALTIMORE: More impact, right. Better people. Younger people who could make a larger difference in science. It was sort of a hide-bound institution, although doing some great things, and at the same time a home for people who were very ego-oriented.

ZIERLER: What was the winning pitch from the board when they made this offer to you?

BALTIMORE: When David Rockefeller got on a plane, even his own private plane, and came up with Dick Furlaud to see me, I was overwhelmed. I mean, David Rockefeller was one of the great human beings of America, never mind being extremely wealthy and the scion of his family.

ZIERLER: Was he relatable? Could you talk to him?

BALTIMORE: Oh, yeah. I continued talking with him even after I left Rockefeller. I would have lunch with him occasionally. No, he was a very approachable person. He didn't want to be seen as above the fray. He wanted to be part of the world. And did, and was, in his professional work at Chase, in his political work in lower New York. I forget what they called it, but there was an organization that was a civic-minded organization. He did a lot of work. He was very personal in his involvement. He was a sort of reticent figure. He was never as personally—not manipulative, but I don't know, maybe it is manipulative—as Eli Broad. But much like Eli Broad, he was the driving force of New York City.

ZIERLER: When he came up in the plane and made his case, what was it? What resonated with you?

BALTIMORE: He said, first of all, "Don't worry about the case. That's behind you." And I figured if you have David Rockefeller behind you saying that, you've got to believe it. He knew that Rockefeller needed an injection of different kind of thinking. He was really very smart about it, and deeply in love with it. The brothers divided their philanthropic activities, and he purposely had taken the Rockefeller University as one of his major charitable works, that and the Museum of Modern Art.

ZIERLER: What was your requirement in terms of the impact on your science, both in terms of how much you would be able to operate in science at Rockefeller, and just the nuts and bolts of moving your operation to New York from Cambridge?

BALTIMORE: One of the things I said was—and he was very comfortable with it—that I wanted to continue in my science. That I would give him my word that my administrative duties at Rockefeller would come first. I had I think shown at Whitehead that I could do that. I maintained a strong research program, but there was no question that I was the leader of the institution. In terms of the logistics of moving, I imagined how to do that very quickly, and did it that way.

ZIERLER: How many graduate students are you supervising at this point?

BALTIMORE: Probably four or five graduate students, and maybe two or three times that number of postdocs.

ZIERLER: The grad students, some came with you, and some stayed back?

BALTIMORE: Right. I gave everybody the option of finishing up, and I planned to maintain the laboratory at Whitehead for another year, and during that time, people would either move with me to New York or finish up, or move to another laboratory. One of them, for instance, became a fellow at Whitehead, so he stayed there, because he I think for family reasons didn't want to move to New York. But a few people came to New York with me, and that was great because they provided continuity. And I downsized the laboratory significantly, because I just couldn't maintain the laboratory that I had at Whitehead.

ZIERLER: Were you involved in choosing the successor to you at Whitehead?

BALTIMORE: No, I was not.

ZIERLER: Who came after you?

BALTIMORE: Gerry Fink.

ZIERLER: Oh! And as you said earlier, he went about making it exactly the kind of big size that you did not want it to be.

BALTIMORE: Well, he made it bigger; it wasn't still very big. But he increased by about 50%.

ZIERLER: When Jack passed, what did that mean in terms of the funding for Whitehead? Was there an estate? How did that work?

BALTIMORE: Yeah, and that happened after I left, because I never had to figure that out. But he had endowed Whitehead from the beginning, and we had a whole superstructure for maintaining the investment. It had no financial consequences when he died. His own estate, I don't know if it included any additional money going to Whitehead, going to the Institute. I don't remember that. I'm not sure I ever knew the answer to that question.

ZIERLER: In your discussions with Rockefeller or the board when you came in, was there a mandate that you felt they were looking for you to pursue? What was the course of action? What did they want you to accomplish?

BALTIMORE: They wanted to see Rockefeller get an injection of some more modern thinking, more modern orientation.

ZIERLER: What does that mean both administratively and scientifically?

BALTIMORE: Administratively, what it meant to me was giving more authority to younger people. Rockefeller had a totally flat organization, no departments. There were, I don't remember what the number was, 60 faculty. Each faculty member had a laboratory with often assistant professors within the laboratory, so they didn't have any independent—there was no ladder that they could climb. There was no tenure track positions. These were positions within a laboratory, totally dependent on the senior figure. Should the senior figure die or leave, the laboratory was dissolved, unless there was one figure that was appropriate to hire. That needed changing, and I had indicated I would try, and then they were very receptive to that idea. The board. Not the faculty. [laughs] What I wanted to do did run up against the faculty, or many members, not all members, but many members of the faculty, who didn't want to see any change and didn't want to see their own power diminished. But unless there were a ladder developed and an ability for young people to run independent programs and to develop their own skills, there was a class of people who were never going to come there, and they were the bright people I was used to at MIT or anywhere else, for that matter.

ZIERLER: Meaning that a superstar postdoc would never seriously consider an offer from Rockefeller in the way that they would at a place like MIT?

BALTIMORE: That's right.

ZIERLER: And that's what you needed to change.

BALTIMORE: But you wouldn't even get an offer from Rockefeller, because they didn't have much of a junior faculty, and they didn't have a procedure for evaluating junior faculty.

ZIERLER: There's no tenure system at Rockefeller?

BALTIMORE: The only tenure was to be a professor.

ZIERLER: Associate professor is not a designation there?

BALTIMORE: There was an associate professor, and many of those associate professors were in laboratories. Some of them were independent, and others were in laboratories. The ones who were independent were really hangovers from the past.

ZIERLER: They were grandfathered in, essentially?

BALTIMORE: Yeah, they were not on their way to becoming professors. They were being held at that associate professor level, and they really shouldn't have been there, but nobody had had the guts to get rid of them, or even the authority, I guess, so there they were. Some of them were doing mildly interesting work. None of them were real stars. And when they hired somebody, they hired a star from elsewhere. They very rarely promoted anybody internally. For instance, the great team of Hubel and Wiesel at Harvard who revolutionized modern neuroscience, they hired Wiesel from Harvard who came and was a professor then at Rockefeller for the next—oh god, he's still alive, I think.

ZIERLER: The whole structure, the whole MO at Rockefeller is, people who do phenomenal work at other institutions are then recruited to Rockefeller.

BALTIMORE: Right.

ZIERLER: That needed to change? That's what you came in—that was the primary mission?

BALTIMORE: Yes.

ZIERLER: Maybe it's an obvious question, but just for the sake of posing it, why is promoting a culture of younger scientists who can be hired earlier in their careers and grow at Rockefeller so important to Rockefeller and what the board and you wanted to achieve?

BALTIMORE: Because you get a different kind of person. Particularly with science becoming increasingly technological and moving in new directions and moving extremely fast, it's very hard to be part of that and still have the great professor syndrome.

ZIERLER: 1990, the backdrop here is biotech and Amgen and Genentech and VC. It's all happening now.

BALTIMORE: All of that is happening, and Rockefeller has nothing to do with any of it.

ZIERLER: And it will get left in the dust if it doesn't figure it out.

BALTIMORE: And New York City didn't have much to do with any of it, so there was the whole question of could you change the culture of Rockefeller so that it became more of an engine for New York City.

ZIERLER: So you get there, and you start floating this idea. You get immediate resistance from the faculty?

BALTIMORE: To be perfectly candid from my retrospective view, I think I made a mistake. The mistake was to lay out all of my thinking.

ZIERLER: You showed your cards.

BALTIMORE: Yeah. I didn't even think of them as cards. Here's where I really was not experienced. I had built Whitehead from the bottom up in a very comfortable situation, because there was no history. Now I'm walking into a more classic situation in which there is a very deep history, in this case a remarkably deep and ancient history going back to the beginning of the twentieth century. I should not have sort of challenged everybody with what I wanted. I didn't understand that as the leader of an organization, you have to be very careful not to get people against you, and that's going to be their first though. When any new person comes in, the first thing you do is try to challenge them.

ZIERLER: If you're coming in to shake a status quo, and they're the status quo, you're going to have conflict right from the beginning.

BALTIMORE: Right, so I shouldn't have aggravated that, and I did aggravate it, and that was really a mistake.

ZIERLER: What would have been the alternative solution to achieve the same goal?

BALTIMORE: To be much quieter about it, and to keep to myself my own view of what my long-term goals were and just start on a campaign to begin to loosen things up.

ZIERLER: The mission that you conveyed, this was a speech, this is one to one?

BALTIMORE: Yes, it was a speech. It was my inauguration speech.

ZIERLER: This was the speech that should not have been given, essentially.

BALTIMORE: Right. Not the way I was giving it.

ZIERLER: Did that sort of handicap you from the beginning?

BALTIMORE: Yeah. I didn't have anybody to advise me. I didn't seek out maybe having advisors. There were only a small group of faculty who were my supporters.

ZIERLER: Do you think your stature, the Nobel, worked against you at this point too, in addition to everything else?

BALTIMORE: I don't know if it worked against me, but it certainly wasn't sufficient.

ZIERLER: When did you start to realize that there was this resistance? Was it immediate? Was there grumbling? You heard through the grapevine? Did people talk to you directly?

BALTIMORE: All of the above. But I was determined. I did institute many changes. Even though in the end I was only there for a year and a half—

ZIERLER: As president, you were only there that long.

BALTIMORE: As president, yeah. I was able to institute a junior faculty track. I was able to review all of the junior faculty in the laboratories and recommend that some of them be given the opportunity to be independent junior faculty, have their own space, their own freedom. Today, I picked up the phone, I had a call arranged at 9:00 which included a guy I have never met before, and he got on the Zoom, and the first thing he said is, "I'm very glad to see you. You saved my career." I said, "I saved your career?" I couldn't remember him, to tell you the truth. He said, "I was a junior faculty member at Rockefeller when you came in, and you got me on an independent track, and I'm now a tenured professor at USC." That's not the first time that has happened. It really worked. I did pull people out and allow them to develop their own independent careers.

ZIERLER: How much of that was promoting from within, the junior people who were there but were sort of stuck in limbo, and how much was it recruiting from the outside?

BALTIMORE: About 50/50, something like that.

ZIERLER: Did you create a tenure infrastructure?

BALTIMORE: Yeah.

ZIERLER: There needed to be one.

BALTIMORE: Yes. What I didn't do was completely get rid of the ability to have junior appointments within the laboratories, and I don't know whatever happened with that. There were independent assistant professors and there were sort of dependent assistant professors. What happened that year I was there was that I tried to institute these changes, but at the same time, not take away things that were the rights of the existing senior faculty.

ZIERLER: You wanted to make sure that the changes were emphasizing this was to the benefit of the institution, and not to draw power away from the senior faculty.

BALTIMORE: That's right.

ZIERLER: Among the senior faculty, if you were to take a straw poll, who said, "This is nonsense, you're actually taking power away," roughly half the faculty? More?

BALTIMORE: Oh, no.

ZIERLER: Vocal minority?

BALTIMORE: No, a vocal probably majority, who didn't want to see any independent junior faculty.

ZIERLER: Maybe it's a naïve question, but why would this be perceived as a zero-sum game? In other words, if you're not doing anything overtly—I'm taking away funding, I'm taking away instruments, I'm taking away students—if you're not doing anything overtly to diminish the power of the senior faculty, why would it be perceived as such? [laughs] That's a psychological question, really.

BALTIMORE: Yeah, I'm not sure I have an answer to it. I think that was the question that I was asking—"What's enough?"

ZIERLER: Obviously the other way of looking at it is that if you're setting out to improve the institution, the long run is that their careers will benefit as a result.

BALTIMORE: But they didn't see it as an improvement of the institution. And what many of them would and did say is, "We don't need to make this institution like other institutions. It can be different." My feeling was if it was that different, it was just not going to be competitive with the rest of the world, the MITs of the world.

ZIERLER: Big Science is coming, at this point.

BALTIMORE: No, there's plenty of Big Science at Rockefeller. Some of these laboratories were enormous. They were whole floors of buildings.

ZIERLER: I'll test that. Could Lee Hood have fit within Rockefeller?

BALTIMORE: Yes, he could have. Oh, yes.

ZIERLER: That answers it. That's it.

BALTIMORE: Remember, I was talking to you about Gerry Edelman at one point. Gerry had I think it was a half a floor or a whole floor in one of the buildings, and had a very large number of people around him, and they were all totally dependent on him.

ZIERLER: These are really more than professors. These are kind of like feudal lords, to some degree.

BALTIMORE: They were. And he was one, Gerry, who left, during my time.

ZIERLER: Where did he go?

BALTIMORE: Scripps. Scripps set him up. They got a big endowment to set him up. He at that point totally withdrew from academic society and ran the place as an absolute lord. Got a new building built for himself, actually a beautiful building. It may be Billie Tsien who was the architect. I think I'm mixed up. He and his wife are an architectural pair, and she's Tsien, and he's Tod, I think. But it was a beautiful building, which now I think belongs to Scripps. But Gerry didn't contribute anything to the institution, because he was just his own man, except his name. His name was very important. He was a Nobel laureate.

ZIERLER: When in this year-and-a-half saga do you start to think, "Maybe this is not working out; maybe I should step down"?

BALTIMORE: Never.

ZIERLER: You never come to this decision?

BALTIMORE: No.

ZIERLER: What about The Baltimore Case? Does it flare up during this year and a half?

BALTIMORE: Yes. That's what happens.

ZIERLER: That's what happens.

BALTIMORE: Yes.

ZIERLER: Rockefeller's assurances notwithstanding.

BALTIMORE: Right.

ZIERLER: What happens at this point?

BALTIMORE: Major headlines in The New York Times. There was a report by an NIH committee that had been totally answerable to Dingell and his committee. Now I don't remember—I haven't looked at that report in ages, and I don't think I have a copy of it. Well, I do somewhere. Released with a lot of fanfare, leaked ahead of time to The New York Times through the Dingell committee. The Times had a very close relationship to Dingell, because Dingell was news, and they needed that. But it meant that I couldn't get a fair hearing from anybody at The New York Times or for that matter almost anywhere else in the press world. The combination of that and the fact that were still a lot of faculty who would just as soon I leave, going to the board and saying they wanted to see me leave, and that I was no longer—and this may be true—that it really diminished my own power enormously—I had to resign, and did.

ZIERLER: Not to be overly conspiratorial but was there anybody at Rockefeller who might have been fanning the flames with the Baltimore Case?

BALTIMORE: I don't think so. There were certainly people who were being nasty and talking to their friends and whatever, but I don't think any of them had a connection to the committee or to the NIH process.

ZIERLER: Was the case that they made to the board that this was just too much of a distraction to the Institute?

BALTIMORE: Yes.

ZIERLER: The fact that you were exonerated at that point was irrelevant?

BALTIMORE: No, I wasn't exonerated at that point. I wasn't anywhere near. I was being charged, or Thereza was being charged, with being fraudulent, and I was being charged with being her supporter and part of the team that wrote the paper. I hadn't done my homework and found out that the paper was fraudulent, was an argument that was made.

ZIERLER: But you had felt at that point that you had cleared your name, that you had demonstrated that there was actually no wrongdoing, even if there were these ongoing charges and investigations? You had done what you wanted to? That was the basis upon you accepting the presidency.

BALTIMORE: That's right.

ZIERLER: Why did this thing continue to linger on? Why did it not end with that hearing in Washington?

BALTIMORE: Because Dingell drove it. He was now after me. Look, I had gone after him.

ZIERLER: Personally, he was after you.

BALTIMORE: Yeah, and nobody had ever done that before.

ZIERLER: Did the faculty at Rockefeller also say, "Oh, and by the way, we don't like what he's doing here" in addition to everything else?

BALTIMORE: Oh, absolutely, yes.

ZIERLER: It was a double-edged sword coming after you.

BALTIMORE: Right.

ZIERLER: What was the communications from the board given that you were simply doing what you had come to do?

BALTIMORE: The first response from the board was support. They got some people to help me, the public relations people and whatever. But the drumbeat continued, and the opponents on the faculty continued to go to the board, over my head. In particular, I had asked my previous associate, Jim Darnell, who was a faculty member at Rockefeller—he was the lead faculty member, I think, chairman of the faculty. I had rested on him heavily for advice or whatever. He turned on me, in a very nasty, very underhanded way, to the point where he is no longer a friend of our family's. Alice in particular hates his guts.

ZIERLER: What did he do?

BALTIMORE: What he did was to fan the flames, and to oppose me, but not openly. What everybody thinks, thought at the time, who talked to me honestly, was that he was trying to get the job. He had always wanted to be the President of Rockefeller. I knew that, but I thought he had come to terms with it, but here he saw the opening and opportunity. All he did was to turn everybody against him. It totally backfired, because it was so blatant. But it added to the problem. In particular I didn't have one of the few people I thought was a really strong supporter. My major support came from the junior faculty at that point, but they didn't have the ear of the board.

ZIERLER: You couldn't have known that the case would flare up again, but in retrospect, do you regret taking the job with the uncertainty of the case?

BALTIMORE: Oh, absolutely. My original instinct to not take the job was correct, for that very reason. Had I not done that, I would not have been so prominent as a target, in particular in New York, because I wouldn't have been in New York.

ZIERLER: What was Rockefeller's position on all of this when it came down to it?

BALTIMORE: David Rockefeller was terribly conflicted, because he knew that he had personally cajoled me into coming, and so was in a sense responsible for the situation.

ZIERLER: And he misfired on thinking that the case was done, also.

BALTIMORE: Right. And Furlaud, his right-hand man, I think convinced him that it was no longer tenable.

