Lee Otterson Professor of Bioengineering and Professor of Applied Physics at Stanford University, Head of Science at the Chan Zuckerberg Initiative
By David Zierler, Director of the Caltech Heritage Project
May 22, June 9, 2023
DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Monday, May 22nd, 2023. I am delighted to be here with Professor Stephen Quake. Steve, it is great to be with you. Thank you so much for joining me today.
STEPHEN QUAKE: Great to be here!
ZIERLER: To start, I know this is going to be a mouthful, but would you tell me please all of your titles and institutional affiliations?
QUAKE: [laughs] I am the Head of Science at the Chan Zuckerberg Initiative, and the Lee Otterson Professor of Bioengineering and Applied Physics at Stanford University. And, former Caltech Professor.
ZIERLER: Of course! That's what brings us together. Let's start with the endowed professorship. Who is or was Lee Otterson?
QUAKE: Lee Otterson was a son of farmers from Colusa, in California, in the northeastern part of the state. He came to Stanford as an undergrad during the Depression and got his degree here, and was very grateful, because if you maintained a minimum of—I forget if it was a B or a C average—Stanford would defer your tuition payments for some time. That deferred tuition is what let him get through. Then he became a successful entrepreneur and businessman, did things in the aerospace industry and other things, and made a gift to Stanford. Lovely, lovely gentleman. I got to meet him towards the end of his life.
ZIERLER: Were you present at the creation for the Chan Zuckerberg Biohub? Were you there as these things were getting planned out?
QUAKE: Yes. I was the Founding Co-President of the Chan Zuckerberg Biohub, which was Mark Zuckerberg and Priscilla Chan's first substantial effort in science philanthropy. We helped plan that and launched it, with my partner Joe DeRisi, who is a professor at UCSF.
ZIERLER: What was exciting to you about being a part of the Initiative?
QUAKE: It was a chance to do something big for science in our area. It was a regional scientific organization. Going back to my Caltech days, when I was coming up as assistant professor, my senior colleagues all looked out for me, went out of their way to do nice things for me, and helped me get started. I was very grateful for that. This was a chance for me to give back to my colleagues in science, here, up in the Bay Area, and also to take on a really big problem. My research, starting from things I had begun at Caltech, in fact, had gotten me to the point of trying to take on some inspiring big projects, like building a cell atlas of all the cell types in the human body. I knew I couldn't do it alone and would need resources, and large collaborations, and this became a vehicle to do that.
ZIERLER: How do you incorporate your research agenda at Stanford with all the exciting things that are happening at the Biohub?
QUAKE: Some of it is very synergistic; my students and postdocs have played a large role in coordinating our cell atlas efforts. But I also work on things that are totally orthogonal and not connected to the Biohub and are just a personal scientific interest. It's a mix.
ZIERLER: How much administrative responsibilities are there for you in this role?
QUAKE: A lot, now, as Head of Science. It's a big job. CZI has a very large endowment. It's larger, even, then the Howard Hughes Medical Institute, and larger than all but five universities. There are a lot of resources being put to work for science, and that's now globally around the world, not just in the Bay Area.
ZIERLER: Do you see CZI as playing synergistically with the larger biotechnology effort in Northern California?
QUAKE: Absolutely. We're already seeing the first sorts of things spinning out into small companies and making their way hopefully into the clinic, to help patients.
ZIERLER: Is this to say that drug delivery and dealing with the FDA, is that sort of the bread and butter of what the CZI is all about?
QUAKE: Not at all. We're really focused on basic science. We want to see our discoveries taken into the clinic by professionals, and we deal with that the same way universities do: we license intellectual property and help independent companies get access to technology, and they have to then raise the money to get into the clinic.
ZIERLER: Some overall questions before we go and develop your personal narrative in a chronological sense—fundamental research and translational research, do you keep those worlds separate? Is it all combined for you? How do you determine when it's all about just figuring out how nature works, and when is it that you have a specific translational goal in mind?
QUAKE: That's a great question. I love this quote from Pasteur—let me try to look it up so I get it right, since we're doing this for posterity. One of my postdocs, who I met at Caltech, and then came with me to Stanford, made me aware of this quote from Pasteur: "There does not exist a category of science to which one can give the name applied sciences. There are sciences, and the applications of science, bound together, as the fruit of the tree which bears it." I think that's very nice. It's all a continuum.
ZIERLER: Why does it speak to you?
QUAKE: [laughs] Because that's consistent with my own experience. There's not a real hard and fast distinction. They're two sides of the same coin. A lot of my work at Caltech was developing new technologies for measurement in science, which were used by me and others to ask both very basic questions in science, but also to develop applications relevant for human health.
ZIERLER: Your work in diagnostics and measuring tools for biology, do you see that as a new era, courtesy of all of the advances in technology and computation? Are you doing something that's different, or more of a continuation from what, for example, Lee Hood was doing in the 1970s and 1980s?
QUAKE: Lee is one of my heroes. An interesting Caltech story—he was at Caltech before me, we didn't overlap there, but I've gotten to know him very well. My lab telephone number at Caltech, I inherited his lab telephone number. So every now and then, the phone would ring, and it was someone looking for Lee or someone in his lab! [laughs] Which was very nice. Lee—one of the great pioneers of biomedical technology development. The idea of automating DNA sequencers and protein sequencers and DNA synthesizers—he played such an important role in that, driving those technologies to the point where they could be used to sequence genomes. He was there from the very early days and was visionary about it. There, the driving motivation was really to understand genetics by getting the genome. That has all come to pass. He was correct, as a visionary, about that.
Now, my own contributions have been different. It has been less about using the sequencers to sequence genomes, and more about using them to count molecules. By counting molecules, that has opened the door to a whole set of blood tests that replace invasive biopsies—NIPT to replace amniocentesis, blood tests to replace invasive biopsies for transplant patients, blood tests to replace biopsies for deep infectious disease. Those are all now in the clinic based on the work that my group has done. I do view it as a real turning point in diagnostics, this idea that blood tests can replace invasive biopsies. It is important both for patient safety and for equity, health equity, and make sure that the fruits of the genome revolution are shared equally. Because there are a very small number of hospitals, relatively speaking, that have physicians with the skill to do biopsies and do them very well, on the cutting edge, but blood can be drawn anywhere and mailed to a lab to be tested. That, for me, is the great leveling value of these genomic technologies, is that they're available to everybody with a simple blood draw that can be sent to a lab. It doesn't matter where you live—rural, urban, anywhere—you can have the benefit of these technologies and the tests that flow from them.
ZIERLER: If I understand correctly, all of your formal academic training is in physics and math, and yet your career trajectory is so squarely rooted in biology. Was that the plan from the beginning? Did you understand that you wanted physics as an intellectual foundation and then go into biology?
QUAKE: Not from the beginning. Like a lot of people in their early student careers, I didn't know what I wanted to do. I had a lot of interests and I was tracing different things. When I got to graduate school, in my first year of graduate school, I spent the whole year systematically looking across physics, trying to figure out, where was the most exciting part of physics to do research in? I kind of got onto this idea that this interface between physics and biology would be very interesting. It was there in the early part of graduate school where I kind of decided, "That's the direction that I want to follow."
ZIERLER: Did you have that epiphany before or after you met Steve Chu?
QUAKE: After. Because I had done my undergraduate thesis in Steve's lab, working with optical tweezers and trying to pull on molecules. He had introduced me to some of these ideas in biophysics and gotten me interested in the field, for sure. But I thought I was going to do something totally different for graduate school and I was going to change direction. I thought about that, then did the survey and realized Steve was really onto something. And that he wasn't steering me wrong; let's put it that way.
ZIERLER: Based on all things you've worked on and your academic pedigree, is biophysics as a combination of biology and physics the best way to describe what you do and what you're after?
QUAKE: I think it is, yes.
ZIERLER: Has that term changed over the course of your career? Does it mean something different now than it might have 20 or 30 years ago?
QUAKE: I think it does, yeah. It has changed. There was a period when biophysics was just about human performance, how you hit a basketball, how you hit a baseball the furthest, how you make a basketball shot. It was about how bacteria swim and how fish swim and animals move and that kind of stuff, very sort of mechanical, fluid mechanics, that sort of thing. It wasn't really molecular for a long time. The physicists who were interested in molecular biology became biologists, right? That's what Seymour Benzer did. He was a physicist, began working on phage, and then got into behavioral genetics, but he just completely gave up on physics. They don't think about him as a physicist anymore, but he was. Another great Caltech person back in the day. Max Delbrück, same thing. Another Caltech person. Those people in that cohort, they were physicists who became biologists, and somehow they were forgotten about in the physics community. It wasn't called biophysics; they just called it biology. Molecular biology was the new field. That was just biology, and the folks who were doing biophysics, it was not molecular, not as interesting. That went through a whole transition. Now, the physicists have discovered that molecules are interesting in biology, and they should be studying them, and there's a whole discipline to it. One of the real eloquent leaders of that movement is Rob Phillips at Caltech, who has written several books about this, Physical Biology of the Cell being one of them, Cell Biology by the Numbers. There is now I think a great community right on the boundary between the disciplines that is exploring a very interesting space.
ZIERLER: You're well positioned to comment on some of the similarities and differences of startup culture, or the culture of tech transfer, as both a previous Caltech professor and now a Stanford professor. What are some of those similarities and differences, when you have inspiration to bring an idea possibly to market?
QUAKE: Again, I have to say, going back to my Caltech experience, Larry Gilbert who ran the Office of Technology Licensing at Caltech, was a real mentor to me, as he was to many other faculty at Caltech. When he took over, Caltech was not a big player on the technology licensing area. By the time he retired, by the time I left which was just before he retired, Caltech was getting more patents than any other university except for the UC system as a whole. That's not per capita; that was total number of patents per year. He did an amazing job! Part of what he did was he just went around and visited all the faculty. He'd go in, sit in their office, and say, "What are you working on? What has got you excited? What's your latest big paper?" They'd tell him, and he'd say, "Well, have you thought about filing a patent on that discovery?" They'd often say, "No, tell me about that." He would explain to them how it all worked. He really built up a very vigorous program and taught a whole generation of faculty how to think about how their research world intersected with things being developed commercially. I learned a ton from him along those lines, for sure.
ZIERLER: Some questions about mentoring undergraduates and graduate students. What opportunities do you have to interact with Stanford undergraduates?
QUAKE: Quite a bit. The first part of my tenure here, I taught a lot. We started a new department. I was teaching undergraduate classes. Since I've taken over these leadership opportunities, I'm not teaching in classes much, but I'm still mentoring in the lab. I have undergraduates who come through to do internships. One just started today, actually, a young woman from Columbia University, but there will be a couple Stanford ones coming through, too.
ZIERLER: I know that your lab is so dynamic; it is filled with so many graduate students and postdocs doing such exciting things. What are the kinds of things that attract graduate students and postdocs to your lab?
QUAKE: Honestly, I don't know. [laughs] I collect oddballs, people who want a challenge. I've got a little bit of a reputation as a challenging person with very high standards, and that doesn't appeal to everybody. So there's a little filter, I think, of people who come in, of people who want a challenge, and really want to strive and do science at the very highest level. If they want to do that, they find a home in my lab.
ZIERLER: Based on your own academic trajectory, are graduate students just as likely to come in with undergraduate degrees in physics, chemistry, and biology?
QUAKE: All over the map, absolutely. It's a very interdisciplinary group. That's part of the fun.
ZIERLER: What about—and this is perhaps a generational question—computational skills? Are you learning the way to utilize computers in some sense from your graduate students these days?
QUAKE: Oh, yeah. The things we do are very heavily computational, require some computational savvy. Everybody in the lab learns how to do experiment and computation. That's part of what I believe, is that I don't try to get specialists in the lab. I try to teach everyone to have an experiment from start to finish, where they've got to be able to do the bench work, and do the computational analysis, and write the paper. That's I think the best path to independence for them if they're going to set up their own labs someday. Yes, they all have far surpassed me in computational sophistication.
ZIERLER: On that point, we're all thinking about AI these days. Has your lab embraced AI? Do you see the benefits and perhaps the pitfalls of AI for the science that you do?
QUAKE: I was a skeptic for a long time, but now I'm a believer. We've really crossed a threshold with these large language models. Both the analysis of DNA sequences, but also in tools like ChatGPT which my students are doing all kinds of creative things with, to try to synthesize scientific knowledge and apply it to research questions.
ZIERLER: What's an example, for people who are concerned about what AI might do in science specifically, that you might counter with this newly found positive assessment?
QUAKE: One is how you do annotation. I mentioned we're trying to make these cell atlases. We're trying to make atlases of all the cell types in the human body. That was our big Biohub project. Once you've described them at a molecular level, you need to give them names and kind of annotate what you'd say their function is, based on your knowledge of the various genes that are expressed. That has been a very labor-intensive task. We have expert humans do it. That's not fully scalable. And so one of my students has been teaching ChatGPT to annotate. That's a very exciting project. I think we're going to be using it at some point in the near future.
ZIERLER: Are you involved in any policy initiatives either at the state or the federal level?
QUAKE: Not directly at this point. No.
ZIERLER: What have you learned about the regulatory framework, in bringing all of your products to market?
QUAKE: It is, I think, largely well thought-out, and designed to protect the safety of people. That's super important. In its specific implementation, there's often areas where one wishes it could be a little faster, or quicker, but in general, I think it's a positive thing, and generally well executed by people who are well-meaning and have the best interests of the country in mind.
ZIERLER: As a snapshot in time, what are you working on currently? What are some of the big projects in your lab?
QUAKE: We're on our second generation of Tabula Sapiens, which is our big human cell atlas project, and we're preparing a paper for that. Now we have a million cells from various donors that characterize hundreds of cell types from two dozen organs in the human body. We're looking a lot at non-model organisms. We made an atlas of the fly and then looked at flies, how they age, and we are trying to compare that with earlier work we did with mice, and how they're aging, and a cell atlas of that. The model organisms are again incredibly informative and providing so much. And, another Caltech connection, right? Wasn't it Sturtevant who brought the fly thing to Caltech?
ZIERLER: Yes, of course along with T.H. Morgan.
QUAKE: It continues to be such a powerful organism to help us understand biology, for sure.
ZIERLER: Let's go all the way back to the beginning, develop your family roots. Let's start with your parents. Tell me a little bit about them and where they're from.
QUAKE: My parents are both first-generation college students, actually. My mom is an immigrant. Her family immigrated to the U.S. from Germany when she was 12. They were displaced people. The part of Germany where they lived in was given to Poland after the war, and so they were thrown off the family farm, and had no place to go, and eventually were sponsored to come here. They moved to a farm in upstate New York. My dad was born in the U.S. but the child of an immigrant, also from Germany. He also grew up on a farm in upstate New York, also first-generation college student. That's where they met and married, and I was born in Schenectady. We lived there until I was 12, after which we moved to suburban Connecticut, just outside of New York City.
ZIERLER: Did your parents speak to each other in German?
QUAKE: They did not. It's something I regret. In those days, it was tough being a German in this country. There were still a lot of bad feelings after the War, and there was strong pressure to assimilate. They, I think, felt it might be a burden for their kids to be called out different as German. That was probably challenging for them when they were younger.
ZIERLER: What was your father's profession?
QUAKE: He was an early software entrepreneur. Started a couple of companies that were successful. That's where I got my entrepreneuring genes from, I think, and the experience. Another funny story—I've got to look this up—his first company was called Bibliographic Retrieval Services. It was an early online database where they indexed all books in print, all patents, all New York Times articles, and so forth. They would sell that service to libraries, university libraries, and you'd go look things up. He sold that company. I'm trying to figure out who he sold it to. Because when I started at Caltech and went to the library and logged in to do a literature search, his screen showed up! Caltech was using the company that acquired his company—
ZIERLER: Oh, that's awesome!
QUAKE: —and the page was still there! It was amazing! I told him that, and he was so proud.
ZIERLER: Did your mom work outside the home?
QUAKE: She was a high school teacher until the family started, and then she raised us.
ZIERLER: The move from New York to Connecticut, was that a business opportunity for your father?
QUAKE: Yeah, it was when my dad sold BRS, and he went to go work for the parent company. He did that for a few years, and then started another company.
ZIERLER: How old were you when the family moved to Connecticut?
QUAKE: I was 12. I was born in 1969, so we can do the math on that.
ZIERLER: Were you always interested in science? Did you know you wanted to pursue physics in college?
QUAKE: I was interested in science, but I was also in that generation of people when the personal computer revolution was happening. My dad was working with these big systems, and I was just fascinated by computers and what was going on in Silicon Valley. So, I thought I'd have a career somewhere between computers and science, and I was interested broadly in that.
ZIERLER: When it was time to think about college, where did you apply? What was in range?
QUAKE: My parents really valued education, and so them having been the first in their families to go to college, they were sort of—and then, they did well, became middle class, and so, a lot of value placed on education. From a very young age, they told both me and my brother that they'd put aside money for us to go to college wherever we could get into. They had basically been very frugal and careful saving money from the time we were born so that we could go anywhere that would take us. That was a very reassuring feeling.
ZIERLER: Did you apply mostly close to home, or did you know you wanted to have a cross-country adventure?
QUAKE: I was applying all over the country. MIT, Princeton, Amherst, Stanford, Harvey Mudd.
ZIERLER: What was the winning consideration for you?
QUAKE: California, Silicon Valley. Yeah, that's sort of what it was.
ZIERLER: Silicon Valley, even in the late 1980s and early 1990s, that was an exciting prospect for you?
QUAKE: Oh, yeah, for sure.
ZIERLER: Do you remember what was happening in computers around that time? What would have been alluring?
QUAKE: Oh, my gosh! I was reading all the trade rags. Our first computer at home was an Atari 800, and then I learned to program on that. One of my buddies and I started a computer camp together, and we bought an Apple IIe, and we were teaching all the neighborhood kids on these computers. That was the thing. It was floppy disks. A different world from what it is today.
ZIERLER: How did you focus on physics as an undergraduate? What was the thing there?