ZIERLER: With their support would you have stayed and continued the fight, the two-front war, as it were? Or was it too much for you, absent those external pressures? It's a lot of street fighting, for a scientist.

BALTIMORE: It sure is. But you've asked a question I've never asked myself: would I have stayed if I had the support of the board?

ZIERLER: Look at your trajectory. Look at all the careers that you had already made at the junior level. And you had clearly shown you're going to stand up for yourself, you're going to see the Baltimore Case to a positive outcome. With that support from the board, would you have stayed?

BALTIMORE: Probably. But the board was a reflection of the faculty, and so it just was not going to happen. That's why I've never asked about it, because it's not a situation that ever would have arisen.

ZIERLER: What does this mean for your career at this point? Do you want to go right back to MIT and pretend the whole thing didn't happen? What are your options?

BALTIMORE: In the first reaction, actually I resigned on the day before Thanksgiving, because we were in the car driving up to Woods Hole.

ZIERLER: There was a satellite conference?

BALTIMORE: No, we had a home there, and we were going to spend the holiday there, and my daughter was coming. She was probably at Yale. I think she was at Yale, undergraduate. But I think she had gone to Yale already, or maybe she was at Andover, still. Whichever way, she was in New England. I got a call in the car from Furlow, and I said—I can't remember now exactly. I thought about it for a little while.

ZIERLER: You got a call in the car, so there was a car phone at this point already?

BALTIMORE: Yeah. As soon as I said that, I had to think if that's really right.

ZIERLER: I remember car phones came before cell phones.

BALTIMORE: Yeah. Yes, there was a phone in the car. I think I must have had the Rockefeller car. Alice and I talked about it in the car. I can't remember if I called back in the car, or when I got there, and I just said, "I'm going to resign."

ZIERLER: The message from him was, "We need your resignation letter" or something final like that?

BALTIMORE: I think the message from him, if I remember correctly, was, "You should think about resigning." I don't think he said, "You should resign."

ZIERLER: Must have been a lousy Thanksgiving.

BALTIMORE: Oh, it was a lousy Thanksgiving. Yes, it was. But I at this point had to put a lot of attention to the Baltimore Case, because everybody was after me about that.

ZIERLER: MIT helped you lawyer up. Were they still involved on the legal defense, or what was your position at that point?

BALTIMORE: Rockefeller really had nothing to do with the case. I had legal representation going back to the time I had been at MIT.

ZIERLER: They were still funding that? Are you personally paying for lawyers?

BALTIMORE: I do not remember how that worked. I had my personal lawyer, Normand Smith, who I was paying.

ZIERLER: But, Akin Gump.

BALTIMORE: I don't know that Akin Gump was involved anymore.

ZIERLER: You said they were pro bono anyway.

BALTIMORE: Right, they were pro bono. Once I was out of Washington, they were out of the picture. I have to figure out how I want to maintain my career. I had a tenured position at Rockefeller.

ZIERLER: The president as part of the faculty.

BALTIMORE: Right, because I was a scientist.

ZIERLER: You had a job at a minimum.

BALTIMORE: I had a job, at least for the—

ZIERLER: A bridge to whatever was going to happen next.

BALTIMORE: Right. And I was running a small laboratory, and actually increased it, and we actually got a lot of good work done at Rockefeller. Then I got a call from the president of MIT.

ZIERLER: But this is later? We're in 1991 now, when you resign.

BALTIMORE: No, this was very soon thereafter. He said, "You know that you still have a job here, because you're on a two-year leave."

ZIERLER: [laughs] Did you know this, or did you forget about that?

BALTIMORE: I had literally forgotten about it!

ZIERLER: [laughs]

BALTIMORE: "And we want you to come back." I think if I remember correctly I didn't say yes right away.

ZIERLER: Were you seriously considering just staying on the faculty at Rockefeller?

BALTIMORE: No, no, I wasn't going to stay on the faculty.

ZIERLER: Because that would have just been too awkward and unpleasant.

BALTIMORE: That's right. But I was thinking about other places in New York.

ZIERLER: Columbia is right there.

BALTIMORE: Right. But I quickly decided that the best thing to do was go back to MIT, because—now, this was not from Whitehead, and I never did get an offer to go back to Whitehead. This was from the MIT Biology Department.

ZIERLER: I thought Whitehead is part of the Biology Department.

BALTIMORE: No, it's not part of the Biology Department. It's an independent research institute.

ZIERLER: Where all of the professors have joint appointments with Biology.

BALTIMORE: Right, and where the students all come from there, but it's not part of MIT.

ZIERLER: The offer was to go back and be a professor in the Department of Biology?

BALTIMORE: Right.

ZIERLER: After you resigned, how long were you on the faculty? What was the interregnum period, or was there none?

BALTIMORE: Where?

ZIERLER: You resign from Rockefeller, you get the call from MIT—

BALTIMORE: No, I resigned as president. I maintained the position as professor.

ZIERLER: For how long?

BALTIMORE: For about two years.

ZIERLER: But that puts you outside of the two-year leave at MIT.

BALTIMORE: No, no, that's all right. I had accepted the job at MIT, but I didn't go back to MIT—I can't remember who was paying my salary; doesn't matter—for a couple of years, because they were building a new building, and the space they were offering me was in that new building. In fact, there was another professor at MIT who had designed the space to move into, and then accepted a job at Caltech [laughs] and moved to Caltech, so his space was available.

ZIERLER: You're not talking about Varshavsky, are you?

BALTIMORE: I am. Yes.

ZIERLER: [laughs]

BALTIMORE: So in saying I would come back, the space had to be finished, and I wanted to get some people whose personal careers had been discombobulated by all this, through their work.

ZIERLER: Administratively, you were treading water at this point.

BALTIMORE: Yeah.

ZIERLER: What was the science? What were you working on? What was your lab doing at Rockefeller during this time?

BALTIMORE: It was all molecular immunology and cancer research. Some of the biggest things we did at that time involved aspects of cancer research. The nature of the SH3 domain. I can explain it but you may not want me to.

ZIERLER: No, please do. What was this?

BALTIMORE: No, no, it goes on and on.

ZIERLER: What are the bigger questions surrounding this research?

BALTIMORE: The question was how does Abelson virus, which is the thing I worked on, actually transform cells? What is the metabolic consequence of the expression of this gene that leads to cell growth and cancer? We had done a lot of mutagenic work to identify the key parts of the gene and knew what they were. One of them was what became known as the SH3 domain, Src homology domain. I had a couple people who worked on this. We figured out what it did and how it worked. It presented a motif or it recognized a motif on other genes that allowed the phosphorylation of that gene product. That was one thing that we did during that time that was especially important. I still had a couple people working on poliovirus, had some people working on HIV. We did a fair amount of work on one of the genes of HIV called Nef, and how Nef functioned.

ZIERLER: Did you interact with David Ho at all at this point, in the formation of the Diamond Center?

BALTIMORE: I was friendly with him, but I didn't collaborate with him or anybody there. One of the guys who worked for me got a job there and was there until it closed, I guess. David has moved since them to Columbia. I worked with some structural people at Rockefeller on the SH2 domain, which is another domain of the Abelson gene, and the Src gene. They're all held in common.

ZIERLER: It sounds like you took full advantage of all of the perks that come with being a senior researcher at Rockefeller, and made the best of the situation.

BALTIMORE: Right.

ZIERLER: Was it known to your colleagues that you were on the way out? Did that sort of help? Nobody had to assume that you would be there for the long term and it would be a difficult situation for everyone?

BALTIMORE: Yeah.

ZIERLER: During these few years, what was happening with the Baltimore Case? How much of that time was taken up?

BALTIMORE: It was largely out of my hands, and it was largely in Washington, but I was not materially affected by it, and I could make my decisions about what I wanted to do and whatever else without reference to it, as long as other people didn't mind. I was just watching what happened. And what happened was the appointment of this judicial panel to review the NIH report, which had been so devastating. They were working in secrecy so I had no idea what they were doing. I guess I was back at MIT when they announced; I'd have to look at the exact dates, as I don't remember.

ZIERLER: The full exoneration, though, your sense is that you were back at MIT at that point?

BALTIMORE: Yeah. They issued their report, and their report was that there were, what was it, 11 charges against Thereza. One or two of them were against me, for not being vigilant enough.

ZIERLER: But what does charge mean in this context? This is not a criminal proceeding. Is it a civil proceeding? What are the charges?

BALTIMORE: If we were found guilty of fraud, then you're blocked from getting NIH grants.

ZIERLER: So that's what this is all about, at the end of the day?

BALTIMORE: Right. And that really related to Thereza. It didn't relate to me.

ZIERLER: How much of your funding was coming from NIH at this point?

BALTIMORE: A significant amount.

ZIERLER: And it wasn't affected? You didn't feel like the spigot was turned off or lowered?

BALTIMORE: No.

A Quick Return to MIT

ZIERLER: Let's go to legacy mode at Rockefeller. Long term, what did you put in place that stuck, and what didn't stuck because of all of the opposition that you knew right from the beginning?

BALTIMORE: Every president of Rockefeller since then with whom I have talked, and that is everyone except the present president, with whom I just haven't had this conversation, has said the reforms that I put in place, they were totally supportive of, and that they were continuing the policies that I had put in place. That was true of the guy who took the job initially temporarily and then stayed on for a couple of years, Wiesel, and then later presidents, notably the Englishman, whose name I'm blocking{Paul Nurse}. There is a junior faculty. Many of the people who we hired as junior faculty then became tenured faculty. Some of those are very famous. Some of them did well but not terrifically. Some of the people I took out of laboratories and gave tenure track positions ultimately achieved tenure. And Rockefeller is a significantly different place.

ZIERLER: All of this needed to happen. You just were unfortunately a lightning rod at this juncture; that's the story.

BALTIMORE: Right. But it was really very impressive how the things that I set in motion continued.

ZIERLER: Probably at this point, just generationally, all of the opposition that you encountered, they're all emeritus or dead at this point?

BALTIMORE: Yes.

ZIERLER: So it must be culturally a totally different place.

BALTIMORE: I think it is.

ZIERLER: The markers that you would measure—

BALTIMORE: But it is still true that they have gone outside to hire senior established figures, and that they had come to Rockefeller and continued their work there.

ZIERLER: Yeah, but Harvard does that.

BALTIMORE: Yeah, it was not a wholesale change in the way they operate.

ZIERLER: But to be fair to yourself, you were not looking to create a wholesale change.

BALTIMORE: No.

ZIERLER: You never advocated that they should never recruit senior star faculty.

BALTIMORE: That's right.

ZIERLER: What have been some of the science that has come out of Rockefeller since the early 1990s where you might be able to draw some line between what you instituted and what the Institute has achieved?

BALTIMORE: There has been a lot of work in epithelial cancers, and epithelial cell differentiation.

ZIERLER: What is epithelial?

BALTIMORE: The skin. By a woman they hired from the University of Chicago, I think, whose name I'm forgetting, but that's notable work[Elaine Fuchs]. There's a very good, younger than me for sure, immunologist named [laughs]—not doing well with names today!—who has done important work in HIV, antibodies against HIV, development of a vaccine, and now work in COVID, Michel Nussenzweig. Now, Michel got his degree at Rockefeller and is a guy who came up through assistant professorship. Whether I hired him or not, I don't remember. I probably did. But he was a student with Ralph Steinman. Ralph Steinman did beautiful work. He was a classic case of somebody who was in a laboratory and who moved out and became professor on his own, and then discovered what are known as dendritic cells, an immune cell, and got the Nobel Prize for it. He was the famous Nobel Prize in which they announced that he would get the Nobel Prize, but he had died that night.

ZIERLER: Ohh.

BALTIMORE: So he never knew it.

ZIERLER: No posthumous Nobel Prize awardees.

BALTIMORE: In his case, they did award it posthumously, because they said, "Well, we just didn't know." But it did present them with a problem for a little while. Both Michel and Ralph came from the same lab, actually. What else? Edelman left, and there was another guy there, Tony Cerami, who left. They have a good neuroscience group. One of the—a guy who died recently but spent his whole life at Rockefeller—and got the Nobel Prize there. Oh, and a guy I had nothing to do with who came after me, and I think they hired him as a senior faculty member, MacKinnon, who did the structural work on a very important transporter protein. I'm just trying to rummage through my head because I haven't thought about this—there have been a significant number of notable successes at Rockefeller. Do they come from junior people who grew up there? There's a young woman—she's not so young anymore, Titia de Lange—who was hired as an assistant professor when I was there, and who has done extremely well working on what's called telomerase.

ZIERLER: It sounds like memories are complicated. Legacies are complicated. On the one hand, you can regret that you took the position to begin with. But on the other you can draw satisfaction with the legacy of what has been done at Rockefeller as a result.

BALTIMORE: That's right.

ZIERLER: Do you think when MIT reached out to you that they were confident that the Baltimore Case would blow over at some point? Obviously they must have had concerns too. If your job was untenable because of the Baltimore Case, clearly somebody at MIT must have seen the bigger picture that ultimately this would come to a positive outcome.

BALTIMORE: I don't think anybody knew that it would come to a positive outcome. I certainly didn't.

ZIERLER: The offer was a leap of faith in some degrees?

BALTIMORE: Yes.

ZIERLER: Because you coming back, big-name researcher, worst-case scenario you lose your NIH funding, and then what happens?

BALTIMORE: No, wait. Remember, this wasn't an offer. I had a position, and I had not yet retired from it.

ZIERLER: They were just proactively—they were being generous: "Remember, you can come back."

BALTIMORE: That's right.

ZIERLER: That might have left your head entirely. You might not have even considered it.

BALTIMORE: I think it had left my head, but I think I would have remembered. [laughs]

ZIERLER: You've got to figure something out.

BALTIMORE: For one thing, I had a lawyer, Normand Smith, who kept track of things like that. He, for instance, had written into my contract with Rockefeller what would happen if I was prematurely asked to resign. I didn't even have to figure that out; it was all there. That I would continue as a tenured faculty member, and that certain perks that I had would continue.

ZIERLER: Did you ever think like worst case scenario, if this was a real witch hunt? Like if this was McCarthyism in Hollywood in the 1940s and 1950s, did you think at some point that you might not have a career in science? What's your off ramp at that point, if that's, heaven forbid, how this played out?

BALTIMORE: I never prepared myself for that, no.

ZIERLER: But not necessarily because you were confident in the outcome. You were confident that you had done nothing wrong, but that's not synonymous with justice being done.

BALTIMORE: That's right. And no, I thought it would—could—end up hanging over my head for the rest of my life.

ZIERLER: When the report came out—

BALTIMORE: When I went back to MIT, it was with the belief that I would spend the rest of my career at MIT, as a scientist, as a faculty member. What I didn't imagine was that I would ever have another offer to head an institution.

ZIERLER: Even with the exoneration, you thought "that's not happening" at this point?

BALTIMORE: No, the exoneration was some time after this. No, after the exoneration, I could have started thinking about having further activities beyond being an MIT professor. But did I?

ZIERLER: When you came back, did you have any involvement with the Whitehead at that point?

BALTIMORE: No.

ZIERLER: Was that difficult for you? Did you want that, and it wasn't available?

BALTIMORE: I was heartsick that I wasn't asked.

ZIERLER: Who could or would have been in a position?

BALTIMORE: Gerry Fink and the other faculty, the senior faculty. These were all people who I had gone out of my way to develop their careers. I didn't expect them to do anything special for me, but they could have been much more supportive.

ZIERLER: Did this science change as a result of being only, as it were, in the Biology Department and not at the Whitehead?

BALTIMORE: No. I was doing the same things I would have done. I guess I didn't have the support, but I never had a problem with support.

ZIERLER: What was the process, back and forth, back and forth, moving the lab back to Cambridge? Were you looking to grow again at this point?

BALTIMORE: Yes, I was but—

ZIERLER: Absent administrative responsibilities, time to jump in and do some science?

BALTIMORE: Exactly.

ZIERLER: This is 1993, you come back to MIT?

BALTIMORE: 1994, I think.

ZIERLER: At the national stage, the Clinton administration, there's new stuff in science policy with the Clinton administration. What was most relevant for you?

BALTIMORE: There was an acceptance of AIDS as an important target of research.

ZIERLER: How does that translate in terms of funding, institutions?

BALTIMORE: There was increasing funding for AIDS vaccine research, AIDS research in general. I maintained a fairly significant part of my lab doing that. The funding for basic research in general was stronger.

ZIERLER: NIH's budget doubled at this point.

BALTIMORE: Yes, whenever it doubled, that was a major opportunity. I don't remember exactly when that was.

ZIERLER: It's over the course of the administration, so throughout the 1990s. What about the Human Genome Project? Are you involved with it at this point?

BALTIMORE: No. I was never involved with it. It involved a kind of work that I just didn't do. I had helped get Eric Lander involved in it when I was at Whitehead, but then it just was going on, on its own. Eric was very involved with it.

Exoneration in Washington

ZIERLER: When the report came out, the exoneration, any apologies from Washington come your way?

BALTIMORE: There was a comment in The New York Times that they had rushed to judgment. That The Times did. I've got a whole folder somewhere of letters that I got.

ZIERLER: Dingell?

BALTIMORE: No. Nothing from the people who had charged me and Thereza. I doubt if she ever got anything from the Dingell committee. That's just not their style. [laughs] Oh, and wait a minute now; wait, wait, wait, wait. When did the Republicans take over Congress?

ZIERLER: There's the bloodbath in 1994. This is Newt Gingrich and Contract with America and all that stuff.

BALTIMORE: That's right. That happened—I just don't remember. I do remember that when the Republicans took over, Dingell was out, and I was overjoyed.

ZIERLER: [laughs]

BALTIMORE: And that in fact, the Republican members of the committee, the minority members on the Dingell committee, had been pretty supportive of me and had—this was Akin Gump working—had drawn in the opposition members of the committee so that when they took over, suddenly the committee was being run by people who were perfectly aware of what had happened, and who were my supporters.

ZIERLER: These things can be very nuanced and hard to track, but did you ever have the sense throughout the whole affair that anti-Semitism was a factor?

BALTIMORE: Not really. The kind of people who Dingell had on his committee were the kind of people you would think could be anti-Semitic, but there was never an overt thing, except for this analogy to the Holocaust. That was sort of knee-jerk anti-Semitism but not I think directed to me as being Jewish.

ZIERLER: What about at Rockefeller? Was that an additional challenge?

BALTIMORE: They had a history of anti-Semitism, but by the time I was there, by the time even when I was a student, there was no overt anti-Semitism.

ZIERLER: Were you the first Jewish president of Rockefeller?

BALTIMORE: No, Josh Lederberg was. He was president before me. Before that, there was Bronk. Bronk was not Jewish. And somebody else—oh, Fred Seitz, but he wasn't Jewish either.

ZIERLER: When the report came out, do you have a clear memory? Did you read about it in the newspaper? Did you get the report in the mail? How did you look at it?

BALTIMORE: It was released in Washington, and this is the kind of thing where you should ask Alice. I was called by somebody.

ZIERLER: Someone on the Hill?

BALTIMORE: I don't remember who it was, whether it was somebody from one of the legal offices.

ZIERLER: But it was a "David, great news" kind of call?

BALTIMORE: Yeah, it was. It was inconceivable to me that they would deny all of the charges. It just seemed—things don't happen that way politically.

ZIERLER: Right, this isn't a movie.

BALTIMORE: Right. It was such—

ZIERLER: You couldn't have asked for a more complete exoneration if you had written the report yourself.

BALTIMORE: That's right. Alice! Do you remember how we first heard about the report, the exoneration?

ZIERLER: Did you read about it in the paper? Did somebody call from—?

BALTIMORE: No, we didn't read about it. I know we—

ZIERLER: It was a call?

ALICE HUANG: You remember that Dan had an excerpt published from his book in The New Yorker.

ZIERLER: Dan Kevles?

HUANG: Yeah. And we heard about that being there, and I remember looking for The New Yorker at some train station; I can't remember which one. Anyway, we found a copy of The New Yorker and that's really—and he predicted that you would be exonerated.

BALTIMORE: I know, yeah, but where did we hear that I was, or that she was?

HUANG: Through reading that—

BALTIMORE: No.

HUANG: Yes.

BALTIMORE: No, because that was just Dan's prediction.

HUANG: Right.

BALTIMORE: That wasn't an official statement.

ZIERLER: You have a memory of a phone call?

BALTIMORE: Yeah, I think it may have been from Dan Josephs—

HUANG: To Normand?

BALTIMORE: To me or to Normand.

HUANG: Yeah, I bet Normand would remember, because that's a legal thing, when you were exonerated. That evening, where we were all together for a dinner, or a short get-together anyway at the—

BALTIMORE: With Normand, and Thereza.

HUANG: With Normand, and Thereza, and the couple of professors at Tufts who had supported Thereza, right?

BALTIMORE: Yeah, Portus.

ZIERLER: Thereza was at Tufts at this point?

BALTIMORE: Yeah. She was hired by Tufts sort of coincident with the breaking of the story. Poor Tufts found itself in the middle of this thing they didn't know anything about.

HUANG: But Dan Kevles was there that evening, too.

BALTIMORE: Really!

HUANG: The photographs, I think, show it.

BALTIMORE: Maybe he was there, for some reason.

HUANG: For a reason, yeah. Or maybe I was imagining that he was there. I have to check the photos now to be sure. [laughs]

BALTIMORE: I don't know why he would have been there. But I do remember that we cracked a bottle of champagne.

HUANG: Yeah. It was in the summer, and he may have been on the Cape already.

BALTIMORE: Yeah, but we weren't.

HUANG: We weren't. No, we were living in Boston. Okay, I'm sorry I'm not that helpful.

BALTIMORE: [laughs]

ZIERLER: Relief, was that the number one emotion at that point, would you say?

BALTIMORE: Oh, no, it was closer to elation than relief. That was a complete vindication of the stance I had been taking for ten years. As I say, I just never imagined it would be that complete.

ZIERLER: What do you see as the long-term outcome of the Baltimore Case? Let's start first on the nuts and bolts, the granular level, in the way that senior people may or may not have changed their practice about attaching their names to a paper for which they were not in the lab doing the work, writing the notebooks themselves. What practices may or may not have changed as a result of this?

BALTIMORE: I think there's more recognition of the inappropriateness of what has been called honorary authorship. But I was not an honorary author. I knew exactly what was going on. I wasn't doing the experiments myself, but anybody who runs a laboratory, in signing on to a paper, should know what's in the paper, and I certainly did.

ZIERLER: Had you been an honorary author on other papers before?

BALTIMORE: No, I had always avoided that.

ZIERLER: That was just your policy—"don't get involved"?

BALTIMORE: Right.

ZIERLER: For precisely this reason, ironically.

BALTIMORE: It wasn't just because of the negative possibilities. It's that I didn't want to take credit for things that I hadn't done. I had enough credit for the things I had done. But this paper was a central part of an ongoing story. There had been a series of earlier papers that set up the questions that we investigated in there. There was no issue about my being an author.

ZIERLER: What about best practices in notetaking? Are these things being discussed at labs?

BALTIMORE: Yes.

ZIERLER: What's happening as a result of the Baltimore Case with notetaking?

BALTIMORE: It's not just the Baltimore Case. There has been a general movement to treat lab notebooks as records of experimentation that can be audited in one way or another.

ZIERLER: Even for the more qualitative visual side of biology?

BALTIMORE: Oh, yeah. In fact, a lot of the charges of fraud have been because illustrations in articles have—it has been charged that they were not records of that experiment, that they were records from some other experiment, or totally fabricated. But in general, that they were records from some other experiment, sometimes that had been published. There are actually many cases in which the published data is questioned on the basis that it was published in another circumstance. That could be a picture, it could be a graph, sometimes it's turned around compared to the way it was published in the first paper and then it's published in a second paper, the same thing, with a different explanation. Because there isn't enough information in a record of experimentation in a journal article. There isn't enough information that really links it incontrovertibly to that experiment. One exponential curve looks like another exponential curve. How do you know that it came from doing exactly what you said it was doing? For visual records, it's even worse, because they're just little dots of color on a slice of tissue or whatever. How do you know what was the experiment behind it? You have to take the word for what it says. But if you can find that that exact pattern of dots is in another representation of this kind of data, then it's very suspicious that there really was—one or the other of those is wrong.

ZIERLER: What about the legacy, the long term impact of the Baltimore Case of the triangle between academic fundamental research, NIH funding, and congressional oversight? How did things change or not as a result of this?

BALTIMORE: Dingell was totally unsuccessful in getting hegemony over NIH activities. Beyond that, I don't know if there are people who have looked back and said, "This is exactly what we don't want to do." I have no idea.

ZIERLER: Was there anyone at NIH who might have been an ally of yours that foiled Dingell's plans?

BALTIMORE: They did not foil Dingell. They went along. When Dingell said, "Jump," they jumped. Even if they believed in me, or in Thereza's work, they still jumped.

ZIERLER: Did you ever talk to Tony Fauci about this, what his perspective on any of this was?

BALTIMORE: No, I haven't. He never got involved, because it wasn't work that came from infectious disease research, which is what he does. He has always been a friend and supporter of work I've done and of my advice in Washington and whatever, but the people at NIH who I had to deal with—Jim Wyngaarden, who was the head of NIH at the time—it went up to top. It was Dingell dealing with the people he deals with. Tony was a step down.

ZIERLER: After the high of the elation, you could do the science now. You could just concentrate on that. Rockefeller's in the rearview, the case is in the rearview. Mid 1990s, before you even start thinking about Caltech, what's the most exciting science in the mid 1990s? What do you want to do at this point?

BALTIMORE: I was continuing work in molecular immunology. I was trying to bring together a new team.

ZIERLER: Who were some of the key postdocs at this period, back at MIT?

BALTIMORE: That is really hard to tell.

ZIERLER: Do you have a clear memory of recruiting, because you want to build up your group again at this point?

BALTIMORE: Yeah, but I never really recruited. People came to me, and I had to choose among them. By the time I came back to MIT it was getting harder to find people, but I never overtly recruited. But I did look around for people. I used to, when I was at Whitehead up until the time I left Whitehead, the very best young people in science wrote to me and offered to come to the lab to be a trainee with me. The same thing was true of the MIT graduate students, for instance. I got really good graduate students, particularly MD/PhD students. I've had a large number of MD/PhD students.

ZIERLER: What was your group doing with HIV research at this point? This is obviously a very exciting time with the cocktail approach.

BALTIMORE: It is, but I had nothing to do with drug development. It was all much more basic. When the genome of HIV was sequenced and we looked at the genes in HIV, there were a whole bunch of genes whose structures we had never seen before. They didn't look like anything we knew about, which meant that there were processes going on that we, the scientific community, had never imagined. I devoted some of my efforts to those genes and to trying to understand them. One in particular was the Tat gene, and that was interesting because its function was linked to NF kappa B. NF kappa B was something we had discovered and was a central element in the research of my lab from 1986 until I closed the lab in 2000-and-whatever. When did I close the lab? In 2020. For all of that period of time—34 years?—we worked on aspects of NF kappa B. It was more complex, more confusing, more intriguing, in 2020, than it was in 2010.

ZIERLER: Why would that be?

BALTIMORE: It's just that its ramifications got broader and wider continually. Every time you looked at something, NF kappa B was doing something new, something different, was involved in ways that we had never seen before. It turned out to be because NF kappa B was central to inflammation, and inflammation is a process that is involved in many diseases—cancer, heart disease—as well as the usual involvements of inflammation from cuts in the skin and colds. All of those things involve NF kappa B in a central way, so it's in some ways the most important transcription factor ever found.

ZIERLER: What about computers? Computers were becoming more and more important.

BALTIMORE: Oh, yeah.

ZIERLER: How did they impact your lab at this point?

BALTIMORE: The biggest uses that we had of computers were the word processing value, data acquisition and analysis, visual representations of experimentation. In all those ways, we used computers. People stopped having notebooks and kept all of their information in their computers. In fact, it's going to be a big problem of storage of these things.

ZIERLER: That's right. Notebooks, you just archive. They're on a shelf. A floppy disk from 1995? [laughs]

BALTIMORE: Right.

ZIERLER: I don't know if you've ever toyed with this question, but if Thereza was on a computer the whole time, how much of this is about work habits, and how much is it about the medium that you're using? In other words, does a computer demand less sloppiness than you might have jotting in a notebook?

BALTIMORE: Depends how you use it. The thing about a good notebook is it's organized for you, so you have to use some kind of an organization. Now, there are today programs that allow to keep a history of experimentation, but there weren't originally. You just had a blank sheet, so you had to figure out how to use the computer as a storage site for information. I had these nicely organized pages in my notebook of biochemical experimentation; I don't know how I would have kept those things on computers, because I just could write into things and make little notes and whatever else. But I've never kept notes [laughs] on a computer, because I stopped doing experiments a long time ago.

ZIERLER: When you got back to MIT, absent the administration responsibilities, did you work with undergraduates at all? Did you enjoy teaching undergraduate classes?

BALTIMORE: Yeah, I did. I taught undergraduate classes. I taught virology. I taught cancer research.

ZIERLER: Did you like teaching undergrads?

BALTIMORE: Yes. Undergrads at Caltech or at MIT are so smart, they're a pleasure to teach. I enjoyed having undergraduates in my lab. When I started out in science, the idea that an undergraduate would work in a laboratory was inconceivable, largely. You just imagined that they were too young and certainly didn't have the scientific background. Today, the kind of scientific information that an undergraduate has is what we only taught graduate students back in the early days. Undergraduates are all prepared. They understand what DNA is, and RNA is, and cells, and how cells work.

ZIERLER: What's that about? The internet? Better high school teaching?

BALTIMORE: Yes, much better prepared. These are kids going to special high schools, generally, but some in public high schools. But yes, the teachers are better prepared. The AP courses are I think a driving force here, because to be able to teach an AP course, the teachers have to themselves know a lot more than biology teachers used to know.

ZIERLER: Comparing an MIT undergraduate circa 1995, their high school education in biology was totally different than what you got when you were in high school?

BALTIMORE: Absolutely.

ZIERLER: Much more sophisticated.

BALTIMORE: Well, we didn't know anything then, either.

ZIERLER: Right. [laughs] Fair.

BALTIMORE: Literally.

ZIERLER: [laughs] That's right. That's interesting. What about supercomputers? DOE and supercomputers and Human Genome, was that relevant for your research at all?

BALTIMORE: Not really.

ZIERLER: Because the data that you were collecting was not that massive?

BALTIMORE: Right. I was not involved in these huge screening operations. The mantra of the Broad Institute is, if you can do it for one gene, you can do it for all genes. I never thought that way.

ZIERLER: Because that's incorrect, or it's inefficient?

BALTIMORE: Neither one. It wasn't possible, at the time. But my own work never got to that point. I worked mostly on single gene interests. For instance, we worked on NF kappa B for all those years. That's something that people at Broad would never think of doing. It was not the only transcription factor that I worked on. I worked on quite a number of different ones, had different projects going, different foci of interest, some that had to do with viruses. But I was much more a one-at-a-time guy.

ZIERLER: When the Baltimore Case ended, was there opportunity or interest to get more involved in policy? Did you want to be more involved in what was happening in Washington, to do National Academies reports?

BALTIMORE: I had done the National Academy report on AIDS, earlier. That had given me a taste of that. I said to myself then, if another occasion came up where I felt that it was something I understood particularly well and could work on, that I would do it again. But I didn't have the desire to just be on committees and to spend my time going back and forth to Washington, which was a lot easier from MIT than it was from Caltech.

ZIERLER: Did you do any advisory work for the Clinton administration, consulting?

BALTIMORE: No, I guess not. I've ended up doing a lot of work, but this is since I've been here, for the National Academy of Sciences.

ZIERLER: What about on the venture capital side? Were you starting to get involved at this point in companies, investing? Things are really starting to happen in the mid 1990s.

BALTIMORE: Right. Yes, I was getting involved, but can I remember, particularly before I came to Caltech—

ZIERLER: Were there any boards that you sat on?

BALTIMORE: Yeah. I joined the Amgen board from MIT, but then I moved to Caltech very soon thereafter. I spent 20 years on the Amgen board, but most of that was time when I was in California.

ZIERLER: What about startups yourself? Were you approached, ever?

BALTIMORE: Yes. I had been with Collaborative Research. We've talked about that. During the time I was at Whitehead, I didn't join any new boards. Then when I was at Rockefeller I didn't join any boards. Coming back to MIT, I didn't do much, really. The things were beginning to happen, but I didn't do much. I was on a board of a small company that Peter Kim started. I guess that's when I was at MIT. It was called Scriptgen. It was a transcription company, because that's what I knew about. That was about all. It was really only when I got out here that I became more and more involved.

ZIERLER: What was, at this point, when things do start to heat up, what was really the driving force? Was it the instrumentation, like automated DNA sequencing? Was it the large-scale projects like the Human Genome Project? What do you see as the driving factor of getting big business, big investment into biotechnology?

BALTIMORE: It was all of those things, but it was also a lot of people saying to themselves, "I've been working on this problem for n years in a lab. A reasonable next step is to see if it's clinically relevant, and maybe the best way to do that is to start a company." So there were many companies started because of the insights and interests of senior scientists. Not even necessarily senior, because in some cases quite junior scientists will be thinking this way. On the other hand, there were the companies that were started because the venture capitalists went around looking for opportunities and actually encouraging people to think about forming companies when they weren't ready to think or planning to think about it. It goes both ways.

ZIERLER: Your lab was always too fundamental to make that leap to the clinical?

BALTIMORE: Yeah, there was nothing that I was doing, until the last maybe 15 years, here at Caltech, that involved translating stuff from my laboratory. NF kappa B, for instance, which you would think would be studied in relation to inhibiting inflammatory disease—the biggest drug companies in the world have gone after making inhibitors of NF kappa B, and all failed.

ZIERLER: Why? What's so difficult?

BALTIMORE: I don't even know the answer to that.

ZIERLER: [laughs] That's the answer.

BALTIMORE: The obvious answer, which is NF kappa B is involved in so many things that if you try to drug it because of one pathological aspect, you in the process screw up a lot of important aspects of health. That doesn't seem to be the reason it's hard to make drugs against it. They have more targeted effects, the drugs. But there have been a whole series of drugs made, and they've all had side effects that made them not possible to develop for therapeutic use.

ZIERLER: This will obviously foreshadow to our next conversation, but were you thinking you were happy, you were good, you were at MIT, you were fully in the science. Was this a place where you could retire to, or before Caltech became something to think about, were you looking for bigger opportunities in the way that you might have been thinking about from MIT to Rockefeller? That's a bigger step, that's a trajectory my career had been on. What were you thinking along those lines?

BALTIMORE: I was thinking that I had done what I could do administratively in academia. I was going to stick with the science. My guess is, because of the way things have developed, particularly around MIT, that I was very likely to have moved into industry if I had stayed in Cambridge, because there were so many opportunities, and leave academia.

ZIERLER: Like CEO of a—?