QUAKE: When I went to high school, I was accepted into the Columbia University Saturday Science Program. They had a program every Saturday where kids could come in and take courses. One of the courses I took in that was physics. I was super interested in that. I, at that point in time, somehow stumbled onto Feynman's book, the autobiography. What is it? What Do You Care What Other People Think? Yeah. I read that, and he really resonated with me. I loved the spirit of it, and it was very inspiring. He became one of my heroes.
ZIERLER: How did you meet Steve Chu as an undergrad?
QUAKE: He taught freshman physics! I took the spring quarter of freshman physics. It was modern physics. I took from him, and it was super inspiring.
ZIERLER: He's a really dynamic guy.
QUAKE: Oh, yeah, for sure.
ZIERLER: Did that lead directly to the opportunity to work in his lab?
QUAKE: Yeah. When it came time to do an honors thesis, I remembered the things he talked about in his lab—he'd take us on a lab tour at the end of the class—and I said, "I think I want to do that." I went and asked him if he would mentor me, and he agreed.
ZIERLER: How much biology did you take as a college student?
QUAKE: The last biology course I took was in high school.
ZIERLER: [laughs] That's amazing! You appreciated from Steve Chu and his lab the value of physics perspective in biology questions?
QUAKE: Absolutely, absolutely. Those were the early days of trying to measure molecular mechanics, and to use optical tweezers to measure forces on molecules. Stretching DNA. That's what I worked on. But also he was working with Jim Spudich on measuring myosin, stepping forces, and things like that.
ZIERLER: I wonder if you could explain, what exactly does optical tweezers mean?
QUAKE: It's a way to use radiation pressure to trap macroscopic objects. It turns out that if you take a laser beam and focus it to a point, that focal point where the fields are the highest will become a stable trap for any dielectric particle, like a glass bead or a polystyrene bead. You can work out the forces on it. There's a bunch of ways to explain it. The easiest way is through dipole forces. But it ends up being a great way to trap particles such as micron sized beads. And you can then steer the laser beam to move them around with applied forces and so forth. If you then take those little micron-sized beads and use them as handles, you can pull on molecules. So you use biochemistry to glue the beads to the ends of molecules, and then you can measure forces on molecules.
ZIERLER: From that experience, did you have well-formed ideas about whether you'd be more on the experimental side or the theoretical side?
QUAKE: Oh, I went back and forth for several years.
ZIERLER: Your interest in computers—it's early, of course, but looking back on your college days, could you see the roots of the dot-com boom that would come a few years later?
QUAKE: That started in graduate school. I still remember in Oxford the computer room was in the basement of the theory building. It was a tiny little room with a couple of SUN workstations in it. Somebody showed me the Mosaic browser from University of Illinois and what it did, and I was like, "Wow. This is amazing, and this is going to be something big at some point." That was my first introduction to the worldwide web. When I was back at Stanford as a postdoc, Yahoo, things like that, Google, all that was starting. These search engines were becoming very powerful, and I began to use them a lot. I could see they were useful and begin to incorporate it in my daily work.
ZIERLER: Did you stay at Stanford during the summers, or you went back home?
QUAKE: When I was an undergrad?
QUAKE: I had a series of summer jobs. One summer I worked at IBM Yorktown. Another summer I worked at Yale. One summer I stayed at Stanford to work at Steve's lab. It was a mixture of things.
ZIERLER: When did you decide that you wanted to go on to a science career, to go on to graduate school in physics?
QUAKE: I had very inspiring teachers my freshman year in both physics and math, and I realized, "Hey, I can do this stuff." It was probably my sophomore year in college that I began to think, "Yeah, it's going to be science, and not computers."
ZIERLER: How did the opportunity come to study at Oxford?
QUAKE: I had a Marshall Scholarship. I never had a chance to do a semester abroad as an undergraduate because the curriculum is so regimented. You can't get out of step with the sequences. I thought, "Okay, I'll do it after I graduate," and I began looking for ways to pay for it, and I began applying for fellowships. I was offered the Marshall.
ZIERLER: What were your impressions when you arrived at Oxford, perhaps starting on a cultural level?
QUAKE: There's this great Oscar Wilde quote about England and the United States being two countries divided by a common language.
QUAKE: There's a temptation to assume just because we have a similar language, everything else is the same, but it's not, and it's deceptive, and it takes a little while, but boy, then it is a shock. You understand culture shock. Maybe more so than a place where the language is different, because you don't have the expectation that it's the same. Yeah, definitely it's a different culture, and it gave me a great perspective on where I came from. You start to look at the United States as an outsider would, and you realize how arbitrary a lot of the societal decisions and conventions are that you always sort of never questioned. It puts you in a position to question some of those things.
ZIERLER: You mentioned previously as an undergrad oscillating between experiment and theory. Were you focused on theory by the time you arrived at Oxford or you were still figuring that out?
QUAKE: Yeah, I was in the theory department, and so that's where I was sort of destined. But, after that first year, I decided I wanted to go back and do some experiments, so I went back to Steve's lab. The second year of my graduate work I did at Stanford with Steve, and then went back to Oxford to finish the theory part for my third year.
ZIERLER: Who was your advisor at Oxford?
QUAKE: A fellow named Robin Stinchcombe.
ZIERLER: What was he known for?
QUAKE: Statistical physics, renormalization group. Super clever guy, great mentor, very generous person.
ZIERLER: What was the value of going back to Steve's lab at Stanford for your thesis?
QUAKE: Because the things I was asking theoretically pointed directly to some experiments that one could do using optical tweezers in single molecules. I thought, "I want to go do those experiments. I don't want someone else to do them for me." I wanted to be doing both, at that point—the theory and the experiment.
ZIERLER: What was the overriding science question that drove your thesis?
QUAKE: The most interesting part of the thesis was to ask what happens when polymers get tied into knots. I was interested in this intersection of topology and statistical mechanics. Because the way the theory worked at the time was you calculate a partition function by summing over all states, using random walk statistics, and there's no way to distinguish one type of knot from another when you do that, and yet clearly topologically they're distinct, so those states aren't accessible from each other, so there's an ergodicity problem. It's essentially an uncontrolled approximation. I wanted to understand, were there physical consequences to that. That's what I was most interested in. Those experiments I didn't do until I was a professor at Caltech, but I did all of the theory as a student. The ones that I was doing experiments for were more simple questions about polymer dynamics, and testing the theories of polymer dynamics that had been developed by Sam Edwards and others. I kind of extended those theories, and then went and did the experiments to test them at Stanford.
ZIERLER: Going back to Steve Chu's lab from Oxford, did you ever think about simply transferring and finishing your graduate work at Stanford?
QUAKE: I did. I thought about doing two PhDs, actually, one in theory and one in experiment. Then, I kind of woke up and said, "Nobody needs more than one PhD. It's a terminal degree. My career will go faster and I will get paid more if I just become a postdoc instead of—" You get tired of being a student after a while. Like, "All right, higher salary, I'll do the postdoc, and then try to move along that way."
ZIERLER: By the time you defended, were you looking at faculty positions and postdocs at the same time?
QUAKE: No, nobody would hire me. It's a three-year degree at Oxford. It's hard to be competitive against American students who have five years. Nobody was going to give me a faculty position, and I was going to have to scrounge for postdocs. But I knew what I wanted to do. I wanted to go back to Steve and continue the work. So I went back to Stanford, and he was nice enough to take me in.
ZIERLER: What aspects of your postdoc were a continuation of graduate school and where were there new opportunities for research?
QUAKE: I wanted to keep doing these experiments to test theories of dynamics and do better versions of them that were closer to fluctuations about equilibrium. The ones I had originated in the first round were just super far from equilibrium, and looking at those properties, and how [0:34:36] from a long way out. What I did as a postdoc was then just look at fluctuations about equilibrium, and measure them, and test some theories about normal mode decomposition and hydrodynamic coupling along the polymer.
ZIERLER: Where were you when Steve won the Nobel Prize in 1997?
QUAKE: I was at Caltech, as assistant professor, and the pressure was enormous to get him to come. Everybody wanted him. Everybody knew I had worked for him, and they said, "Steve, Steve, you gotta get Steve Chu to come." And so, I got a hold of him, I twisted his arm, got him to come down. It was one of the first talks after the Nobel Prize, and I had to do the introduction, to the lecture. There were a couple hundred people there in the auditorium; everybody showed up. I got up, I gave the introduction, and before I gave the introduction, like a wave of nervousness swept over me, very unusual, and I just became very nervous. I got through it, gave the introduction, I went and sat down, and everyone had turned and looked at me. I was like, "Oh, shit. What happened?" I thought back and I realized in my nervousness I forgot to say, "He just won the Nobel Prize!" [laughs]
QUAKE: So I said, "Oh, yeah—he won the Nobel Prize this year." [laughs]
ZIERLER: As either a graduate student or a postdoc or maybe even as an undergrad, did you feel the buzz, did you see the significance of where this research was headed?
QUAKE: Oh, everybody knew that, yeah, he was on a good trajectory for that, and the work he was doing in laser cooling and trapping was so important that there was a decent chance he would get the call from Stockholm.
ZIERLER: How long did you stay in his lab as a postdoc?
QUAKE: Three years, 1994 to 1996.
ZIERLER: At that point, what options were you considering?