BALTIMORE: Yeah. But that's retrospective guesswork.

ZIERLER: Is Cambridge, is Boston already starting to be a biotech hub or that comes later?

BALTIMORE: No, no, it's already happening.

ZIERLER: I'm assuming the Whitehead has a lot to do with that? Because of the translational impetus?

BALTIMORE: Whitehead itself did not do much translational. Whitehead was not a clinical—

ZIERLER: But that was Jack's vision, that ultimately that's where it's headed?

BALTIMORE: Yeah, but when he pivoted to a basic research focus, he knew that that meant that he was leaving the translation, leaving the clinical associations, to other institutions. Whitehead was too small and too divorced from any hospital to be a center of clinical work. We had very few MDs. Rudolf was an MD from Germany, but he had never done any clinical work at all. It was just that in Germany, that was a way to get an education in biology. Weinberg was not an MD. I was not an MD. Fink was not an MD. Rick Young was not an MD. Peter Kim was not an MD. David Page was an MD, but also totally focused in research, on sex chromosomes. He ultimately became the director of Whitehead. There were almost no MDs there.

ZIERLER: A CEO of a biotech pharmaceutical company, that would have been more attractive than like science advisor in the Gore administration if that had played out, or something? You still enjoyed policy, national policy.

BALTIMORE: I did enjoy national policy, but I had largely believed, been told that I was anathema in Washington. Even with the exoneration.

ZIERLER: The lightning rod. It was just not happening.

BALTIMORE: Right. Partly because Dingell was so powerful. Until Dingell resigned, I had to worry that people were just afraid of him, even when he was in the minority. Oddly enough, his wife, who is now a congresswoman, has been very kind to me. I see her one way or another occasionally, and she goes out of her way to say hello.

ZIERLER: Makes sense?

BALTIMORE: To say how sorry she is.

ZIERLER: That's nice.

BALTIMORE: It is. I would have been interested to be involved as science advisor or advisory in some way, but I never held out hope that that is what was going to happen.

ZIERLER: That would be of interest but not realistic. The business track may have happened. But becoming the president of another university, that was not something you were thinking about or something that was a reality of any kind. [laughs]

BALTIMORE: Right.

ZIERLER: We'll pick up next time to see what happens next!

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Friday, March 4th, 2022. Once again, I am delighted to be back with Professor David Baltimore. Hello!

BALTIMORE: Hello! For the record, it's almost my birthday.

ZIERLER: That's great. It was my birthday a few days ago.

BALTIMORE: Oh!

Caltech Biology and the Caltech Presidency

ZIERLER: There you go! What I'd like to do today, to set the broader context for the discussions and decision-making that led to you becoming president of Caltech, is to ask you where Caltech loomed in your professional mind over the course of your career, maybe from undergraduate through the 1990s. Maybe I'll pose the question like this: let's say in a parallel life, you were interested in physics and astronomy as an undergraduate. It's obvious that with Feynman, Gell-Mann, Caltech is just there. Did you appreciate earlier in your career, even as an undergraduate, all of the formative research in biology that happened at Caltech? Was biology and innovation at Caltech, was that always there in your mind, leading up to when you considered becoming president of Caltech?

BALTIMORE: The answer to that is yes. If I go back and say, when did I first start thinking about Caltech, it was when I was in high school, because Howard Temin, who was at Jackson Lab and was the college guru of the high school program, was on his way to Caltech as a graduate student. I think. I think that's right? I don't think he had another year—or maybe he had another year at Swarthmore before. But for sure, when I was an undergraduate, I was very conscious of Caltech, because that's the center of phage biology.

ZIERLER: Who were the individuals that you are associating with it being the center?

BALTIMORE: It's Max Delbrück. I went to Cold Spring Harbor after my junior year at Swarthmore. At Cold Spring Harbor, Caltech was mecca, because Delbrück was there, but also because Delbrück had built around him the school of phage geneticists—Stahl, Bob Edgar, Charlie Steinberg. There was a Steinberg and Stahl paper that was the central—and I must say very confusing—paper in phage genetics—and then the Meselson-Stahl experiment. I was totally conscious of Caltech. But, I never thought about going to Caltech, because California was a fantasy land. It was so far away, so distant in every sense. From my parents' lives—they had never been to California. They had hardly ever been on an airplane. People didn't go on airplanes, then. This is just after the War.

ZIERLER: What about Linus Pauling? Would he have been more peripheral to your association with biology and what you were interested in?

BALTIMORE: I just don't know whether I was aware. I must have been, because the story of sickle cell was so absolutely central to the development of biology. But I'm not really sure whether I was in graduate school when I first got aware of that.

ZIERLER: What about when you became interested in immunology? Was the work of, for example, Ray Owen—did you associate Caltech with being a mecca for immunology also, or was he more operating on his own?

BALTIMORE: He was on his own. Caltech was not a center of immunology. Ray had done these very central experiments, but they weren't appreciated generally.

ZIERLER: He was ahead of his time to some degree?

BALTIMORE: He was way ahead of his time. The thing he was working with, which had to do with cattle, was certainly not the main line of anybody else's thinking. When the Nobel Prizes were given out in immunology, Ray never participated because he just wasn't appreciated. Now, the real aficionados appreciated him, knew him. My friend Irv Weissman thought Ray was one of the most important scientists of the twentieth century. Then he didn't really build on what he had done. He was a wonderful man. He was very well-known around campus. He was a very thoughtful academic.

ZIERLER: What about from the institutional perspective? All of your years at MIT and the so-called MIT/Caltech rivalry. Did that register with you, or that was more about undergraduate high-jinx and things like that?

BALTIMORE: I didn't know anything about that. At MIT, there was not much of a feeling that Caltech was a rival. It was a peer, for sure, if you knew anything about it, but it wasn't a rival in the sense that it was so much smaller, so much further away. Again, this distance thing; it depends on when you talk about it, but up until jet travel, the distances were enormous. That's why the story of the building of Caltech is so amazing, because that was all done when the only way to get across the country was rail, a few days on trains.

ZIERLER: How do you convince Millikan to come out here, like that?

BALTIMORE: Right. It's really amazing. With my parents being focused in New York and hardly ever out of New York in their lives—god, I don't know if my mother ever got out of New York except on holidays when they went to the Caribbean. . My father did a little bit, because in his business, he had a lot of business contacts in the rest of the country, and he did occasionally travel.

ZIERLER: When did your mother live to?

BALTIMORE: She lived until she was in her mid-seventies. Oh, and then finally, she traveled to Europe, and she traveled, but up until when I was thinking about even graduate school, when I went to California—well, when I was thinking about graduate school, it was just California was in the distance. It might as well have been Timbuktu.

ZIERLER: What about when you were in La Jolla? Did you make a point of ever visiting Pasadena? Was Caltech a place to go to when you're that close?

BALTIMORE: Yes, and I did come up to Caltech once or twice. When I was a graduate student and I published these things in virology, the people at Caltech around Dulbecco, particularly the younger people around Dulbecco, were very aware of what I was doing, and they invited me to come to Caltech and give a seminar. That was the first time I was ever in California, and that was probably 1962 or maybe 1963.

ZIERLER: What about your awareness of the perception—whether it's right or wrong is a different story—that biology always lived in the shadow of physics and astronomy at Caltech? That for all of the great research in biology, obviously there had never been a president who was a biologist.

BALTIMORE: At the time when I was first considered to be president of Caltech, then all of that was part of the thinking.

ZIERLER: New direction for the Institute.

BALTIMORE: Right, but it's not a new direction, no. Because if you go back, at least in my career, to when I was in graduate school and in the short period thereafter, Caltech loomed enormous, because of the people who had been there and the central role that Caltech played in molecular biology. I was actually surprised to discover that biology wasn't appreciated, and that people said, "Is biology important at Caltech?" I've said this to any number of people over my whole career, that Caltech is the school. That's where molecular biology is born and brought up. Remember, when Luria went to MIT, he had already had his career. Max had his career almost entirely here at Caltech. I think he was hired as a full professor. He was hired from Vanderbilt. That was still relatively young compared to Luria, who was already a senior figure when he was hired. MIT never had any biology and wasn't known for it, but with the combination of the influence of Pauling and the influence of Max Delbrück here, this was the most important place. But it never got through. It didn't become part of popular understanding. Again, because Caltech is so small, its influence in terms of just the number of people involved is small. Then MIT being close to Washington and on the East Coast meant it was a much more central participant in the policymaking, political side of the world. Caltech—it was amazing that Hale had a huge influence in Washington, which meant that he was on the train continually going back and forth. He had these serious mental problems, which would come out on the train. If you want to write a biography, that's the book that needs to be written, is a great biography of Hale.

ZIERLER: [laughs] Okay!

BALTIMORE: There's a good biography of Hale, but there's not a great one, and nobody deals with his role in the social world of Pasadena, which it's going to be pretty soon impossible to do that, because there aren't people around who remember. But the stories about Hale are remarkable. Have you read this biography of Hale?

ZIERLER: No. I will now!

BALTIMORE: I forgot who wrote it.

ZIERLER: Let's get back to Cambridge. To pick up from last time, you were in recovery mode from Rockefeller. You were thoroughly enjoying being back in your scientific life. Other administrative leadership positions were really not something you were actively seeking out at that time. In fact, as you said last time, if there was a different career path for you to choose at this point, it might be leading a biotech company or something in the private sector. That's where you are when the possibility of leading Caltech comes up. How does that happen? You get a phone call?

BALTIMORE: Yeah, I got a phone call from—I don't remember what the first contact was. David Anderson was on the committee.

ZIERLER: Did you know David before? Were you aware of his work?

BALTIMORE: I was. He was a Rockefeller graduate, and I had heard about him. He had done a whole lot of beautiful work, so he was one of the really important people, young people in molecular biology. He hadn't yet gotten involved in neuroscience or in behavior, which is where his career has gone. Let me ask Alice, because she's more likely to know.

ZIERLER: Let's ask her.

BALTIMORE: Alice? I want to ask you a question but maybe it's better if you come—what was the first contact I had with Caltech? [pause] If this ends up a book, I probably should do a little research. I can just ask David Anderson. There's an archive of all the work done by the search committee, so we can find it.

ZIERLER: I'm hearing between David Anderson, Kip Thorne, your sense is that it was probably a faculty member and not a trustee who would have reached out to you?

BALTIMORE: That's for sure, but do you know how they choose a president at Caltech?

ZIERLER: Tell me.

BALTIMORE: The board hears that the previous president is resigning. The board then constitutes a board committee which will do the search work for the board and report to the board, but the board ultimately makes the choice. That committee goes to the head of the faculty. There's somebody who is the faculty head at any one time. The chairman of the faculty.

ZIERLER: That's a position at Caltech?

BALTIMORE: Yeah.

ZIERLER: Where are they in the hierarchy?

BALTIMORE: They're sort of nowhere, but when important things are decided—I think they're actually a member of the board? They may be a member of the board? Anyway, it was Dan Kevles who was the chairman of the faculty at the time. He goes to the chairman of the faculty and says, "Would you constitute a presidential search committee of the faculty? We will work with you." The way they work with that committee is they make that committee responsible for all of the contacts. That was the committee headed by Kip Thorne. It had one representative from each division and a couple of other people. I don't remember how everybody was chosen. Ed Stolper was on it.

ZIERLER: Representing GPS.

BALTIMORE: Yeah.

ZIERLER: Dave Stevenson was on it.

BALTIMORE: Right.

ZIERLER: Also from GPS obviously. Dave Anderson. Then whoever else.

BALTIMORE: Right. It was probably somebody from that committee. Now, was it Kip directly? That, I don't remember, but it seems unlikely, because the first approach always is to ask for advice from an individual. They asked me for—

ZIERLER: "We need a new president. Who do you think would be a good idea?" Like that?

BALTIMORE: Right.

ZIERLER: But that's a back-door approach to gauging your own—

BALTIMORE: Yeah. You know what that means, but nobody is making any commitments. They're sort of testing whether you'd be—and I know that one of the very first questions that was asked was, "Would you be interested yourself?" That was amazing to me, because I had pretty well assumed—

ZIERLER: You were radioactive.

BALTIMORE: Yeah, that I was radioactive and that nobody would want—

ZIERLER: That's assuming, though that—again, Rockefeller is a tiny place, and maybe it didn't resonate beyond Rockefeller. Also, the Baltimore Case was resolved at that point?

BALTIMORE: No, no, no, it wasn't.

ZIERLER: 1994.

BALTIMORE: Oh, sorry. The case was resolved, right. But the whole scientific community was aware of that whole process. The fact that Rockefeller is a small place is not—it loomed very large, and it was covered by Science magazine and Nature magazine and The New York Times, for that matter. There was no secret, and I just assumed that because it had been so prominent that if I was ever to take up that side of my career, it might be ten years hence or something, but it wasn't going to be then.

ZIERLER: The counternarrative could just as easily be that you were the good guy, operating in a less than ideal environment. Look, you were brought in by Rockefeller himself, to modernize—

BALTIMORE: No, it's true. It's all true. But I was viewed as arrogant, as in some ways the enemy of the scientific community. We've never gotten into what Jim Watson was doing to turn people against me, but he was full-time at it, along with some other people from Harvard. There was a whole side to the opposition to me that were some of the most honored people in the scientific community.

ZIERLER: But again, this is all preceding on the assumption that that's the narrative that people are coming away with. Why isn't Jim Watson the bad guy in this?

BALTIMORE: Because Jim Watson was Jim Watson.

ZIERLER: [laughs]

BALTIMORE: Jim Watson was such an awful person, but it took a long time before that was recognized. His misogyny and his prejudices, none of that was known, although he didn't do anything to hide it. It's just that people ignored it and remembered him as half of Watson and Crick, and that that was the—and it was—the most important thing that happened in biology in the twentieth century.

ZIERLER: Rightly or wrongly, you perceived that this was the word on the street about you.

BALTIMORE: Yes.

ZIERLER: So that would translate to an offer to lead another university, let alone Caltech, was like different planet as far as you were concerned. That was not happening.

BALTIMORE: That's right.

ZIERLER: When you got this call, you must have been blown out of the water.

BALTIMORE: I was.

ZIERLER: How high were your antibody levels at this point, just in terms of having PTSD yourself from this experience? Was the knee-jerk reaction, even if you read between the lines about asking for you advice, "My god, I don't want anything to do with this"?

BALTIMORE: No, I had said to myself years before that I didn't want to run a big university, that the distance between a president of a big university and the issues of the faculty and the issues of research—and I was always focused on research as the most important thing I cared about, even though in the academic world, teaching and the bureaucracy of the university itself is a very big part of life. But what I really cared about was research. To be president of even MIT, which was a very research-oriented university, meant that you were dealing at a level at which you had very little to do with that research. I had found no reason to want to do that, because I didn't love power, and I didn't love bureaucracy.

ZIERLER: And MIT is enormous.

BALTIMORE: MIT is enormous. I hadn't even ever wanted, when I was at MIT, to be chairman of the department.

ZIERLER: Whitehead was as big as you needed to get.

BALTIMORE: Whitehead was the kind of thing that I found an interesting challenge, but being the head of a department I didn't find an interesting challenge.

ZIERLER: Part of the challenge with Whitehead is building it from scratch.

BALTIMORE: Right. A, I was building it from scratch. B, I was involved in issues about research, because that's all Whitehead was. The rest of the academic appointments were at MIT. And I had a really enormous amount of resources to make that all possible, whereas in the position of head of a department or even president of a university, all you're ever worried about is getting enough money together to do anything. Here, money was—Jack was offering me $135 million. That was real money at the time. I was excited to take that on. There was also the challenge of putting it in place since he wasn't—we didn't know it was going to be at MIT to start off with, and I needed to find its niche in the world. That's very different than being asked to be president of a university. About the only university that was of a size and nature that I would want to be president was Caltech.

ZIERLER: Now, the x factor here, of course, is there's JPL. Did you recognize the Caltech-JPL connection and the fact that there would be this massive FFRDC that the director of that would report to you? Did that register with you when you started thinking about leading Caltech?

BALTIMORE: No, to be perfectly honest. I was told that, very early on. I knew that as a fact. But I had absolutely no sense of how the president of Caltech interacts with an FFRDC, or interacts with JPL.

ZIERLER: Let alone one that's much bigger than the university itself.

BALTIMORE: Right. I don't think I was aware of how big it was. The people who talked to me about it did not emphasize it, and it was my impression that it was largely a separate issue from the core of Caltech and sort of took care of itself, which in fact is in a sense true. If I really thought it through, I probably would have realized that there was one thing, and one thing only, that was critical that you did as president of Caltech, and that was just to choose the director of JPL, but I'm not sure I even was aware of that nexus.

ZIERLER: I would imagine that a steady hand like Ed Stone in the middle of his directorship, that was very easy for you? There was a good operation running, solid leadership, don't touch it; it's working well. That could be your approach.

BALTIMORE: Yeah. Until it wasn't.

ZIERLER: Right. [laughs] We'll get to that. Now, with this call, and the going assumption that you're radioactive and you'd never get this kind of call, did that make you rethink whether this perception about you was true, or did that make you think, "Well, this is Caltech, and they do things their own way, and maybe I am radioactive and maybe they don't care about that, and that makes it all the more intriguing"? How did that change your perceptions at that point?

BALTIMORE: You put it well, because I really thought maybe this was a way to start anew. If the people at Caltech were willing to ignore a lot of what had been said and—

ZIERLER: But not necessarily ignore; don't believe it.

BALTIMORE: That's what I mean by ignore. Not believing it is ignoring it. And were willing to rethink me and the whole thing, and could maybe see it even as a positive, in the sense that I had come through a real testing period without totally breaking under it.

ZIERLER: [laughs] Stress test.

BALTIMORE: Yes, exactly. At first, I was willing to go along and be interviewed and whatever, but I didn't think it was going to ever happen. I was just sure that someplace around the way, there was going to be somebody or something that was going to be a stumbling block, and it wouldn't—

ZIERLER: Did you have a sense—and this is where I want to get into this—that Caltech was intent on hiring an eminent biologist at this point?

BALTIMORE: That was clearly a plus. They had started a Biological Sciences Initiative. Tom Everhart had quit sort of in the middle of this initiative. The initiative was established as a sort of mini campaign, so it was a campaign but only in biology. A fundraising campaign, looking for a new building, looking for resources for graduate students, various things. The board had decided to start this mini campaign. It was really because they saw in the world around them that biology was the most exciting science, and they talked to people, and everybody said the twenty-first century was going to be the century of biology, and Caltech was not in a strong position to play in that arena.

ZIERLER: What about at Caltech where there's this culture of—there's no departmental walls. Like if Carver Mead and John Allman want to get together and do some really cutting-edge wild stuff, that's the kind of collaboration that happens at a place like Caltech. Did that register with you? Did you appreciate that there was a fearlessness or a boundlessness that would allow new innovations in biology simply because of the way Caltech is structured administratively?

BALTIMORE: No, I don't think I appreciated, until I did serious diligence, how Caltech was administratively organized.

ZIERLER: The divisions and the unique way of not having a department of biology, that was only when you started looking into Caltech administratively?

BALTIMORE: Yeah. It's the kind of thing that nobody outside of Caltech knows, or imagines. I love telling people about the simplicity of the administration of Caltech, but I didn't know it. But I have always felt, and organized Whitehead around this, that small is beautiful, and that a small environment is catalytic, because people bounce off each other. It has nothing to do with the administrative structure, but a small place inevitably has a smaller administration. As I said, I never wanted to be head of a large place, because I just didn't think that was fun, whereas to be head of a small place, you could have all of the levers at your command. That had worked at Whitehead. I was attracted to Caltech because I saw it as just the step up from Whitehead that I could handle, and wouldn't overwhelm me with bureaucratic activities but give me enough freedom to actually dig into the science. That turned out to be true.

ZIERLER: You came out to interview when? That would have been 1995?

BALTIMORE: It would have been 1995, yes.

ZIERLER: Who did you meet when you came out?

BALTIMORE: Kip Thorne, and this is a story worth interviewing Kip about.

ZIERLER: Oh, I will.

BALTIMORE: Kip had organized this committee in dead secrecy, and was infinitely careful about making sure there were no rumors about who they were considering, or how they were considering, and swore all this committee to secrecy, and they had secret email identifications and things. Everything was secret. Kip arranged for the committee to meet me at the Bel Air Hotel on the theory that no person from Caltech has ever been [laughs] into the Bel Air Hotel. It's probably true. I certainly haven't been back. [Actually, I have, but very rarely.]

ZIERLER: Think if you were interviewing for UCLA presidency or something like that, maybe. [laughs]

BALTIMORE: Right.

ZIERLER: That's great.

BALTIMORE: He had cars with smoked glass.

ZIERLER: [laughs]

BALTIMORE: It was way overboard.

ZIERLER: Do you remember who was there at the hotel?

BALTIMORE: I think it was all the members of the search committee.

ZIERLER: It's small. We named some, but there's probably not many more.

BALTIMORE: Right, and it was just the ones from the faculty.

ZIERLER: The representatives from each division.

BALTIMORE: The faculty search committee, not the board search committee. Then somewhat later, Alice and I were invited out to—I think she came with me to the Bel Air Hotel. We came out and then we were invited to campus, but it was again done very secretively and very carefully. Then I met some of the members of the board as well as—someplace in there, there's a meeting with—oh, what's his name, who was chairman of the board?

ZIERLER: Ben Rosen?

BALTIMORE: No.

ZIERLER: David Lee?

BALTIMORE: No, it was before David Lee, before Ben Rosen. It was the head of Intel.

ZIERLER: Oh, Gordon Moore.

BALTIMORE: Right. Gordon. Then they had appointed a committee, and the head of that committee was I think Wally Weisman who was vice chair of the board. There's a little vagueness there. Ben Rosen was—no, he was just a member of the board, but I think he was on the committee. By that time, they had already decided—

ZIERLER: To go with you?

BALTIMORE: Yeah. Or at least that I was the head of the list.

ZIERLER: Obviously, the meeting at the Bel Air Hotel went well.

BALTIMORE: I guess. [laughs] Yes.

ZIERLER: Did it get into specifics? Did they ask you to lay out your vision? Did they talk about what they were looking for and to feel you out if you were a right match? What was discussed?

BALTIMORE: I really don't remember what was discussed, but I do remember that I couldn't be very specific, because although I had read the materials that they had sent me and looked at whatever I could, and I think I talked to David Anderson in particular, I didn't have a plan for Caltech, and I really felt like I needed a number of months to sort of steep myself in the culture of Caltech and the thinking of Caltech before I could say word one about what I wanted to do. I guess they appreciated that [laughs], partly because, as I think I had said to you, I had made a strategic error in being very open about what I wanted to do at Rockefeller. I wasn't going to repeat that mistake. But also I was in a very different position, because I had never been at Caltech as a faculty. I literally had spent about three days on the campus in my whole life.

ZIERLER: One difference, even if it was a strategic mistake at Rockefeller is, there was a mandate that you were brought in to accomplish.

BALTIMORE: Yes.

ZIERLER: It doesn't sound like at Caltech, there was a mandate.

BALTIMORE: No.

ZIERLER: You could be sort of more of a closed book, but if you were to open it up, it seems like there isn't much there in terms of a specific goal for you to come in and achieve.

BALTIMORE: Well, there was, and that was to finish the Biological Sciences Initiative, and to bring in those resources, to get the building done, and to rejuvenate biology at the top.

ZIERLER: Maybe you know this now retrospectively or perhaps you knew it at the time; to zoom out from Caltech, what was happening in biology more broadly that convinced Caltech that it needed this campaign, that it needed to up its game in biology? What was happening more broadly or what were the blind spots at Caltech?

BALTIMORE: The major figure at Caltech in biology was probably Lee Hood.

ZIERLER: Who had left at that point.

BALTIMORE: Who had left at that point.

ZIERLER: The message clearly was Caltech was too small for him.

BALTIMORE: Right. But the board wasn't happy about that.

ZIERLER: It wasn't happy that he left?

BALTIMORE: Yes. Because Lee was the kind of guy who had made friends with members of the board.

ZIERLER: And he could hobnob with people like Bill Gates.

BALTIMORE: Right. It was clear that there was something wrong in biology.

ZIERLER: A fustiness, perhaps.

BALTIMORE: And there was. At the same time, as I said, if you asked anybody in the scientific community or even in the general intellectual community, they would say, "Yes, we're entering the age of biology. Physics has done its growth, has had its day in the sun." Not true—

ZIERLER: Of course. And this is pre-LIGO, or LIGO is cooking right now.

BALTIMORE: That's right, yes. We had not yet sequenced the human genome, but the process was underway the sequence the human genome.

ZIERLER: And we've already established that the biotech revolution is well underway at this point.

BALTIMORE: Right, and the biotech revolution is well underway, and it's not affecting Caltech at all.

ZIERLER: Because the culture of startups here is—this is one reason why Lee Hood left, because there wasn't that culture here.

BALTIMORE: Right. Although Tom had done something really important, which is to hire a guy to run technology transfer from Boston University. Larry—I forgot Larry's last name. It's a simple last name, like Gordon, except it isn't Gordon, but it's easily found out. Larry had been Silber's right-hand guy in developing things which were borderline unethical. Exactly why Tom thought that Larry was the right thing for Caltech, I don't know, but he was. He was just arriving when I came, so he hadn't yet had much influence. A lot of the faculty were totally suspicious of him. But he was my great ally, as it turned out, and we thought very similarly about the role that startups and biotechnology could play in biology. He stayed for a long time. He died, but all the people you know now who are in technology transfer were trained by Larry. Rich Wolf in particular was trained by Larry. But that hadn't happened yet, so Lee was sort of leaving, but there were influences that were congruent with Lee's strengths that were beginning to be felt around the campus.

ZIERLER: There was probably also a recruiting issue at this point. Star postdocs who were now on the job market who saw Lee Hood leaving, they're probably not looking at Caltech at this point as the hot place where they can go and do the research and do a startup.

BALTIMORE: No, they certainly were not. But we hadn't reached the point where starting out postdocs, certainly graduate students, had an idea that they were going into a startup culture. That was happening at MIT, beginning to happen at this point, but it certainly hadn't happened around Caltech at all.

ZIERLER: Which is a strategic disadvantage.

BALTIMORE: Yeah. But I don't think that people at the time when they were making those decisions were making them on the basis of the strength of a startup culture. I just don't think they saw that that's what the end result might be of things that were happening. But—and I made this point more often than people would have liked, but I said it when the search committee met with me at one time—I know that—when I was looking at applications to graduate school at MIT, and MIT was generally considered to be the best graduate school in biology in the country at this point—this would be in the early 1990s—those kids had not applied to Caltech. There was almost nobody who turned down MIT for Caltech.

ZIERLER: Like there would be in physics and astronomy, perhaps.

BALTIMORE: Right, or chemistry. When I came here, Caltech Chemistry was second-best, I guess, in the country. Harvard was the best. I think that's still true. But biology, Caltech wasn't even on the radar for the very best students. I can tell you, the quality of the students was a step down from the quality that I was used to at MIT. I think we've actually turned that around now, but it has taken a long time. But it was a measure of why the Biological Sciences Initiative was necessary, and why we needed to really make a push in biology. What I wanted to say was that the sequencing of the human genome was going to, did, give us knowledge of two things. One was the complete sequence of the genome, which meant that there was nothing hiding. Up until that time, if I wanted to know how many genes there were that were involved in, let's say, the growth of poliovirus, which I cared about, there was no way to answer that question, and there was never any sense that I knew all of them, because I didn't know what "all" was in there. When the sequence of the human genome was done, that question no longer was a question. You could know that there were actually 245 genes that played central roles in the growth of poliovirus or whatever the number was. I was going to frame another question like that, but I've forgotten what it is now. In 1995, 1996, we're getting to the point of having sequenced a lot of the genome and things are coming out. Oh, I know what it is—whatever the number was going to turn out to be of the number of genes—it took a long time to settle that number to the roughly 20,000 it is now—that was going to be 20,000 big questions that I could just sit down and write for you in biology. Never mind the questions about how they interacted. Never mind the questions of how they get multiply spliced. Biology was suddenly the generator of a vast number of scientific questions, and you could easily see, and it is turning out to be true, that every department on the campus, every division on the campus of Caltech, every department at MIT, was going to be thinking about biology, and that biology was going to be the central science of the next century, the century we're in now, in a very simple way—20,000 genes, hundreds of thousands of questions that I can just sit down and write for you. No science had ever done that before, or come close to it. Even the number of rocks that aren't [laughs] doesn't approach that. And people sensed that. They may not have been able to write it down in that way, but they sensed that. Caltech really had to take its deficit in biology seriously. People had forgotten that Caltech was the central generator of molecular biology. That was just not known anymore. Max went into the history books and most people don't know anything about Max anymore.

ZIERLER: Given the centrality of genetics to all of this, were there strengths in chemistry, all of the work in DNA, that were being done in chemistry, that you can build on for the campaign, for addressing this issue of the fact that biology is now going to be all over the Institute? Was that a strength, a strong point to build on?

BALTIMORE: Yeah, it was, and most people couldn't have actually made the distinction between chemistry and biology, looking at Caltech from a little distance, because Pauling had been such a central figure. And maybe four other people. One was Jerry Vinograd. Jerry was in I think chemical engineering. I don't think he was in biology. But he was one of the central people who worked out the mechanics of DNA. Not the chemistry of DNA; the mechanics of DNA, topological considerations of DNA. He had retired or maybe even died by the time I got here. Meselson and Stahl, because the Meselson-Stahl experiment were so important, and they were two remarkable guys. They actually built on some of the technology that Vinograd put in place. Without Jerry Vinograd, you don't get a Meselson-Stahl experiment. He was running the E type centrifuge, the Beckman centrifuge, and that's the machine that the Meselson-Stahl experiment was based on. And Max. This place was absolutely central. All of that was gone, that influence, but there was still the influence of genetics.

ZIERLER: Was electron transport relevant to what was happening in biology?

BALTIMORE: Not here. That was metabolic. And if you're worried about the connection to chemistry, that kind of chemistry we weren't doing, that kind of biochemistry, unless there's something I don't know about. I know who the other person is who I was trying to remember—Norm Davidson. He was in chemistry. When biology ran into a leadership vacuum, he moved into biology and headed biology. That's how close chemistry and biology were. But it revolved around DNA. Phil Sharp, who discovered splicing at MIT, was my junior colleague at MIT, came here as a postdoc to work with Davidson. Davidson, at that point, was looking at the structure of DNA in the electron microscope, so what Phil did was electron microscopy when he was here. They figured out how to use the microscope to look for hybrids between two different DNA molecules, which is very important for understanding the overall structure of DNA. We used to say, "Genes are carried on DNA." Well, what's a gene? Where does it start? Where does it end? We didn't know any of the topology of it. Between Davidson and Vinograd—and by that time, Pauling was out of the picture; he was in Vitamin C land. He wasn't here, either. Yeah, we drove out Pauling and Lee Hood [laughs], Pauling because of his politics, and Lee because of his insatiable appetite.

ZIERLER: [laughs]

BALTIMORE: But the question you asked, which is the relationship with chemistry and biology, very strong, happened over long periods of time, and no real distinction between the two of them.

ZIERLER: Let's go back to the process. After that initial meeting at Bel Air, you go back to Cambridge. What happens next? You had a good feeling, and you thought this was for real, or you thought this was not legitimate?

BALTIMORE: I couldn't tell. They were very circumspect. I just answered their questions and told them what I was thinking about and what I knew about, what I cared about, and what I thought Caltech needed.

ZIERLER: Coming out of that discussion, were you more enthused about the possibility about becoming president?

BALTIMORE: I was, because everything I heard said that the smallness, the research orientation of Caltech, was real, and that that's what they wanted.

ZIERLER: How central was the campaign in that discussion? Were they front and center about, "We're doing this campaign. This is really important for the Institute"? That came out loud and clear?

BALTIMORE: Yes. But that was a positive, because they were saying, "We know why we want you, and we've made a commitment to this campaign, and it needs leadership, so you would make at least on paper the perfect person to do that." That was why they were interviewing me and serious about that.

ZIERLER: Did they think that you had another Jack Whitehead up your sleeve?

BALTIMORE: No, no. And they had some perfectly wealthy people, Eli Broad and Don Bren to mention two, both billionaires. No, they had the people of wealth. What they didn't have was a way to convince them that we could make this change in the focus at Caltech.

ZIERLER: You were not brought in to make it rain; you were brought in because your gravitas would convince the people who had the funds to make this happen. That's the idea?

BALTIMORE: Yeah.

ZIERLER: After that initial meeting, you come back to Cambridge. What's the next step?

BALTIMORE: I—

ZIERLER: That's another detail.

BALTIMORE: Yeah.

ZIERLER: But probably it's a faculty member from the committee calling yet again?

BALTIMORE: At that point, I think my conversations were with Kip, and they fairly soon invited me out for a second meeting, for a sort of definitive meeting, on the campus. Alice came. It was screaming hot, so it must have been in August. She almost fainted. But I met then with biologists and with the committees. I'm mixing up two meetings, I think. I need to do research. Actually I don't have a simple record of what happened, but—

ZIERLER: Was there anyone in biology who was doing work that you were admiring at that point?

BALTIMORE: That's an interesting question. I think the answer is no. The kind of biology—and this actually became an issue between me and the Biology Department. The kind of biology I cared about, which was virology—and there was one good virologist here but he was on his way to retirement, Jim Strauss. There was almost no cell biology. There was no cancer research. Oh, there was some microbiology, and in fact one guy who I really had great admiration for was Mel Simon. Mel left about halfway through my presidency and went back to—because it was a place he loved—San Diego—and he's my age now, so he's largely retired. He worked very closely with John Abelson, and I knew John's work and had a lot of admiration for him. There were some people who I really—and they had been chair of the department before or right after Lee, I guess. Let's see, who was chair? When I came, Elliot Meyerowitz.

ZIERLER: He started in 2000, so there was someone before him. Was it Jackie?

BALTIMORE: No, she was chair of Chemistry. She wasn't in Biology. And it was later than that when she was—it was after I was president. Yeah, there is somebody I am forgetting who was chair.

ZIERLER: We'll come back to that. Did you meet with the board on that visit to campus?

BALTIMORE: No, because the board is only here like four times a year.

ZIERLER: I thought maybe your visit would have coincided with a board meeting.

BALTIMORE: I don't think so. But I did meet with, I think the board committee. But it's all vague in my mind.

ZIERLER: What were some of the more specific and definite conversations in that second visit that got closer to an offer and acceptance?

BALTIMORE: They were very clear that it was Kip's orders that they should be transparent, they being anybody I talked to should be transparent in talking about the finances, in talking about intellectual directions, the student body—there were a lot of problems with the students—and people shouldn't hold back anything. His mantra was, "If David comes here, I don't want there to be a single surprise."

ZIERLER: That's a wise approach.