QUAKE: I had a couple of job offers. The two that were serious were Rice and Caltech. Again, I wasn't the most distinguished candidate, because I had done this three-year doctorate and two-year postdoc, didn't have that many papers. But Tom Tombrello at Caltech, who was a character—sadly passed away now—I owe it to him that I got to Caltech. He had somehow convinced the powers that be in Caltech to let him run a search ad every year, even though he had no billets or positions to hire people. He would run a little virtual search committee, and anybody that applied to this thing that he thought was interesting, he would try to matchmake them with an existing search in another department. So he was like this quality control filter, talent scout, who was trying to find people, had license to do that. I had applied to this thing, he liked what he saw, he got me down there and plunked me into the Applied Physics search, and basically helped me get that job, for which I am eternally grateful.
ZIERLER: You came in as a Physics hire, not a Biology hire?
QUAKE: Applied Physics.
ZIERLER: That's in EAS?
QUAKE: Yes, that's EAS. I have a theory about a university that has a department of physics and a department of applied physics. That means that sometime in the past, there were two physics faculty members who couldn't get along with each other and they had to be separated into different departments.
QUAKE: At Stanford, which has the same thing, it was Ginzton and Varian. They just couldn't get along, and they had to be put in different places. At Caltech, the problem was that Gell-Mann would not allow any solid-state physicists to be hired. He called it "squalid state." So Applied Physics was established to hire solid state physicists at Caltech and to get somebody to work in that field.
ZIERLER: Your hire at Caltech, you mentioned how the Feynman book really resonated with you. Had Caltech professors loomed large in your education? Did you have an appreciation for what kind of research had occurred at Caltech over the years?
QUAKE: Oh, yeah! It's such a legendary place. Not just Feynman, but Pauling—everybody knew about that. In Physics, Gell-Mann. The whole cohort of folks there was amazing. In Biology, Delbrück and Benzer, just incredible names. The list went on and on. So, yeah, it was a place—why I was attracted to it—it just had such amazing history of exquisite, wonderful scientists.
ZIERLER: I've come to appreciate the unique way that Caltech supports its junior faculty. I wonder if you could speak to that.
QUAKE: Oh, yeah. Well, I'm an example of that. They came, plucked me up, and took a chance on me, and helped nurture my career. Largely by leaving me alone. But as I said, key senior faculty went out of their way to help me get connected to certain grants or postdocs or whatever, and made sure I had the tools I needed to succeed. I had great collaborations. They tell assistant professors not to collaborate with senior people because you won't get promoted, but I ignored that, and it worked out just fine. Axel Scherer and I had great collaborations. We did a ton of stuff together. It was really marvelous. Frances Arnold and I did a bunch of stuff together. She was one of my mentors. Axel and Frances were my two biggest mentors there at Caltech, I think, that I worked closely with. Kerry Vahala in the Department, I think who chaired the search committee and then got me promoted. Those were the ones. Frances, I think her most cited paper is with me.
ZIERLER: Talking about new tools, the opportunity to build your own lab, what was most important to you, both in terms of instrumentation and your overall science objectives at that point?
QUAKE: I knew it had to have both wet bench biology and physics. I was stronger as a physicist then. I was kind of learning my way around biology, but not really confident in it. When I was at Stanford as a postdoc I went to the Biochemistry Department where had been assigned a bench to work with to do our pipetting, and I took out a ruler and I measured everything, and I said, "This is what I want. Just clone this." I measured the benches, the shelves, duh-duh-duh-duh. "Make me a version of this." Which they did. The physics part, I knew I just needed rooms with certain vibration isolation laser tables blah-blah-blah-blah. We got all that going. I was more comfortable with that, at that point.
ZIERLER: What were some of the big research projects as you got your lab up and running?
QUAKE: When I started, I continued to work on optical tweezers on single molecules, so we built next-generation optical tweezers, began using them to measure more aspects of fluid interactions between beads and polymers, several things like that. Began also getting interested in microfabrication. The microfluidics stuff, I had gotten started because my postdoc officemate, a guy named Wayne Volkmuth, who had done his PhD with Bob Austin at Princeton, had built microfabricated sieving devices to do electrophoresis, and I thought that was super interesting. I got him to teach me how to do that. We used to sneak into the FabLab at Stanford on weekends, and he taught me how to do lithography. I knew I wanted to do that at Caltech, and that was why I began collaborating with Axel, because he had all the lithography equipment. We mentored a joint student together, Hou-Pu Chu, who began making devices we wanted to use to make two-dimensional DNA and to make a DNA flow cytometer. That was when I got started doing the microfluidics stuff.
ZIERLER: Tell me about the field of microfluidics and why it was so interesting to you at that point.
QUAKE: I wanted to find ways to automate biology. I looked at biology, and it was so labor-intensive, lots of people pipetting all day, and I thought, "I don't want a group with a lot of people just pipetting all day. We'll invent machines to do that for us, and then that will let us scale. We won't need a bigger group and it will be more powerful." So, I got interested in trying to develop the integrated circuit for biology, and what would that mean. What it meant was plumbing, and automating plumbing. There was a little bit of literature out there, people trying to do things, but it was very primitive, and nobody had really solved the outstanding problems. We managed to be the ones to do that, in my group, and we invented the first microfluidic valve that could be built at scale, with thousands of valves on a chip. We call that microfluidic large-scale integration. That really revolutionized the field.
ZIERLER: Your collaborations with Axel and Frances, were you specifically looking at the kinds of things that they were doing, and there was a point of inspiration? Were you co-equals, based on your own expertise?
QUAKE: They always treated me as an equal, yep. They always did.
ZIERLER: You mentioned it was at Caltech that your entrepreneurial side really blossomed. How did that come about? What did you see as an opportunity there?
QUAKE: It started with the microfluidic devices, and we decided to make a company to try to commercialize them. I found the CEO, who was an old college classmate of mine, and Larry Gilbert found us the first investor, who was someone he had been cultivating, a guy named Bruce Burrows. He introduced us to Bruce. Bruce wrote us our first check and got the company financed. That turned into Fluidigm, which became a public company, market cap more than a billion dollars at some point, and became the leading microfluidic company in the world.
ZIERLER: Is it still in existence?
QUAKE: It is, although they changed the name to Standard BioTools last year.
ZIERLER: Are you still involved at any level?
QUAKE: I'm not, no. I stopped being involved a number of years ago. We founded that in 1999. [laughs]
ZIERLER: So many biotech companies, they start out promising and then they flame out. What do you think the secret to the success of this was?
QUAKE: We had great leadership. The CEO, Gajus Worthington, he led the company for 20 years, and really built it to last, and did a great job. Also we had great technology. It really was revolutionary, and that allowed them to build unique products.
ZIERLER: I wonder if you could explain if there was a particular moment where you really appreciated the symbiotic relationship between fundamental research, the kinds of questions that you were after, and building the tools necessary to answer them. If there was a particular moment where that really became apparent to you.
QUAKE: There were a number of those. One was, when we invented the valves, we were thinking, "This is a technology that will have a lot of uses, and we don't know what the uses are going to be yet." But we knew it was going to be interesting, and useful, or we believed it. I had just gotten the Packard Fellowship and I was up there at the Packard meeting, and I gave a talk, and I said, "Here are some cool videos. We just invented these valves and this plumbing, and I think it's going to be useful for something, and I'm going to spend a few years figuring that out." One of the other Packard Fellows in the audience was a Berkeley professor named James Berger. He approached me afterward, and he said, "You should use this for protein crystallization, to solve protein structures, because it's a challenging problem, you've got to do a lot of experiments, the protein is hard to get, and it's a great thing to miniaturize and automate." So I said, "Huh." Went back to Caltech, started doing some calculations, thought, "Huh, this could work." I had a young graduate student named Carl Hansen who was just ready to join the lab. I said, "Carl, why don't you work on this? The numbers look like it's going to work. Let's try to build protein crystals in the chips." Carl did a bunch of work on that, and it turned into a really cool tool. He figured out how to grow crystals on the chip. Then I sent him off to James's lab, for a week, and in a week, he did more experiments than James's best graduate student did in a year. At that point I knew we were onto something! That became Fluidigm's first product. They licensed that and they built that, and they launched a whole product, a number of innovative structures solved using that, and it was a great example of that interplay.
ZIERLER: I wonder if you could just explain, what does it mean to grow a crystal on a chip?
QUAKE: At that point in time, the primary method to determine protein structure was through x-ray crystallography. If you wanted to do that, you had to have a crystal. The proteins all had to be grown on a crystal where the order was the same so they would diffract the x-rays and make diffraction patterns in a coherent way. There was no way to predict crystallization conditions. It required a lot of brute force experimentation, about finding the right combination of salts and buffers that would cause the proteins to grow as a crystal and not just sort of crash into a disordered mess, and condensed. Very interesting physics of the phases of that, that we were able to explore and work out. That's the thing; it's like growing rock candy. That's a crystal of sugar. That's what you had to do with proteins in order to get their structures.
ZIERLER: Did you see this in some ways as an entrée into human health science, for you?