BALTIMORE: It is a wise approach, and they were very good about it, and very open. I met in various mixtures with people, and they followed that. By the time I was done, I felt like I really had a view of the place. I learned about JPL. I don't think I met with the head of JPL. But at that point, I met with people who were not on the committees.

ZIERLER: Who was provost at the time? Was it Robbie Vogt?

BALTIMORE: [laughs]

ZIERLER: Did you have to deal with the whole helping ease him out of LIGO?

BALTIMORE: No.

ZIERLER: That's all before you came?

BALTIMORE: Yeah.

ZIERLER: It's not Steve Koonin yet; it's somebody in between?

BALTIMORE: Oh no, it was Steve Koonin. Of course. Yeah, because I kept Steve on, as provost, because he had been provost for probably four or five years.

ZIERLER: It's the president's call to keep or pick a new provost?

BALTIMORE: Yeah.

ZIERLER: Strategic mistake on your part?

BALTIMORE: Yeah. As it turned out.

ZIERLER: We'll get to that. [laughs] But at the time, you had no idea.

BALTIMORE: No, I didn't. And look, for the first four or five years, Steve was great. The mistake was that that was enough, and I should have gotten somebody new. But for a long time, he was terrific. And I needed the continuity that he provided in order to fully become comfortable with the place.

ZIERLER: He had deep institutional appreciation.

BALTIMORE: Oh, yeah. He had been an undergraduate here.

ZIERLER: Was the offer made on that second visit or it was over the phone when you got back to Cambridge?

BALTIMORE: I think it was made over the phone later.

ZIERLER: Did you make MIT aware that you were on the short list at this point?

BALTIMORE: Yeah, I certainly discussed it; I can't remember with whom. Maybe with the president.

ZIERLER: How much was not being part of Whitehead coming back to MIT after Rockefeller, being hurt by that, was that a push factor for you? Did it make the acceptance easier?

BALTIMORE: Yes.

ZIERLER: MIT obviously had nothing to offer to make you reconsider staying.

BALTIMORE: No, not at that point.

ZIERLER: So you get the offer, probably over the phone. Do you remember that phone call? Would that have been Kip?

BALTIMORE: That would have been Kip, yeah.

ZIERLER: Any recollection of—?

BALTIMORE: At one point, there's another meeting—and this is what I can't integrate exactly—with the board committee.

ZIERLER: Which is probably before or after the visit, when it was hot in Pasadena?

BALTIMORE: That's all fried in my brain together, but I know I met with Gordon and with Wally and Ben.

ZIERLER: Any early signs that you would be sparring with Ben Rosen sooner than later?

BALTIMORE: No. We got on fine. Ben's an itchy guy, and I'm still friendly with Wally. We had dinner with him just the other night. Gordon, because he has never lived here, was not so close. And I see Ben in New York.

ZIERLER: So you accept the offer from Kip. What does he say? Do you talk anything besides the offer?

BALTIMORE: At that point I had thought it through and said that I would come in the Fall of 1996.

ZIERLER: You had given yourself enough time, as you said, to get steeped in Caltech culture?

BALTIMORE: Yeah.

ZIERLER: Kip's policy of airing all of our problems so that there's no surprises, what jumped out at you immediately, things that you needed to concentrate on? Maybe we'll start with the undergraduates. You said there were problems with the student body.

BALTIMORE: Yeah. Under the houses, had their own culture, first of all individually and then together. And because—I think—Caltech is sort of 70% a research institute and maybe 30% a university, it didn't have highly developed ways of controlling the students, so the students—it was a little bit of a Lord of the Flies world. The students loved it, and they had built a structure whereby incoming students were inculcated into this culture immediately, and by a few weeks, certainly a couple months after the arrival of freshmen, they were totally into this culture of, to a large extent, self-governance. Some of this was terrible, and a lot of it was left to students without much connection to an adult culture of any kind. There was that whole side. For instance, the alumni remembered it very fondly and were great supporters. The alumni in L.A., for instance, were really a dominant force on the campus and through the alumni organization. You weren't going to be able to change this very quickly, but I wanted to get sort of more adult behavior into student life, and more cultural appreciation. It turned out to be very hard, and I sort of gave up in the end. One of the things that bothered me, or one of the things that I thought was responsible, was that there were no professional people in student affairs. They were all faculty who played the role of dean or whatever in a temporary fashion. And they sort of loved the students and the student life, many of them having been through it, but they were not professionally trained. They were not setting up any sort of behavioral norms for the students. But in the end, when the students graduated, they rapidly became perfectly good citizens of the world, so you could argue that, why bother interfering with any of this, and to some extent I finally got to that position. But then when the next president took over, he had all of this to worry about again.

ZIERLER: Was anyone talking about diversity back then? Was that part of the project to work on? Get more women, get more students of color at Caltech?

BALTIMORE: Yes, and in particular more women, because it was about maybe 75/25 at that point. It was the same thing as the rest of the academic world, very few women as tenured faculty, and an increasing number of women as you went down the hierarchy into graduate students, where in places like biology, they had 50% women, but at the faculty level, they had almost none. Alice was also an influence on this. And we really changed that, and we got a lot more women at all levels, and that trend has continued and is now I think a non-issue. We had, of course, a fair and increasing number of Asian students. We had a policy of acceptance really solely on the basis of capability or measured capability, with some of those measures being maybe not so perfect, and a commitment that no student would have to pay any more than their family could afford as determined by the methods that were then available and still are available. But there were no legacy students. There was no way for an alumnus to put any pressure on getting acceptance of a student, whether it be a friend or a family member. Although we were very proud of those families that had managed to get accepted students over a couple of generations. It was sort of the ideal world, and unique. MIT was close, although MIT had some legacies, but nothing like the Ivy League. Women were an issue. Getting diversity of color; nobody knew how to do that, and so I more or less said to myself, "If I can deal with the issue of women, I will have done my job, and I'll leave the other issues of diversity to later people." That is how it has worked out, and of course the commitment to blacks in particular has only really happened in the last year.

ZIERLER: What else from that list of things Kip wanted you to know about sticks out in your memory?

BALTIMORE: Also, the finances, that really we were very dependent on philanthropy, more than most schools.

ZIERLER: Had Gordon Moore's mega-gift come through?

BALTIMORE: No, I had to get that.

ZIERLER: Was that in the works? Did you know he was thinking about that before you became president?

BALTIMORE: Yes, and one of the attractions was that there would be this large gift from Gordon. But then, the Intel stock—he didn't have money; he had Intel stock—the Intel stock took a hit, Gordon suddenly was worth a lot less than he had been, and he was not talking about how he was going to do this. The mechanics of it, the nature of the gift, none of that was ever talked about. Wally talked to Gordon a lot and was very close to him, and I would talk to Wally. Wally was the head of the campaign. We got into a new campaign. First of all, we finished the biological sciences. Then we got going into a new campaign.

ZIERLER: That campaign, was that dependent on federal funding also, or this was strictly private benefactor stuff?

BALTIMORE: The campaign was private. Something like 50% of the Caltech budget comes from the federal government through grants, and those grants are gotten individually by the faculty, by groups of faculty, and in the case of LIGO by a large group of people. But in the end, Gordon gave us the biggest gift ever given to a university.

ZIERLER: Which would have been bigger, had not the Intel stock—?

BALTIMORE: Yes.

ZIERLER: Wow.

BALTIMORE: Oh, a lot bigger.

ZIERLER: Like a billion dollars or something like that?

BALTIMORE: Yeah, what he gave us was more like $2 billion worth of stock, but it was only worth at that point $650 million. Yeah, he had much bigger hopes, and yet what he gave us, as I said, was the biggest ever. But that was about two years into my presidency, I guess, or maybe even three or four years in, so it took a long time. I thought something was going to happen on a much faster time scale.

ZIERLER: Those were unrestricted funds, what Gordon had given?

BALTIMORE: Oh, you want the story of Gordon's gift? We'll get to it. It's so—

ZIERLER: We haven't even gotten to the ceremony.

BALTIMORE: I know. It's so remarkable, but we'll talk about it later.

ZIERLER: We're still on the list from Kip. What other issues were on your radar at that point?

BALTIMORE: There's the financial issue, which meant that fundraising has to become more important. I wasn't particularly excited about that, because I was never a great fundraiser and never a great schmoozer. But they made that clear.

ZIERLER: The relationship that you had with Jack Whitehead was not perceived as a fundraising coup?

BALTIMORE: I think it was.

ZIERLER: Even though you thought of it more as he fell into your lap.

BALTIMORE: That's right. But at least I had not scared him off. [laughs]

ZIERLER: And you built something that you could leave, too.

BALTIMORE: And also, it was well-known that Jack was very happy about it, and I was very conscious of that and made sure that my relations with him were as close and effective as possible. I tried to do that with Gordon; Gordon is a much more distant person and had his own problems. The finances, as I went into them later, but even in the beginning, they made it clear that something like this was true, was that we didn't have a source of income that could cover our expenses.

ZIERLER: What was the endowment at that point?

BALTIMORE: The endowment was close to $2 billion, which for the size of the institution, was impressive. But we were spending the 5% or actually even a little more than that from the endowment.

ZIERLER: The endowment was not self-sustaining at that point?

BALTIMORE: Certainly not. We needed more than that to fulfill our budgetary desires. It's actually a miracle that Caltech exists.

ZIERLER: [laughs]

BALTIMORE: It doesn't add up, but somehow we manage to make it balance every year.

ZIERLER: Was there a VP for Development at that point? Did they have a full-time—

BALTIMORE: Yeah, we did, Jerry Nunnally. He's an interesting story. He was very nice to us and took it on himself—maybe somebody could say he should, but it seemed like he took it on himself—to help Alice and me get settled, to deal with getting the house renovated, and just mechanics.

ZIERLER: The president's house needed some work?

BALTIMORE: Yeah, the president's house needed some work. It's an old house. It needs continual work. Although it's a nice place to live. Jerry was head of—well, it's a later story, but the story is that Jerry sort of helps me get into running a campaign, a major campaign.

ZIERLER: After biology?

BALTIMORE: Yeah, this was a new campaign.

ZIERLER: What building came of the campaign for biology?

BALTIMORE: That's also a good story. It's the Broad Center for the Biological Sciences. We had to design that building and get architects. Pei Cobb Freed were the architects, but Jim Freed was the key architect, a very interesting man, in the later stages of Parkinson's disease when he was doing this, but he did a beautiful job. Anyway, so we did that, and the Biological Sciences Initiative included a fair amount of money for professorships as well as other monies. Actually, Ben Rosen gave money for a building that never got built for a variety of reasons.

ZIERLER: Did the new biology building sort of suggest that Kerckhoff would be continually in a state of benign neglect?

BALTIMORE: No. I think the general feeling was that Kerckhoff was too hard to renovate.

ZIERLER: Just keep patching it up, or tear it down.

BALTIMORE: It's a historic building; you can't tear it down, but it's a strange—you've been there, I'm sure?

ZIERLER: Yeah.

BALTIMORE: It's like going into a monastery.

ZIERLER: [laughs]

BALTIMORE: Very odd. But those big walls make it very hard to put in pipes or take out pipes or change anything about the overall mechanics of the building, or the electricity or anything. Very difficult building to work with, but beautiful in its historic way.

ZIERLER: There has been some amazing research done there over the years.

BALTIMORE: And there's great research. That's where Pauling's labs were. It's interesting that that's half biology and half chemistry, so from the very start—

ZIERLER: It underscores the connections.

BALTIMORE: They're connected, yeah.

ZIERLER: What was the induction ceremony like?

BALTIMORE: I was inducted—what's the word for it? Not crowned [laughs], but whatever—the following March.

ZIERLER: You're in office from fall, from the beginning of the new semester of 1996?

BALTIMORE: Right, in 1996, but—and most places do this—they put it off for six months after you arrive.

ZIERLER: Oh! I know what we need to talk about; we haven't discussed this yet: what conversations did you have either with the board or the faculty committee about your desire to be a member of the faculty and an active researcher?

BALTIMORE: To be a member of the faculty was more or less assumed.

ZIERLER: That's not always how it was?

BALTIMORE: Yeah, I think so.

ZIERLER: Hmm.

BALTIMORE: I know Tom Everhart was in the Engineering faculty.

ZIERLER: Harold Brown, is he in Physics?

BALTIMORE: What department would Harold have been in?

ZIERLER: He was a physicist.

BALTIMORE: He was a physicist, yeah. He must have been in Physics. But he never had a lab. Maybe he was never a laboratory scientist.

ZIERLER: DuBridge? I don't know. I have no idea.

BALTIMORE: I don't know whether DuBridge had a lab. But Millikan did research for his whole time as president. Hale, of course, was an active scientist, although he wasn't on the faculty.

Maintaining an Active Science Agenda at Caltech

ZIERLER: Did you communicate clearly that you intended to have an active lab, and you would be an active part of the lab?

BALTIMORE: Right.

ZIERLER: How was that received? They were fine with that?

BALTIMORE: They were fine with that. That was my choice. I said to them, and I followed through, that being president would be my priority job and that the research would be done in time that I could muster for research.

ZIERLER: Did you articulate that having that outlet would make you a better president, for your own enjoyment, mental health, however you—?

BALTIMORE: I did. In fact, at one point—I'm not sure whether it was when I was first hired or a little later—I began to say that this was my hobby. As soon as you say that, it triggers off a whole lot of thought on the part of whoever you're talking to about how CEOs need hobbies and don't have them generally. It suddenly becomes a positive instead of a distraction.

ZIERLER: But your hobby, you're doing really good work at this point, too.

BALTIMORE: Right. I mean, I think so.

ZIERLER: Look at the postdocs who were in your lab at MIT at this point; this was solid work that was happening.

BALTIMORE: Right.

ZIERLER: Did you take anyone with you from MIT?

BALTIMORE: Yes, I did.

ZIERLER: Who came with you?

BALTIMORE: A number of people. One was Carlos Lois, who is now on the faculty here. Sort of [laughs]. That's a story. I had some people working on HIV who came with me, and I set up an HIV lab and facility where I could work safely with the virus.

ZIERLER: No one was doing HIV here, I assume?

BALTIMORE: No. I'd have to go back and see, but I had maybe 10 people in my lab, something like that, maybe 15, and probably a third of those came with me.

ZIERLER: Where did you set up shop here?

BALTIMORE: I first set up shop in Church, in a couple of rooms that had just been vacated by somebody else, somebody who left, I think. That provided a little space for me. But I actually kept a lab at MIT for a year in overlap, and allowed the two thirds of the people who didn't want to come to have a year buffer to finish up what they were doing, to find another place to work, however they wanted to do it. That worked out fine for them. Some of them stayed for a while and then moved out, because I didn't have a lot of space, but I meanwhile renovated two thirds of the upper floor of Braun Laboratories, old laboratories that had been designed actually by Lee Hood in the days of high biological containment, so there were a bunch of little rooms—it was a terrible layout—that he was sort of forced into. I've talked to him about it. He had left, and so there was a fair amount of space there. What I did was to take half of that space, and I had a little office in that space, and we were just hiring an immunologist, actually the first immunologist that had been hired at Caltech in years and years. I designed half of the lab for him and half for myself. We shared that space for some years. He didn't get tenure in the end, and he left. Then when I stepped down as president, I took over all of that space. That was a nice lab for many years. And I kept that office. [laughs] I never wanted a huge office.

ZIERLER: Were all of the things that Kip wanted you to know, did that accord with what you found out? No surprises?

BALTIMORE: No, not really. I guess the biggest surprise may have been the importance of JPL. I spent more time worrying about JPL than most presidents had up to that point, and they were very appreciative of that. Even though what do I know about astrophysics or planetary sciences? Not much. But I learned a lot.

ZIERLER: Why did you feel compelled to pay extra attention to JPL?

BALTIMORE: As you pointed out, it's larger than Caltech. I thought it was an important thing to pay attention to. Then I had to choose a new director for JPL.

ZIERLER: Did Ed resign, or what happened?

BALTIMORE: Yeah, Ed resigned. I sort of helped Ed resign. There had been a number of failures around that time.

ZIERLER: Which JPL is not used to.

BALTIMORE: No, and Ed was having to deal with the NASA director, Dan Goldin, and Dan was issuing dicta about how everybody had to behave, and the "faster, better, cheaper." It was pretty clear that "faster, better, cheaper" had led to the failures. It wasn't clear to me that Ed could get us out of it, so I just decided we needed a new director. I thought that the only way this was going to work was if we got a new director in from outside who could think differently, who could stand up to Goldin. Because Ed didn't stand up to Goldin.

ZIERLER: He's such a sweet guy.

BALTIMORE: Yeah, he is. [laughs]

ZIERLER: Soft spoken. That's not him.

BALTIMORE: Right, and he was good at calculating what he needed to do, but he couldn't push back. With failure and whatever, I began to realize I had to understand it better, which took more time.

ZIERLER: Did you lean on any faculty members on campus to help you wrap your head around JPL?

BALTIMORE: No, because there weren't any. There were people in GPS in particular who did joint work with JPL on Mars rocks, but the core of JPL is engineering, and the kind of engineering that allows you to put satellites around Mars was not anything that the Caltech faculty did or knew a whole lot about. I never found a lot of advice that I could get about JPL. I had to develop at least enough understanding about it myself. We put together a committee to search for a new director, and that committee had some faculty on it and some—maybe it had a faculty member on it—had a number of board members on it. It was led by somebody from the board.

ZIERLER: Bob Inman, probably?