QUAKE: Yes! Some of the proteins that the structures were determined, it was so they could be either developed as therapeutics, or others that were structures with therapeutics bound to them, understanding how to design small molecules to bind to them.
ZIERLER: Do you have a specific memory of when computation really became a game-changer in the lab, for you?
QUAKE: Really as we got into genomics and sequencing when I was up at Stanford, that was when it really cranked up, because the sequencers were throwing off so much information, and how you computed on that and calculated with it became central.
ZIERLER: Tell me about your decision to move to Stanford, especially after receiving tenure at Caltech.
QUAKE: Yeah! Well! That was one of the hardest decisions I made in my career, probably the hardest. I loved Caltech. I fit in there. They treated me incredibly well. I was probably one of the youngest full professors they ever had. What happened was Steve Chu began to recruit me back, and there was a new department being formed in Bioengineering, so there was an opportunity to start a new department, and hire two dozen faculty members. At a place of Stanford's caliber, that doesn't happen very often. I figured it would be a once-in-a-career opportunity. Also my wife preferred the Bay Area over L.A. She never found her niche in L.A., so she was eager to go back. It was those two things that drove it. I didn't sleep for two weeks, trying to make my mind up on that. I have to say that I spent almost a decade at Caltech, it has been almost two decades at Stanford; I still identify more with Caltech. It was such a formative experience. Frankly, I fit in better. Because I'm kind of an oddball, and Caltech is much more tolerant of oddballs than a place like Stanford. It was such a wonderful part of my career.
ZIERLER: Influencing this decision, I'm curious, were there already discussions with people like Y.C. Tai about creating a medical engineering program at Caltech? Were those already entrain when you were making this decision?
QUAKE: Oh, absolutely. I'll tell you a story about Y.C. He was the guy in microfabrication when I got there, right? He had this gigantic engine of a lab that was just cranking stuff out. I was trying to just scrap and get things started. I went to go see him. I said, "Do you have any used equipment you don't want anymore? I'll take anything you've got that you're not using."
QUAKE: He offered me some really aged equipment, which I took, and was grateful for. But I think he appreciated the chutzpah and the [laughs] entrepreneurial sense of that. He told me later that somebody was worried I wasn't getting mentored enough—and I'll tell you about that in a minute—but he told them, "Don't worry about Steve. He's okay." [laughs]
ZIERLER: [laughs] Then tell me about the mentoring.
QUAKE: Mentoring! Applied Physics hadn't hired anybody for a decade. I mean, really, I was the first person they had gotten in a long time. It was a small department. So there was no mentoring. I mean, the secretaries were my mentors. They were the ones who taught me how to write grant proposals! They took me under their wing and showed me all the ropes. If it weren't for them, I never would have got it going. I have to laugh—I look today at all the structure and mentoring for young faculty, and I'm a little bit of a curmudgeon, to say, "That's not how it was back in the day."
ZIERLER: [laughs] Do you have a sense of the origin story of the bioengineering initiative at Stanford?
QUAKE: Yeah. That was Mory Gharib. Mory Gharib really wanted to do that. he had moved from UCSD, and he wanted to create a bioengineering program at Caltech. He recruited me and Paul Sternberg, and the three of us were kind of the founding group of Bioengineering at Caltech. If you look back, there's an interview with us in one of the Caltech magazines where we talk about it. We got the curriculum and the whole program off the ground a couple years before I left for Stanford.
ZIERLER: At Stanford, this new initiative there in bioengineering, how did that get started?
QUAKE: There had been a bunch of false starts over the years, where Stanford had tried to do bioengineering. They tried to do it out of the Mechanical Engineering Department. They tried to do it out of the Chemical Engineering Department. None of those guys really had the right vision to generate enthusiasm in the administration. Finally, we had two deans, Jim Plummer and Phil Pizzo—Jim was the Dean of Engineering, and Phil was the dean of Medicine. They decided that they wanted this to be part of their legacy, to start a new department in bioengineering, and it would be joint between Engineering and Medicine, and it would be de novo, not derived from an existing department. They got John Hennessy to buy into this, and to commit a lot of resources to it. They pulled in Scott Delp to be the founding chair. He was a Mechanical Engineering professor at that point, but he had been in a Bioengineering Department at Northwestern before Stanford. Got him to be the leader. He's the one who recruited me to the Department.
ZIERLER: You said this was just simply too exciting to pass up, along with the fact that your wife was more comfortable there.
ZIERLER: Tell me what made it work so well after these false starts.
QUAKE: Part of it was that it was de novo, and part of it was Scott's vision and the other faculty he got involved in it. All these faculty were willing to put aside their parochial self-interest of what they were researching, and say, "We want to do something new and interesting, and get people working on new frontiers." The first search, they hired no engineers; they hired a physicist, a psychiatrist, and a chemist. Those were the first three faculty in Bioengineering at Stanford.
QUAKE: But it took guts, right? That took guts! It was done very well. My program took off, was very successful. The psychiatrist was a guy named Karl Deisseroth, who invented optogenetics, and was Viviana Gradinaru's mentor. She's Caltech faculty now. He has won a ton of prizes. He will probably win a Nobel Prize; it's a matter of time. The chemist was Jennifer Cochran, who has gone on to do great things as well, founded a number of companies. She just served as department chair and has been just an awesome colleague. It started with a very diverse set of people, and we have managed to maintain that spirit as we have hired and grown the Department.
ZIERLER: As you explained, letting go of some of your parochial interests, in coming back to Stanford, how did that change your research agenda? What aspects did you take with you from Caltech? What did you take on anew?
QUAKE: It seemed to me the research opportunity at Stanford was to work with great cell biologists. My research, I could tell, was moving from molecules to cells, and I wanted to understand cells and work with them. Stanford had a very deep bench of great cell biologists, and I thought, "I'm going to collaborate with those folks." Irv Weissman, the Stem Cell Institute, it kind of went on and on. That all came to pass. That was awesome. We did a lot of wonderful things together. It was everything I hoped it would be. What I didn't anticipate was how much fun I would have with the clinicians. We've got a hospital, a medical school, here, and as we got into these diagnostic tools, using genomics to do these diagnostics, that all happened because of the ability to work with the clinicians here and do this clinical studies. I had no idea that was coming. That totally changed the course of my research, and has been a ton of fun.
ZIERLER: Why was it so fun, after not really knowing to expect it?
QUAKE: These were very direct, immediate applications. The first big diagnostic we did was to replace amniocentesis with a blood test. When that paper came out, it was like I was a hero to all the moms in the neighborhood, right? It hit the popular press. Everyone was like, "Wow, this is amazing what you're doing." That never happened when I was writing papers about polymers! [laughs]
QUAKE: People appreciate it a lot more—let's put it that way—the lay public.
ZIERLER: The issue of amniocentesis, how did you come to that specifically, to tackle that problem?
QUAKE: That was through my own experience becoming a parent. We had our first kid when I was at Caltech, my daughter Zoe. We were seeing the OB down at—he worked at the Huntington Hospital, so it was near there in South Pasadena. He was a very well-regarded OB. He was a great doctor. My wife—he told us at one of the visits, "Well, you're of the age you should probably get amnio, check for genetic defects. Is this something you want to do?" We looked at each other and thought it was kind of a theoretical question, like, maybe a follow-up appointment or something. We were like, "Yeah, that sounds right." And he turned around with a gigantic needle in his hand, and plunged it right into her belly! Did the amnio himself, right there. And we were just freaked out by that, right? There's risk associated with it. It made a huge impression on me that, why would you risk your baby's life to ask a diagnostic question? That didn't make any sense. That's what got me thinking about that. It was years later at Stanford that I kind of cottoned on to the way to solve that problem.
ZIERLER: Did you immediately appreciate that it would be blood test that would be the way around invasive procedures?
QUAKE: That was the lightbulb that went off. I discovered there was this literature about cell-free DNA, that there was DNA from all the tissues in your body, including the fetus, in your blood, and so there was a way to get at the genetics of the fetus from a blood test. That had been known since the late 1940s, and nobody had ever managed to turn it into a practical test, until we did.
ZIERLER: It begs the question—for all significant discovery, it seems so obvious only in retrospect—do you have any insight why it took so long, and why it took to you, to make this connection?
QUAKE: Part of it was, this was an obscure phenomenon. I think most people weren't making the connection—there was a very small community working on it, of people that—it was moving at a snail's pace. It also needed technological innovation. A key insight was to figure out how to count molecules, and none of the pathologists or doctor types who work in that field were thinking along those lines. It took an outsider like me, who had been counting molecules, through the single molecule experiments, and then thinking about the sequencer as a way to count molecules, to really get at the answer.
ZIERLER: One big difference, I wonder, between medical devices, drug delivery, and a blood diagnostic test—what's the regulatory mechanism for bringing this concept to a clinical environment?
QUAKE: Diagnostics in this country, the U.S., there's something called CLIA, which is an association that certifies testing labs, so you've got to get certified by them to have a test. Interestingly, it doesn't need FDA approval, but if you can get CLIA-certified, and you can get the doctors to recommend it, which usually means working with the doctor professional organizations, you can develop a commercial diagnostic. FDA approval is useful in cases around reimbursement, and people usually get that in the end, but you don't need it in the beginning.