BALTIMORE: No, it wasn't Bob, although he helped, a lot. The point was that when we got to the end of the search process, they had two strong candidates from industry, and a third candidate from JPL, Charles Elachi. We were looking for a change agent, so my instincts said that—and this board committee certainly agreed with this—that it shouldn't be Charles, because his whole career had been at JPL. How could he be a change agent? That left us with the other two. I met the other two and I just did not feel that they were up to this job. One of them was overly arrogant—he was their favorite—and the other was too mild. I can't remember exactly what it was about him. I said, "I want to have another look at Charles."

I had a discussion with Charles, and I learned two things, or I felt I had gotten two things out of that. One was that Charles understood completely what was needed, the extent of the change in culture and organization for that matter that was needed. He was chief scientist, but had been chomping at the bit with Ed, but never got at loggerheads with him. It's hard to get at loggerheads with Ed. The second thing was that he was prepared to do what it took. That was a surprise to me. I was faced with a recommendation that we take this guy from industry, and my own feeling that A, he was not the kind of guy I wanted to see in that job—he was too arrogant, and had too much of his own idea of what he wanted to do with it—and Charles, who answered all the questions right, and who seemed to be the perfect person for the job. I overrode the committee and recommended Charles.

ZIERLER: As is your right as president. You can do that.

BALTIMORE: That's right.

ZIERLER: Did you appreciate Charles' technical mastery as well?

BALTIMORE: Yes. He was a member of the National Academy of Engineering. He had been validated as a technical person completely.

ZIERLER: Obviously you appreciated his "golden boy" status within JPL, his rapid ascent, all of that.

BALTIMORE: Right. I talked to people there, and there were people who said, "Charles can do it. You've just got to let him." Even though they understood that "letting him" was sort of counter to everything that the situation seemed to be calling for.

ZIERLER: Was that also—I don't know if the right word is a diversity win—but is there something poetic about this Lebanese-born guy?

BALTIMORE: That's a lot poetic about it!

ZIERLER: [laughs]

BALTIMORE: For just the reason—

ZIERLER: He's a very different character than the string of previous directors, where the new direction that you were emphasizing was, he was it.

BALTIMORE: Yes, yes. He was it. The heads of JPL had all been various different sorts of people. What was that guy who loved to dance? The little guy. For 20 years, I think he was head of it.

ZIERLER: I know who you're talking about. [laughs]

BALTIMORE: He would still come in. But he and his wife just loved to dance. They'd come to every event that had a dance. He was a Caltech—they were often Caltech graduates. One of them had been a military guy. They were all sorts, so there wasn't any pattern for how to choose a director or who would make a good director. Oh, I know—I think Kent was the guy who actually I was facing down.

ZIERLER: Kresa?

BALTIMORE: Yeah. Because he was a guy who should know this.

ZIERLER: Mr. Industry.

BALTIMORE: Right, and he was absolutely certain it had to be from industry. Of all the decisions I made at Caltech, none is more important than that one.

ZIERLER: It worked out. [laughs]

BALTIMORE: Yeah.

ZIERLER: Where was LIGO when you became president? Was that something you needed to spend a lot of time on?

BALTIMORE: Not a lot of time, but some. LIGO was through its worst times, as you were talking about with Robbie, and with Drever.

ZIERLER: Drever, he's not around anymore?

BALTIMORE: Drever is around, yeah.

ZIERLER: It's an awkward situation?

BALTIMORE: Oh, I mean, it was a very awkward situation, but by that time, who was running it? In the end, it's Barry Barish. Barry may have been head of it by that time, and he had cleared out a lot of the difficulty.

ZIERLER: Coming from MIT, were you able to leverage the MIT-Caltech partnership? Did you know Rai Weiss when you were at MIT at all?

BALTIMORE: No, I didn't, really. Vaguely. Rai loves to quote me because of my love for the F&T Diner, which he loved, too. But we didn't really know each other. [laughs]

ZIERLER: That was not really a factor?

BALTIMORE: No. I was surprised to discover how important the role that MIT was playing. I had never seen a project like that in any way. That was just a total education.

ZIERLER: Did Kip try to convey to you just how big a deal LIGO was and why it was worth this effort?

BALTIMORE: Yes.

ZIERLER: Did you appreciate that there was a Nobel Prize at the end of this if they did what they said they were going to do?

BALTIMORE: Yeah, I think so. It's hard to ignore. If they could demonstrate gravity waves and link them to events in the universe, that was going to be big news. You never know what happens with the Nobel Prize.

ZIERLER: What about the big shift among undergraduates where the dominant major was physics and then it became computer science? Was that happening? Had that already happened by the time you became president?

BALTIMORE: No, it was happening, I think. There was a period in there where biology actually was a very big major. It has fallen a lot in recent years.

ZIERLER: Part of that is because, as you said earlier, biology is in everything now. You can do biology in almost any division.

BALTIMORE: That's right.

ZIERLER: Computers, math, it's everywhere.

BALTIMORE: Yeah, everywhere except astronomy.

ZIERLER: Right. There, you have astrobiology. [laughs]

BALTIMORE: They do have astrobiology.

ZIERLER: What else? What about in EAS? Did you need to pay attention to what was happening in EAS at all?

BALTIMORE: Not a lot, except for biological engineering, which was beginning to grow up.

ZIERLER: Was it BBE at that point?

BALTIMORE: No, it wasn't. That's actually very recent.

ZIERLER: After you stepped down?

BALTIMORE: Well after I stepped down, yeah. But there was a growing interest in engineering and biology. I had seen that at MIT before I came, because at MIT, where there was a closer connection to medicine, the Harvard hospitals, there was a fair amount of medical engineering going on that led to a biological engineering division at MIT, actually. It was mostly Mory Gharib at Caltech who was an intermediary in medical technology. Other than that, EAS took care of itself. We did a fair amount of renovation of space in EAS, but again, they found donors, and it wasn't a problem that I had to worry about much.

The Historic Moore Gift

ZIERLER: Last topic we'll cover for today, and if it's too big, it will bleed into next time: the odyssey of Gordon Moore's gift.

BALTIMORE: It's just a story about it. Gordon, as I said, had been talking to me about this gift, or actually Wally had been talking to me about Gordon's gift, and Wally was getting frustrated that it was talk and no money. Wally had organized a proposal to Gordon for a billion dollars, I think.

ZIERLER: Cash or stocks?

BALTIMORE: He didn't care. That didn't matter, because whatever it was, it would turn into cash. We were trying to develop a proposal that would excite Gordon, and we just couldn't get it. Gordon is not a very excitable guy. We just couldn't get him excited.

ZIERLER: A proposal about a specific area of research, or things that would enhance the Institute across the board?

BALTIMORE: Things that would enhance the Institute across the board, because Gordon didn't have a commitment to any particular part of the Institute.

ZIERLER: I was thinking like the Carver Mead EE connection.

BALTIMORE: You could see that as something that Gordon might care about, but in the end, he cared about the institution.

ZIERLER: Right, he loves Caltech.

BALTIMORE: Right. Wally had an office, and he would get mail there, but he didn't go there very often. He was retired. One day, I get a call from Wally. He said, "Are you sitting down?" I said, "Yes." He said, "I've got to tell you this story. I don't often go to my office, but my son was there and he picked up the mail and brought it home to me, and in the mail was a letter and let me read it to you." It was a little short letter from Gordon Moore saying, "I want to give the Institute—" He didn't say $650 million; I later had to calculate that. He said, "—so many shares of Intel over some period of time." There was a little bit of mechanics in it. But that was it. He didn't want any acknowledgement of it. He just—this is what he wanted to do. I called Gordon and thanked him profusely.

ZIERLER: Is this the result of a schmooze campaign, or what's the tipping point when he makes this decision?

BALTIMORE: The proposal that we had put together, he had more or less turned down, sort of ignored.

ZIERLER: Did he say why?

BALTIMORE: No. We had no idea. There was no recent proposal that we had made. It's just that Gordon, in getting his finances together, it was part of a much larger actually effort to restructure his wealth, particularly after the Intel stock had fallen and whatever, he decided this is what he wanted to do. There were two parts to the gift. One part was Intel stock, and that was denominated in shares, and it wasn't being given at all the same time. It would be given over five years; I think that's right.

ZIERLER: So Caltech is tied to the fortunes of Intel.

BALTIMORE: Yeah. The other half of it was a draw of $300 million—I think that's the right number—on the foundation that he was establishing. He was establishing a foundation with a couple billion dollars' worth of his stock, the Moore Foundation, and we would have an opportunity to get gifts from the Moore Foundation that aggregated $300 million, again over the next five years. It was up to the Moore Foundation to decide whether they wanted to give us the gift, but he was directing them to be responsible. He was just being a little careful, in that. At that point, the Moore Foundation didn't have a professional head. It was his son's, who never cared a whole lot about it. There was somebody in there, but I can't remember who. That was real money, and we could write that one down, but you couldn't write down the value of the stock gift. I said, "Gordon, we need an estimate of how much it's worth." He said, "Well, I don't know."

ZIERLER: [laughs]

BALTIMORE: I said, "Gordon, I can't announce this gift unless there's a number on it." He said, "Do you have to announce it?" I said, "Yes, Gordon, we have to announce it."

ZIERLER: As in, "This is the largest gift ever given to an institute of higher learning." [laughs] Kind of a big deal.

BALTIMORE: "Yes, we have to announce it." [laughs] Also, this actually was going to be the keystone gift of the new campaign, so of course you have to announce it. I said, "Gordon, there's nothing here to memorialize this." He said, "I don't need anything." Actually, I spent a fair amount of time thinking about what we could do on the campus to name something in Gordon's honor, and I invented the Moore Walk, which is what it became. Later, I called Gordon and I said, "I want to name this the Moore Walk." He said he thought that was nice.

ZIERLER: [laughs]

BALTIMORE: I mean, there is no more humble man. There is no man who is more committed to doing what he felt was the right thing than Gordon Moore.

ZIERLER: Irrespective of glory and honor unto him.

BALTIMORE: Absolutely, that's right.

ZIERLER: How did that work out for Caltech, dealing with the stocks?

BALTIMORE: What I did was to take an average value and figure out how far could it go down, and I figured $350 million was what it was worth, or that I could justify it being worth that.

ZIERLER: This is real money in hand, you mean?

BALTIMORE: No, it wasn't. No. It was money that was going to be given to us as stock over five years, so it was not money in hand. When people tell you the worth of a gift, they don't look under the hood, so I needed a number that could be the front number, and I could justify it, I could explain—and I did explain to some people—exactly where it came from, but to a large extent, in The New York Times, it was a $650 million gift.

ZIERLER: Where does the 650 come in? How is that calculated?

BALTIMORE: The 300 from the Foundation, and the 350, which was a lowball estimate of what the stock was worth. In fact, over time, the stock did go down some, and I think the 350 was about right.

ZIERLER: In the end, the 650 is a real number, or it's actually lower than that, what Caltech actually got?

BALTIMORE: It was about that.

ZIERLER: Did it go into the endowment?

BALTIMORE: Different things happened to it.

ZIERLER: Again, the question is, is this unrestricted as far as Gordon is concerned? You can do whatever you want with it?

BALTIMORE: Right.

ZIERLER: President's discretionary funds, like that?

BALTIMORE: Yeah, I guess.

ZIERLER: Who else has a say over how to deploy the funds besides you?

BALTIMORE: No one.

ZIERLER: So it's the president's discretionary funds.

BALTIMORE: Right. What I did was, I went to the IACC, which you know that's the head of all of the—

ZIERLER: The Grand Council.

BALTIMORE: The Grand Council. Or no, I had done this before, actually. There was when I was trying to get together a proposal to Gordon. "In order to be your chief fundraiser, I need to know what each division really wants. I want you to think through your grandest desires and tell me what it is that you really would like to have." I said this to all the divisions.

ZIERLER: You have the funds now where you can challenge everybody?

BALTIMORE: No, this was before that. This was to help me position a request, for the campaign. The campaign ultimately was for $1.6 billion, and I think it ended up closer to $2 billion. What are we asking people for?

ZIERLER: You want to get people inspired.

BALTIMORE: Yeah, that's exactly it. "Inspired" is the right word. I had another reason for doing that, which was that Tom had left me Caltech after years of telling people there was no money to do anything. And there wasn't, and I told you, when I went over the budget, we didn't have money to run the place! But you can't look at it that way, and you've got to give people a sense of excitement, of a future.

ZIERLER: You can't look impoverished.

BALTIMORE: Right, so at least I wanted to put together what it is people would really like to do. Once the gift was given, I could turn around to the divisions and say, "We can do what you wanted." That was in fact the core use of those funds were for the individual divisions to do something big.

ZIERLER: What stands out in your memory as the real dreams that they were articulating?

BALTIMORE: We wanted a beamline on the Stanford Accelerator for determining biological structure, and that was a joint desire, actually, of Chemistry and Biology, but it was done through Biology, I think.

ZIERLER: This was an operation that Caltech would set up at SLAC?

BALTIMORE: Right, and we did that, and we were able to do many structures that way, and until cryo-EM came about—another thing was we wanted to build a cryo-EM facility, and we built into the Broad building, in the basement, you can open up actually in front of the Broad building—all of those big pieces of concrete come out, and you can then put machines in, and we put in a cryo-EM facility as well as a number of MRI machines for magnetic resonance of the brain. A lot of the money for those things came from the Moore gift. GPS put in a sensing network in Indonesia, which actually became operational just before the earthquake in Indonesia.

ZIERLER: Oh, wow.

BALTIMORE: That ended up being very important. A lot of it was machinery, but on the scale that Caltech never could have afforded. LIGO was already taken care of, and LIGO was largely funded by NSF.

ZIERLER: What about astronomy, like telescope projects? Did this help TMT, at least at the design phase?

BALTIMORE: Yeah, and that was my direct direction, that they should do that. Yeah, the whole design phase was paid for by money from the Moore Foundation. There were other things.

ZIERLER: The idea is that you were well positioned because you had asked the divisions to articulate their dreams. The gift came through, and you already had a plan. You already had a giving plan.

BALTIMORE: That's right. They went back over it and they filled it out and they changed things, and to a large extent, my provost, Steve Koonin, was responsible for doling out that money to the individual divisions and running these various projects, and he was terrific at that.

ZIERLER: Until he wasn't.

BALTIMORE: Until he wasn't.

ZIERLER: We'll pick up for next time. [laughs]

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Friday, March 11th, 2022. I'm delighted to be back with Professor David Baltimore. As always, it's great to be with you.

BALTIMORE: Hello!

ZIERLER: Today I want to go back to a point you made last time where in the negotiations up to you accepting the offer to become president of Caltech, you made it very clear to the committee and to the board you were going to take your science with you, that that was going to be part of your world here, even though obviously being president was the primary agenda.

BALTIMORE: Right. I had a moment when I thought I might not, and then I looked myself in the eye and said, "You're not going to be happy."

ZIERLER: Before or after you accepted?

BALTIMORE: It was while I was accepting. I tested out the idea, because it was easier to imagine not continuing in science, just because there were fewer things to do, but I really worried that I wouldn't be happy and that I wouldn't know what to do with myself when I was done, too.

ZIERLER: As a matter of planning, realistically, as a proportion of your time, how much did you expect to be devoted to science—5%, 10%?

BALTIMORE: Probably 10%.

ZIERLER: Given the circumstances, it really forces you to narrow what's most important to you, what you do with the 10%. At that time when you began as president of Caltech, what was the science most interesting and important at that point?

BALTIMORE: We had relatively recently discovered all these transcription factors that controlled aspects of immune development, or we thought controlled aspects. I had people working on a number of them, so I decided that in cutting down the purview of my program, to focus on one transcription factor, and that was NF kappa B.

ZIERLER: Why that one?

BALTIMORE: It seemed to have the broadest significance, and I had been able to guide people in the lab to some very unusual information about it, how it got activated, how it moved from the cytoplasm to the nucleus, a variety of things about it, so it seemed the richest, most interesting one and had so many different aspects that I didn't have to worry about competing with my own trainees.

ZIERLER: What about the development of HIV vaccines and the cocktail approach, retrovirus, the AZT? Were you involved in that at all?

BALTIMORE: No. When it was discovered that HIV was a retrovirus—which I didn't do; some other people did—it was a fairly rapid thought that inhibitors that had been designed as anti-cancer drugs might be valuable as anti-HIV drugs, because it was the same kind of process, reverse transcription, that HIV used and other retroviruses used. There was, on the shelf, I think at NIH, a drug that had failed as an anti-cancer drug, but that was a good reverse transcriptase inhibitor, called AZT. When they tested it, it worked very well, and so AZT was developed as an anti-HIV drug, and when it was realized that the virus could mutate against AZT and so it only worked for a short while, even though it worked terrifically for that short while, many pharmaceutical companies and many academic laboratories started searching for other analogs that could do what AZT did but maybe the virus couldn't get around so easily. In particular, there was the notion that had been developed years before for cancer that if you used multiple drugs at the same time, you would be able to keep the virus in check.

ZIERLER: Like a shock-and-awe campaign kind of thing?

BALTIMORE: It's not so much shock-and-awe. It's much more that the virus can't mutate around all of them at once, and so if you've got three drugs that are hitting the virus from somewhat different points of view, so that the virus, in order to become immune to those drugs, had to make three different mutations, the likelihood that they would all occur at the same time was very small, and so one would continue to work while another one, the virus might get around, but it will still get stopped in its tracks and so it can't go any further. What I'm saying is that all of that happened and was known and brought the pharmaceutical industry strengths into this search, so my laboratory wasn't going to get involved in that.

ZIERLER: Were you following or interacting with David Ho at this point?

BALTIMORE: I was on the advisory committee to his institute, and I knew David and kept up with what he was doing.

ZIERLER: What about Tony Fauci? Were you interacting with him on a policy level at that point?