ZIERLER: What partners did you need in order to make this a viable commercial project?
QUAKE: We'll start with the viable research project. I partnered with doctors here at Stanford who began recruiting women and collecting their blood and doing the amnio separately so that we could have something to compare with. Without them, we wouldn't be able to do this, so there was a great collaboration there with the maternal-fetal medicine group here at Stanford. Then once we published the paper, one needed—we had a very small study, just proof of principle, two dozen women. But it was obvious; we proved the principle. But to really get the clinical use, you have to do much larger cohorts. There are other questions you have to answer that are important. We weren't in a position to do like a 1,000-woman study or several-thousand-woman study at Stanford. So, the patent was licensed to a company that raised the money, did the study—it was called Verinata—and they brought the test to market after that study.
ZIERLER: What has come of the company since?
QUAKE: Verinata was acquired by Illumina, and they've now licensed it very broadly on their sequencers. There are multiple companies in the space, all using more or less some version of what we developed, or a derivative of it. Now, like eight million women a year get some version of this test.
ZIERLER: Is there any case to be made that there's some clinical or diagnostic value of amnio for which a blood test cannot be relevant, or does the blood test really replace everything?
QUAKE: It depends who you ask. The blood test is on its way to replacing everything. The performance is nearly as good as amnio, so good that I wouldn't take the risk of an amnio, really, unless I had really good reasons for it. It's hard to find those. There are certain very rare things that you can find with an amnio, but they're so rare no sane person would risk their baby to test for it. Right now, amnios are used to sort of verify after the blood test, and eventually that is going to become obsolete, because I think confidence in the blood test and the performance is just going to keep growing over time.
ZIERLER: Just as a matter of intellectual curiosity, is this what got you into thinking about blood tests replacing biopsies, with the amnio work?
QUAKE: Yeah, because the amnio is a biopsy right? It's essentially like a biopsy. You're grabbing a fetal cell out of the womb, there.
ZIERLER: What other kinds of procedures were most interesting to you, that you can tackle with the same approach?
QUAKE: After we published the first paper on the non-invasive prenatal testing, I got a call from a colleague at Stanford named Hannah Valentine, who is a cardiologist. She said, "Steve, I saw your paper. We have a similar problem for heart transplant patients. We biopsy them every couple of months after the transplant to see if the heart is being rejected, and to adjust their immunosuppressant drugs. But the patients hate it, and it's painful. Is there a version of what you did that will work for this?" We got together to talk about it, and I realized there was, so we developed that together. That became CareDx's test, which now hundreds of thousands of people get every year.
ZIERLER: The obvious question here with this trajectory—do you envision a system where biopsies in their entirety are replaced by blood tests?
QUAKE: That would be great! That would be a great thing. We're trying to knock them off one by one. I'm not sure you'll ever get rid of all of them, but I think we're going to be able to knock down their usage enormously.
ZIERLER: What do you see in terms of the role of advances in imaging technology as another way to reduce the need for biopsies?
QUAKE: There was a big push in pregnancy to use imaging and blood tests of protein markers to replace amnio, but it didn't work very well. Imaging—in pregnancy, there are certain congenital things you can detect that can be surgically repaired, and ultrasound is good for that, for detection. Imaging is still a powerful way to do certain things. It works together. Like in cancer, there's now a very strong effort that is being successful to use the techniques we developed in pregnancy in cancer, for early cancer detection. If you get a positive on that, you've got to go find where the tumor is. That means doing imaging. Those are paired together very well, imaging to follow up a positive test for cancer, for example.
ZIERLER: Tell me about the value of being an investigator for the Howard Hughes Medical Institute. What was the advantage for you there?
QUAKE: Oh, that was terrific. I spent 10 years in that program. It first of all provides essentially unrestricted funds for research. You can do whatever you want. And I wanted to do whatever I wanted! Including a bunch of this diagnostic stuff that I wasn't funded for, and including a bunch of using microfluidics for single-cell genomics, which I wasn't funded for. It also introduced me to a lot of great biologists. You had to go to one meeting a year, and everyone had to give a 20-minute presentation, and everyone brought their A game, I mean really their best science. There were a lot of great scientists that were part of it. I just learned a ton of biology listening to those talks and meeting that community. It was really, really good.
ZIERLER: Is there a time, a specific end to the program? Can you renew it?
QUAKE: Yeah, you could renew on a five-year cycle. I renewed once, and then the next time I was going to renew again, but I got offered the opportunity to lead the Biohub, and so I stepped down to do that.
ZIERLER: Before we get to the Biohub, an overall question—the Human Genome Project, were you involved with it over the years?
QUAKE: I was not, not directly. I received some NIH funding for technology development, but I wasn't part of sequencing the human genome. That was a little—how to say—a little ahead of my involvement in the field.
ZIERLER: Your overall contributions and interests in genomics—were you a beneficiary of the findings of the Human Genome Project?
QUAKE: Absolutely! I mean, the whole prenatal test used the human genome reference. Because the way it works is, you sequence random pieces of DNA and then map them back to the genome to understand what chromosome they came from. So we needed the reference genome for that. I would argue this is really the first clinical application of the human genome, was our NIPT work, and it is used in the clinic at scale.
ZIERLER: I'm curious what aspects of the Human Genome Project you see as complete, and in what ways this is prelude for the next phase of the project?
QUAKE: In roughly 2000, the two efforts created a draft human genome. Twenty years after that, we're finally getting it to be more or less complete, but there's a lot of subtlety around it. I would also say that the initial efforts were very expensive. It was a couple billion dollars to get the first human genome draft done, so that's not enabling of personal genomes. There was then a huge wave of effort in developing so-called next-generation sequencing technologies, which allowed re-sequencing of human genomes, using the reference as a scaffold. That's the part where I got involved.
ZIERLER: When the opportunity to become co-president of the Biohub came about, who found you? What was the initial point of contact?
QUAKE: I was asked by John Hennessy who was then the president of Stanford to serve on the committee to make a proposal to Mark and Priscilla. Mark and Priscilla let it be known they wanted to do a research institute in the Bay Area involving UCSF and Stanford, and I was on the planning committee. I did a bunch of work on that, and through that, I got asked to be one of the leaders.
ZIERLER: Did you get a sense in your interactions with Mark and Priscilla what their vision was, what they hoped to do with their generosity?
QUAKE: Yeah. It has definitely evolved over time, but I think—Priscilla is a pediatrician, a doctor, and Mark is one of the great technologists of our time, and they wanted to combine those two interests and fund things that would be technology driving science to improve human health. That was really their vision, and they've stayed faithful to that over the years I've worked with them.
ZIERLER: In terms of siting, in terms of building the headquarters for the Biohub, what were the considerations relative to proximity to Stanford, for example?
QUAKE: Well, that's a funny story. My first meeting with Mark—he sent me an email out of the blue—"Why don't you come by the house? Let's have a chat." That's when he was interviewing me to be the leader. I went to the house and we chatted a little bit, and at one point I said, "If you really want to do something for the Bay Area, you've got to include Berkeley, too. Because they've got great engineering and great basic science, and it would be crazy to leave them out. So it shouldn't just be Stanford and UCSF." He said, "Okay." I don't think my Stanford colleagues ever forgave me for that! But it ended up being really important. In choosing the site, we decided to pick something that was in Mission Bay, equidistant from Stanford and from Berkeley, easy to get to from both, and sort of equidistant from the original UCSF campus.
ZIERLER: Was the founding vision that the Biohub would have professors with joint appointments at a university, or would there be fully employed scientists at the Biohub exclusively?
QUAKE: We decided to employ scientists at the Biohub, and that the professors we were going to fund, we would do that through gifts and not take them out of their labs. We didn't want to disrupt the fabric of the university departments. So, we decided all the space we had would be filled with our own employees, and we'd ask the professors to come in, once or twice a month, to come to seminars and share their research, but to keep their research efforts in their own labs and departments.
ZIERLER: Did the Biohub have a clinical environment from the beginning? Did it need to have a hospital affiliation?
QUAKE: In order to satisfy the tax laws, we have to have a hospital affiliation to be a medical research organization. So, we had that affiliation with the hospitals, but we weren't doing clinical translational research, really. Basic science.
ZIERLER: Was there a particular kind of basic science that was the intellectual foundation for the Biohub?
QUAKE: Yes. Mark and Priscilla, and Joe and I, we kind of hatched this vision that we would bring together great universities to take on a big scientific problem they wouldn't do otherwise, and the Biohub would be the fulcrum for that. In my case, I wanted to make cell atlases. So, one of the first big projects of the Biohub was to build these cell atlases, of human, mouse, fly, and so forth. This was like Big Science. We had dozens of labs from the universities involved in the collaboration. We had a big part of the Biohub team working on it. These papers have like 150, 160 authors on them, and we managed to quarterback all that with the resources of the Biohub.
ZIERLER: I'm sure it's an obvious question, but still, why does building a cell atlas require a Big Science approach?
QUAKE: It requires a lot of expertise, because all these tissues are different. We wanted to have people with domain expertise on each tissue to make sure the experiments were done right, and that the annotation was done right. Then there's just a lot of back-end sequencing and data analysis needed that we could do with the Biohub infrastructure.
ZIERLER: Has it been enjoyable using the Biohub as a point of interaction with colleagues at UC San Francisco and Berkeley, in collaborations that might not otherwise exist?
QUAKE: It has been great. There are many examples of that. It's something we're all very proud of.
ZIERLER: You said that Mark and Priscilla's vision for the Biohub has changed over the years. In what ways?
QUAKE: I think the vision has stayed similar, this idea of bring three universities together and solve a big problem. But I think their science philanthropy, the broad outlines have stayed the same, but they have acquired their own sense of taste and judgment for the things they like to fund. It has been awesome to see that. They can both converse at length about anything we're doing at the Biohub, or grant funding-wise at CZI, or Imaging Institute, you name it.
ZIERLER: Was there any analog to the Biohub? Did you or Mark or Priscilla, did anybody look at other organizations? Or was this, as you say, with Stanford Bioengineering, really a de novo enterprise?
QUAKE: It was a de novo enterprise, but we sought input and guidance. We talked to Bob Tijan, who had been the president of HHMI, had Janelia Farm under his belt. He was a very close advisor early on. Called up Eric Lander, talked to him about what it was like to start the Broad Institute, and what he learned from that, what he would do differently. So, yes, we were talking to other people out there about the lessons learned, and trying to not make the same mistakes that they made, rather to make our own mistakes. [laughs]
ZIERLER: Given the size of the endowment, all of the resources, I wonder if you could talk about some of the challenges in establishing parameters that, there do needs to be limits on the kinds of things the Biohub gets involved in?
QUAKE: We had a finite budget from the beginning, and we spent a lot of time talking to Mark and Priscilla about how that should be allocated. We're very conscious that we can't do everything. You can't boil the ocean. This has been something Mark and Priscilla learned, I think, as well, that in their experience, not just with the Biohub but with grant giving, that it's pretty straightforward to fund good science, it's not that difficult, but that also feels like boiling the ocean. They wanted to focus on a smaller number of deeply inspirational big projects. That's definitely something in their thinking that evolved.
ZIERLER: Among those deeply inspirational big projects, what do you count as some of the successes, with the full appreciation that these things have very long time scales, and you're right in the middle of it?
QUAKE: The cell atlas stuff has been great, a prototypical example of what philanthropy should do to open up a field. That has been awesome. CZI has funded some of the innovations in electron microscopy that led to the founding of the Imaging Institute. I have high hopes that that's going to lead to some really revolutionary advances in cryo-electron microscopy for structure determination. Right now, the resolution revolution on the detector side has been just awesome, for determining individual structures. The next generation of technologies is going to allow us to image proteins directly in cells, in the milieu of cells, and that's going to reveal a whole other set of interesting biology.
ZIERLER: Do you see the Biohub as retaining its commitment to basic science completely, or is there evolution in the works to make the Biohub more translational at some point?
QUAKE: Time will tell. We're doing it in 10-year chunks and we've got a big horizon.
ZIERLER: On that basis, given that it's a basic science organization now, all of the discovery that's happening there, what's a logical place for it to go to, from the Biohub? Is it an Amgen? Is it back to the universities? Where do those ideas go?
QUAKE: We take an approach very similar to the universities. We license it out. Whether it's big company, small company, we have very similar licensing policies to what universities do. And with that, maybe this would be a good time to pause, and pick it up on the next one? Would that be okay?
ZIERLER: Yeah, that would be fine. We'll pick it up then.
QUAKE: Awesome. Thank you so much, David. This is a lot of fun.
ZIERLER: I'll see you next time!
[End of Recording]
ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Friday, June 9th, 2023. It is great to be back with Professor Steve Quake. Steve, once again, great to be with you. Thanks again for joining me.
QUAKE: Great to be here!
ZIERLER: What I want to do today is, you're involved in so many initiatives at Stanford, I wonder if you can talk at a broad level, how Stanford avoids being siloed in all of these initiatives, and to what extent professors like you, with your interdisciplinary purview, serve as a sort of connective tissue to make sure that chemistry and biology, physics, bioengineering, all of this amazing research is talking to one another. I wonder if you could speak to that.
QUAKE: Stanford is a pretty siloed place [laughs], and that was a big difference from Caltech, which is not. Caltech, everybody knows each other. Stanford, it's, A, siloed, and B, so big that I have a hard time meeting the new faculty that are coming and whatnot. It's very different in that respect. Just before I came to Stanford, there was a systematic effort to try to address that, and that was the creation of the Bio-X program. It was a deliberate attempt to break down silos within Stanford, and it has been successful at that. I am sitting in the flagship building right now, in the Clark Center, which is the Bio-X building. For sure, some of those boundaries have broken down over time by having a building with people from different departments, by having graduate student funding that requires multiple mentors, and that's really incentivized people to work across departments. So, Stanford has evolved. I think it's still probably more siloed than Caltech, but it has definitely improved, people tell me, from what it was before these efforts started. I came here to start the Bioengineering Department, which was the first department that was owned by two schools, so that was breaking down siloes right there, that we were in both the School of Medicine and the School of Engineering. Stanford figured out how to do that. Now, there's a new department that's across schools, for the new School of Sustainability, in the School of Engineering, the Environmental Science Department. So, the model is getting replicated.
ZIERLER: When you came to Stanford, was Bio-X baked into the deal? Was that one of the attractions for you?
QUAKE: Yeah, for sure. My old mentor, Steve Chu, was part of getting that off the ground. He and Jim Spudich had conceived that as their brain child, as this way to break down the silos, and they raised money for the building, the building got built, and when I came up here, the building was like half full. So it had just gotten off the ground. It was definitely part of the attraction for me.
ZIERLER: What was your research at the time? Why might Bio-X have served as a perfect housing for what you were working on at the time?
QUAKE: I had been doing the work in microfluidics and finding applications in different areas of biology. We had just started building the first single-molecule sequencer and were thinking about getting into genomic questions. I knew that I wanted my research to get into other areas, like into cell biology. That was part of the attraction for me, was being at a kind of nexus of different research areas and to be able to graze on that. I knew I wanted to do that; what I didn't anticipate was how much fun I'd have with the clinicians, being here in a hospital, a medical school, and having that also basically right next door. All the doctors get their coffee here at the Clark Center, and I run into them all the time. That created all kinds of interesting research opportunities.
ZIERLER: You mentioned going from sequencing to genomics. Intellectually and scientifically, if you saw this as a real one-two punch, that you had to do sequencing as a foundation point, perhaps, to getting into genomics?
QUAKE: Yeah, because the field was going through this revolution, and that there were these efforts to sequence the human genome, and people appreciated that using existing technology, it was going to be extraordinary expensive. Which it was. NIH spent the money, a couple billion dollars, to do it, but there was an opportunity to develop novel sequencing technologies that would lower the cost dramatically. Many people were interested in that, and I was one of them.
ZIERLER: What were some of the big questions in genomics? Where did you want to jump in?
QUAKE: The first is, could you sequence the human genome in a way that's reasonable to do it for multiple people, for medical purposes? What had been done for a billion dollars was to get the average consensus genome, but you want to re-sequence people, and could you do that in a way that was cost-effective? That all came to pass. People wanted to do genetics at scale, on human populations. The kind of genetics you do with bacteria, they wanted to do with people. There was a tremendous effort to develop the tools to do that. Then there were many diagnostic opportunities. That was the direction I ultimately took, was getting into liquid biopsies. I kind of realized that sequencing a whole human genome was going to go one direction. A lot of people were raising money to do that. I thought I'd try to turn into a less busy area, and that's how I got into non-invasive prenatal testing.
ZIERLER: Just some clarification points in nomenclature. When we talk about sequencing the human genome, there's a singularity that's implied there. What exactly does that mean? Is there a human genome? Do we all have our own distinct human genome? What does that mean?
QUAKE: We all have our own distinct genomes. We're 99.9% the same, so we differ roughly about a part in a thousand, from each other, in genome. When people say sequence the human genome, they mean sequence the average human genome. It was actually a mixture of people put together to create a genome that, but for those part per thousand, represent the shared bits, that we all have.
ZIERLER: When we're talking about personalized medicine, are we trying to get to a point where we can sequence that 0.1% that's distinct? Is that really what is going to get to truly personalized medicine?
QUAKE: Yes, that 0.1% is exactly the part that is the personalized part of personalized medicine.
ZIERLER: How expensive will it be? It seems like obviously the vast majority of the work has already been sequenced. What is so difficult, what is so expensive, about getting to that 0.1%?
QUAKE: It has been basically technology costs driving the whole thing. The first genome was Sanger technology; it cost a couple billion dollars to do. When I got Helicos launched with single-molecule sequencing, did my genome, that was about $50,000. That was a big improvement. Nowadays it's a couple hundred dollars per genome. So it has really been dramatic, dramatic, the decrease in cost over time.
ZIERLER: Your pivot to diagnostics, was that directly related to advances in genomics?