BALTIMORE: I was. After I headed up this commission for the National Academy and NIH started a much more intense program of research, I was asked to head up an advisory committee to the NIH, and I did that for many years. It was basically Tony's division of NIH that did this, so I saw him with some frequency.

ZIERLER: A broader question from a policy perspective—as president of Caltech, what opportunities do you have from that perch to interact broadly with the federal government, with the private sector? What can you do and what latitude do you have as president of Caltech and a biologist?

BALTIMORE: When you're the president of a university, you have enormous latitude to decide how you want to spend your time and what you want to do. But I think most presidents find that they have enough to do locally that trying to develop a bully pulpit on a national scale is difficult, and very few university presidents do that successfully. Then there aren't that many people who want to hear from [laughs] university presidents, either.

ZIERLER: I'm thinking, for example, like the controversies around stem cells at that point. That's something that's relevant for your own research, you're a national figure; would that be a topic where you would interact with the media, you would liaise with federal agencies?

BALTIMORE: Yeah, in particular in relation to stem cells, I was involved. In relation to HIV, I was involved.

ZIERLER: Did that hold promise? Were people thinking about stem cell therapies for HIV?

BALTIMORE: No, those were two separate thoughts. Then I later became involved in the CRISPR gene editing, but by that time I was no longer president of Caltech. Those kinds of issues, I would take on, because they were the kinds of issues that I thought I could make a contribution to.

ZIERLER: With the origins of CRISPR, was your lab when you were president doing gene editing stuff that laid the foundation for CRISPR?

BALTIMORE: No, not at all. The CRISPR work came originally out of people interested in how microbes defend themselves against viruses, bacteria defend themselves against viruses, and was developed as a biochemical system from bacteria. The whole patent fight was because the initial work that Jennifer Doudna and Charpentier did was in vitro work on enzymes from bacteria. Then the question was, could you make these enzymes function in mammalian cells, in particular in human cells, and actually edit human genes with them. I wasn't involved in that at all, but Feng Zhang at the Broad Institute was involved, and he figured out how to adapt it to mammalian cell culture and published that, and they put a patent application in for that adaptation. Just recently, the patent office decided, or I guess a judge decided, that the patent that Feng had was the controlling patent for the adaptation to mammalian cells, and therefore the use in developing therapeutic regimens, and that invalidated the patent application from Berkeley. Although at Berkeley they had figured out the initial biochemistry, that wasn't sufficient in the eyes of the law to make the adaptation to mammalian cells not a separate and still patentable observation.

ZIERLER: A comment you made earlier, where when you were considering this possibility, you wanted to absorb yourself in the culture of Caltech, but obviously you were doing that from afar. What were you not prepared for once you got comfortable in the role? Some of the idiosyncrasies, the way things were done at Caltech that you were learning on the fly?

BALTIMORE: It was the whole nature of the place, because I had grown up at MIT. MIT was my view of academia. MIT, like all big universities, was very siloed. It had biology, it had chemistry, it had engineering. It didn't have of course the great strengths in the humanities that Harvard would have, but it had the same form as a Harvard would have, and deans. It was all hierarchical in a sort of tree, coming down from the president to everybody else. When I came to Caltech I discovered first of all there was virtually no hierarchy like that. The whole place was run by a president, a provost, six division chairs, and that was it. There was nothing like that, that I had ever seen. It took me a while to recognize that this was a way that a university could be basically controlled by the faculty. Now, there was a provost, and the provost came from the faculty, generally. Didn't have to, but generally did. And the president was brought in from the outside, always, partly because everything else was insular, was coming out of people many of whom had been at Caltech, some from the time they went to college. Lifers. Caltech is full of lifers, because it's such a wonderful place to be.

ZIERLER: Why go anywhere else?

BALTIMORE: Yeah, so many faculty get tenure and then go into their tenure, and then they say to themselves, "Am I going to spend the whole rest of my life? Aren't I going to do anything new? I may do new science, but aren't I going to be in a new place?" They get attracted to go somewhere else and they leave Caltech. When people leave Caltech—and this is true in lots of schools—we give them a two-year leave, and they can come back. Well, a fantastic number of these people come back! Because they discover the grass isn't greener anywhere else.

ZIERLER: It's like the Amish rumspringa model. [laughs] The Amish have this tradition where you can go and look at the modern world, and you decide for yourself whether you want to come back into the fold, and if I understand correctly, it's similar numbers.

BALTIMORE: Is that right? I didn't know that! Any number of people who left—there was a couple who went to MIT, one in Chemistry and one in Biology, and within two years they were back.

ZIERLER: Had the biotech revolution arrived at Caltech by the time you became president?

BALTIMORE: No. Yes, people were aware of it, some people were involved in it, but in general most faculty were not involved. There was a general feeling that it was not for Caltech, that Caltech was a place for small science, but even within that, that it was sort of unseemly or a deviation from the style of Caltech for people to startup companies or to become involved in companies, or to leave to join companies.

ZIERLER: Was the campaign supposed to be part of moving Caltech into the biotech revolution?

BALTIMORE: A little bit, but much more to go into academic biology more deeply. It wasn't particularly designed around starting companies, for instance, and not many companies appeared during the time that I was president, although in later times, more have occurred. By now it has really taken hold.

ZIERLER: Of course, the other revolution happening at this time is the dot-com revolution. What opportunities did you see for information science, for big data, for computer science, as president?

BALTIMORE: Computer science was an interesting problem. I was educated to understand that Caltech was probably never going to have a number one computer science department, and the reason is because computer scientists really gravitate towards those universities that have big operations—Stanford, Berkeley, MIT, and notably Carnegie in Pittsburgh.

ZIERLER: Computer science is clustered.

BALTIMORE: Yeah, and we're so small that there can't be any group that's really large, so any group that thrives on size is going to have a difficult time. We're going to have a difficult time being a first-rate contributor in that area. That was true in computer science, and it was also true in mathematics for very similar reasons.

ZIERLER: This is going to be a problem for recruiting both faculty and grad students and postdocs?

BALTIMORE: Yeah, they're linked. You get the best students by having the best faculty.

ZIERLER: What leeway did you have there? What opportunities could you pursue?

BALTIMORE: We could involve the computer scientists broadly in the university, in other fields, like in biology, and that would give a special flavor to computer science. Mathematicians really live in their own world, so you can't get them involved in other things. In fact, you pretty well have to start an applied mathematics group, and we have that at Caltech, that does very well. We've had some great mathematicians, but—

ZIERLER: What about quantum information? Were you following what John Preskill was doing around that time?

BALTIMORE: It wasn't only John Preskill. It was Jeff Kimble in particular that I was aware of. Yeah, we supported that heavily and were very much aware of the excitement around quantum machines.

ZIERLER: Obviously you can't be an expert in all of the fields that Caltech professors are in, so do you have a kitchen cabinet? Who do you rely on to give you technical advice on what's for real, what's hype, what deserves support, what's so much not deserving of that?

BALTIMORE: One of the things that I learned over time at Caltech, because my initial belief was just what you said—I needed to get help in making decisions about areas that I didn't know—what I discovered was that almost everybody at Caltech was worthy of real respect in their fields. It's hard to believe that a place can be generally as high-quality as Caltech is. I stopped worrying about that along the way. I had Steve Koonin, and Steve of course had grown up at Caltech. He knew all of these people from the time they had been hired and had followed their doings. Then I met with the division heads on a weekly basis, and so I had an opportunity to ask them about—now, they were of course very loyal to their divisions, but they were also pretty honest about who was doing really pathfinding work and how important it was. I can remember without talking about individuals a case in which there was one of our faculty who was working in a very important area, had to do with batteries, and I asked the division chair, "Is this individual really making fundamental discoveries that are valuable in the development of batteries that are needed—" for holding solar electricity, for instance, solar generated electricity. I could tell from the response that it wasn't really something that was going to make a big difference. What that meant was you couldn't depend on that person's output to help solve the world's problems.

ZIERLER: I assume there was none of the issue like at Rockefeller where you had a mandate to create a culture of promoting young scholars. That was fully successful at Caltech.

BALTIMORE: Absolutely. We had a whole process of bringing in and developing the talents of young people, getting them to the point of tenure, and developing their careers.

ZIERLER: If you look at that compared with, say, and perhaps it's a caricature, but a place like Harvard or Stanford, where assistant professors, they are like glorified postdocs and the expectation is that they will not get tenure, from the institutional perspective, why is Caltech's approach better?

BALTIMORE: First of all, because we invest literally money in the careers of young people, because our assumption is that they are going to stay, and it's about 75% true that the people we hire stay on to tenure. It's more than 75% now. We want to help them be successful, and that's good for science, it's good for the institution, it's good for the students because it means that particularly graduate students can go into the laboratories of these young people and they're going to be exciting and they're going to be cutting edge. It gives the right flavor to the institution. It gives the right progression within the divisions.

The problem—and this is throughout academia, actually; it's not just at Caltech—is that they come in in their thirties, let's say, some a little younger, they're tenured by their forties, and then they stay. When they get to the expected retirement age of 65, they don't retire, because the only thing they know in the world—this happened to me, and I can tell you it happens to all of us—the only thing we know how to do is science, and we love it, and why should we—? The law of the country is that you can't fire these people, or let them go, even if they're not being the most productive, most innovative. It's generally true that over the age of 65, people slow down, and the field—I can tell you this is true of biology; I presume it's true everywhere—the field moves on, in its considerations, and people who are particularly significantly older don't have the flexibility, don't really want to start over again in some new area, so they keep doing what they have been doing.

ZIERLER: There's also ageism with federal funding, that your grants go down over time.

BALTIMORE: Yes, although people have become so good at writing grants and explaining themselves that they can make up for that some. I don't think that's a big effect. In fact, I think a lot of older people do very well in funding their programs. We, in the individual divisions, put a certain amount of capital into encouraging people to switch fields, and in their forties and fifties, very often they will do that, sometimes switching enormous intellectual distances, sometimes shorter. We encourage that and help them do it, by funding these new areas where they don't have an established track record and therefore do find it difficult to get financial support. We renew internally. You can do that with people, as I said, in their forties and fifties. It gets harder later.

ZIERLER: The National Medal of Science in 1999, how do you get notified of this? Who gives you the call?

BALTIMORE: I have no remembrance of that at all.

ZIERLER: Probably a phone call from the White House, something like that?

BALTIMORE: It's handled I think by the National Science Foundation, so I may have heard from that, but I really do not remember how I heard about it.

ZIERLER: What was the experience like, being at the White House?

BALTIMORE: It was wonderful, and I was given the award by President Clinton. He was a great hero of mine, and so it was a pleasure.

ZIERLER: In the way that he elevated scientific issues?

BALTIMORE: That's right, and also in his political savvy. He was able to be a very effective politician.

ZIERLER: Given what you had been through, you admired that?

BALTIMORE: Yes, and we had been through Reagan, and I had been through problems. That's right.

ZIERLER: Did you get to interact with him substantively during that visit?

BALTIMORE: Yeah, he was around, and actually I got to know him and saw him later; in Davos, once. I went to a Super Bowl party in his suite in Davos.

ZIERLER: [laughs] What were you being recognized for in 1999?

BALTIMORE: It was for my whole career.

ZIERLER: Sort of a Lifetime Achievement Award.

BALTIMORE: It's a lifetime—yeah.

ZIERLER: Is signal transduction in the mix at this point?

BALTIMORE: Absolutely. The work that we did in cancer, the work that the whole field did in cancer, opened up areas of signal transduction, because it turns out that a lot of the oncogenes, the genes that cause cells to be tumors, are in signal transduction pathways. Now, we didn't know that at first. For instance, when we found that that this virus that I was interested in, Abelson virus, had a tyrosine-specific protein kinase, that meant nothing in terms of the physiology of the cell, and we had to learn that cells use phosphorylation of tyrosine as a very important signal in the signal transduction pathways that lead to cell growth and other behaviors of cells. That's why when you mutate that pathway so that it's on constitutively, it can cause the cells to keep dividing and dividing and dividing. But we didn't know that when we set out to work on it. What we assumed, and correctly, was that if we put a lot of effort into understanding the nature of oncogenic proteins, that we would learn about how cancer happens, and that's exactly what happened.

ZIERLER: Was there a specific end goal for the Biology campaign, a number that you wanted to hit and then the campaign was over, or was it more open-ended?

BALTIMORE: No, there was a number, but the number is never the controlling factor. There was a list of things that we wanted to achieve. We wanted to get a new building for Biology, which we got, the Broad Center. We wanted to get support for graduate students, which we got some of, not enough. We wanted to get some named professorships, which we actually did very well in. Those are the things I remember that were targets. I think there were probably one or two others.

ZIERLER: When did you meet Eli Broad?

BALTIMORE: I met him as soon as I came, because he was a member of the Board of Trustees. He went to the board meetings, at least in the early days.

ZIERLER: Did you make him a fan of biology? Was he predisposed to support biological research?

BALTIMORE: He was already being cultivated for involvement in the building, actually.

ZIERLER: What's his money? Where did he build his wealth?

BALTIMORE: Through two ventures. One was housing. He started Kaufman and Broad, K & B home builders—this was after World War II—and they built a lot of the suburban projects.

ZIERLER: I wonder if the thinking was your relationship with Jack Whitehead was a useful analog in cultivating Eli Broad.

BALTIMORE: There was no question that the success that I had had with the Whitehead Institute was one of the positive aspects that people saw in asking me. To come to Caltech. There's no question at all about that. Clearly I knew how to speak with and involve myself with wealthy people. But the other side of the wealth of Eli was that he sold his involvement in Kaufman & Broad, and used that to buy a small insurance company, because he realized that as these people who were moving into his homes got older, they were going to need insurance, and so he structured this little insurance company to become an enormous supporter of the lives of the people who had come back from the War and were now developing their lives. SunAmerica became a real force in insurance. That later got sold.

ZIERLER: You mentioned that the campaign did not make Caltech do so much bigger science but deeper science. What stands out in your memory? What was able to do be done deeper as a result of the campaign?

BALTIMORE: It was all the things that I talked about that were supported by the Moore gift. Everybody kept going on with what they were doing, so there were major advances in quantum phenomenology, in these very strange effects at a distance that the quantum world has. Each division continued—we earned a number of Nobel Prizes, in chemistry, in physics. The economists went deeper into experimental economics, which was a sort of invention of Caltech and one of our great strengths. People in other areas of the social sciences started thinking in experimental terms. Stuff happened everywhere.

ZIERLER: You mentioned Nobel Prize. What was it like, for example, when David Politzer won in 2004? What was your day like that day?

BALTIMORE: [laughs] Whenever a Nobel Prize was announced, drop everything, and support those individuals, because they are now entering a new part of their lives.

ZIERLER: David is a very private person, too.

BALTIMORE: Right, that's true, and he had to decide whether he wanted to become more public. At first, he hid himself. I think he has become more comfortable with that role over the years. A very funny story is that when I was at Whitehead, I started a symposium that was held every fall, and it brought people from universities around the world to speak. It was held in the biggest auditorium at MIT, and we filled it, and people came from Harvard and elsewhere to listen in. Of course we tried to get and were able to get the very best people. A couple of times, the symposium overlapped when the Nobel Prize was announced—we hadn't done that purposely but it was just a convenient week in early October—and people who we invited to the symposium were announced as winning the Nobel Prize. This happened when Brown and Goldstein won the Nobel Prize.

It happened when Tom Cech won the Nobel Prize. Because I was a Nobel laureate and had been through the whole process, I knew a number of things. One was that they would have just infinite numbers of questions, just about details, how you do this and how you do that, what you wear. Secondly, that their university is going to want them back instantly so that they could hold press conferences and parties and whatever else and make the world know where these people came from. That meant getting Brown and Goldstein back to Texas from Cambridge and getting Tom Cech back to Colorado, I guess. I got my staff to get them reservations and get them out of there as fast as you could, and I was able to kind of help them deal with the changed circumstances. We were sort of known for having created Nobel laureates.

ZIERLER: The Nobel Prize is really an opportunity to have an Institute-wide celebration.

BALTIMORE: Absolutely, and that's just what we have. We would have them in the Athenaeum at Caltech. The press is used to coming to Caltech, A, because we get lots of Nobel Prizes, but B, because every time there is an earthquake, the press descends on Caltech.

ZIERLER: To go back to the biology campaign, nowadays it's remarkable—an undergraduate who has interests in biology can pursue that in math, in chemistry, in computers, in engineering. Did the biology campaign lay the foundation for that multidisciplinary approach that would not have been possible earlier?

BALTIMORE: Yes, it did, and the way we populated the Broad Center was to bring in people who were actually in chemistry and engineering, into the building. The notion of this building was very much to be a center where these kinds of interactions could happen, and it worked out that way.

ZIERLER: The successful effort to bring the Einstein Papers to Caltech in 2000, were you involved in that? Were you supportive of that?

BALTIMORE: I was supportive of it, absolutely. In fact, I thought it was just a wonderful opportunity.

ZIERLER: Did you need to get involved? Were there any difficulties that required your—?

BALTIMORE: No, there weren't, because Diana Kormos Buchwald had handled that herself. In fact, there weren't, if I understood correctly, many places that wanted the Einstein Papers. There weren't many places that had a historian ready to devote his or herself to bringing the Einstein Papers together. It was going to be a long slog, and it has been a long slog.

ZIERLER: Did you know they're only halfway through?

BALTIMORE: Yeah, I know, it's just unbelievable.

ZIERLER: It's amazing that he did anything else besides write letters. [laughs]

BALTIMORE: Yes. [laughs] Right.