QUAKE: It was more that we had done my genome, and I was trying to figure out, "Should I do more genomes and think about trying to do this at scale, or should I do something more creative?" I decided to do something more creative. When I became a parent, my wife had amniocentesis done. It was like stuck in my head, "This is a terrible thing to do. To ask a diagnostic question, you're risking the life of the baby." I stumbled across some literature on a phenomenon called cell-free DNA that I realized, in combination with sequencing or other molecular counting approaches, could lead to a powerful blood test that would replace amniocentesis. I got onto that, and we sort of opened that field up.
ZIERLER: I'd like to ask about some of your other affiliations around campus. Tell me about the Cardiovascular Institute.
QUAKE: Oh, I think I'm on that so I can be part of their training grant. [laughs]
ZIERLER: I see, I see. What about Wu Tsai, both the Human Performance and the Neuroscience Institute?
QUAKE: The Neuroscience, I have a small grant from them, and so they must be including me in something. That's the Wu Tsai. The Human Performance, again, I provide informal advice to them, but not closely involved in their day to day research.
ZIERLER: What about the Cancer Institute at Stanford? Are you involved there, more?
QUAKE: I collaborate with a bunch of people in that, for sure. Mike Clarke and I, and Irv Weissman and I, had tremendous collaborations. The cell biology stuff I was talking about, that all came to pass with them, and we were dissecting tumor complexity using these single-cell microfluidic tools I had developed, and that was my connection with them.
ZIERLER: What are some of the exciting frontiers in cancer research from your perspective?
QUAKE: Well! Irv and I began tracking the natural history of mutations that led to cancer in a given patient. That had never been done before, in an actual human, measuring what was the order of mutations that happened before cells became tumor cells. We figured out ways to do that, in leukemia. Then Mike Clarke and I were working on solid tumors, using single-cell approaches to measure transcriptomes and look at the various types of cells, the heterogeneity within the tumor, and discovering drug targets based on that heterogeneity. We've now got three molecules in the clinic for various potential cancer therapeutics.
ZIERLER: There's always so much hope and so much disappointment with what cancer treatment can do. Just in sort of the broad sweep of history, circa 2023, where are we now? What feels really advanced to you, and in what ways are we still in the stone ages?
QUAKE: Within cancer?
QUAKE: Interesting question. I think we're in this golden age of immunotherapy right now, and that has been amazing. That is where there's tremendous progress at the moment, and we're seeing the benefit of that. Interestingly, that didn't come out of any of the cancer genomics. That was a couple of cell biologists working by their lonesome for a couple of decades, and that all has now reached fruition. That has just been an amazing story. That's the highlight of cancer right now. More generally, the cellular therapies that are surrounding that are, I think, going to be very promising going forward.
ZIERLER: Do you think chemotherapy at some point in the future is going to be abandoned as primitive or even a barbaric approach to cancer treatment?
QUAKE: I wish it would. I don't think we're there yet. The truth is that many of these small molecules are the best effective therapies we've got. Not all of them are barbaric. I think people with these more targeted therapies are getting the things where the toxicity is a lot lower. These are the drugs that Mike and I are involved in, actually—fairly low toxicity. They're going to remain an important part of the arsenal, for sure.
ZIERLER: What about diabetes research? Are you involved there at all?
QUAKE: I'm not, but one of the companies I helped start, Clearnote Health, they are developing—they have developed—a blood test for pancreatic cancer, which it turns out, if you've got new-onset diabetes, you're at enormously high risk for pancreatic cancer. This is something that hopefully all people with diabetes are going to be tested for shortly in order to catch those cases that have cancer.
ZIERLER: An overall question about all of the ways that your research has been translated both into clinical applications and for startups, when is it important for you to be closely involved in launching the business, and when, either as a matter of just your bandwidth or not having the business expertise, when do you hand that off to a CEO?
QUAKE: I try to get a CEO as early as possible. I've never run any startups. But early on, I'm very closely involved, because I'm close to the science. I understand the ins and the outs, and have a very good sense of where it needs to go next. So I can be helpful. But as the companies mature, and they're deeper in their clinical trials or technology development, I'm obviously less close to it, and it's harder for me to provide useful advice. At that point, it's more higher-level board advice rather than direct scientific advice.
ZIERLER: For your graduate students and postdocs who want to go into the startup space, what are the considerations, the firewalls, that you have to put up, to make sure that you have these clear delineations from your Stanford faculty life and all the things that are happening in the business world?
QUAKE: We watch that very closely. These questions of conflict of interest are important. When we start a company in the area, I stop the research in the lab in that area to avoid conflict. So, we try to create a very clear line between them. When the students are in the lab, they're students first. I've had cases where they want to go be at a company, and if they want to do that, they take a leave of absence, so there's again a clear line between what they're doing as part of their academic studies and what they do in their own entrepreneurship.
ZIERLER: I'm not sure if you've ever run the numbers, but generally, are students that come to you about equally split in terms of their interests, what they want to do afterwards? Going into the academy, going into the startup space—what do those numbers look like?
QUAKE: It is roughly an equal split, I think, yeah.
ZIERLER: Is it about the same in terms of, a student that's interested in becoming a professor versus going into business, do their dissertations, does their research in your lab, do they look very different, even from that perspective?
QUAKE: No, not really. In my experience, the best way to start a company is to do absolutely first-rate research, and so that's the foundation. I tend not to work on incremental things. The folks I've had in the lab and have gone on to start companies, it's often on the basis of very prominent papers, published in the top journals, just like the ones that go into academia.
ZIERLER: When COVID hit, first of all, what did that mean for running a lab? When did you shut down? How did you manage things?
QUAKE: That was complicated, for everybody. Stanford just shut essentially everybody down for two or three months, unless you were a doctor treating COVID patients, essentially. Then they got it reopened, and did a pretty good job with that. There were limitations on density in the lab and things like that, but they kept it going. So, did a good job with that. I, at the same time, was running the Biohub in San Francisco, the Chan Zuckerberg Biohub, along with Joe DeRisi. But as the co-presidents, we had to make the decisions, do we shut down or keep it going? What are our protocols? What are our testing things? I have a lot of sympathy for people who were running universities having to make those decisions, and I know it wasn't easy. We kept the Biohub going too, because we ended up setting up a testing lab, for COVID, and so we had people come in, running that lab, and we had to figure out how to have lots of people come to work every day and do that safely. Which we did, successfully.
ZIERLER: Did you get involved at all in COVID research itself? Immunology, virology, that kind of thing?
QUAKE: It seems like everybody did, because it was the way to get your lab reopened. [laughs] Definitely all of a sudden, some of my students and postdocs were finding collaborations analyzing some patient samples, things like that, and that wasn't unusual. I would say the thing I'm most proud about, during that period, is not what my group did, but what my former student did—Carl Hansen, who was a student of mine at Caltech, and became a professor at the University of British Columbia, and then started a company called AbCellera, based on the work originally we had done together on microfluidics for single-call analysis. He refined that and built a company to do antibody discovery based on that. Part of what their business was, they had grants from the Department of Defense and NIH to practice for the next pandemic, so they were very well positioned when COVID happened. So, they got one of the very first North American blood samples, and over the course of a weekend, discovered hundreds of antibodies against COVID, and partnered with Lilly, and the very first approved COVID drugs in this country were AbCellera's, were Carl's. An amazing story! Millions of people took the drugs. Tens of thousands of lives saved. It's just incredible. It's an amazing story, and it's a Caltech story.
ZIERLER: So many amazing things to learn, for good and bad, from the COVID crisis. Do you have any strongly felt opinions about how COVID originated?
QUAKE: [laughs] I think we'll never know, just because China is not being forthcoming, and there's no ability to do the scholarly research on the origins there, really. I have a little principled calculation that's probably not worth going through now, but on balance, I think it's likely to be some sort of lab leak, of a sample that was mishandled, or something like that, that happened. It's just too striking that it happened in this city that had this coronavirus research lab in it! [laughs]
ZIERLER: Is that a way of understanding also why COVID was so different than other coronavirus epidemics, why SARS and MERS, for example, didn't become a global pandemic? Does that complete the puzzle for you?
QUAKE: No, because if you look at the last several SARS outbreaks, they were lab leaks, and they didn't turn into pandemics. There have been lab leaks of SARS, and it didn't turn into global pandemics, so it doesn't all connect that way for me.
ZIERLER: What does the biology of the COVID virus tell us? What makes it different? Whether lab leak or not, why did it become this global crisis?
QUAKE: I think the key part of that was the fact that you're asymptomatic over the first few days of infection. That was what made this one so pernicious and different than the others. That the virus evolved to do that is what made this just the giant world disaster that it was.
ZIERLER: This is as much a generational question as anything else, but all of the vaccine skepticism, all of the misinformation, were you prepared for that? Did you think that's where American society was in 2020?
QUAKE: Ugh, gosh, I would say I was not prepared for it. I was as surprised as everybody, I think. You can see that public health is not a science. It's science, and human psychology, and policy, all mixed together. People say, "Follow the science." It's not quite that simple. Public health is a much more complicated beast than that. And our infrastructure is quite antiquated in this country. Although I have to say, the Europeans didn't do much better, in the end, with maybe a couple exceptions. The ones that really did well, the countries that did well, were the ones that dealt with SARS and MERS 20 years ago. They had the near miss and they put into place very rigorous public health, and people bought into it, because they knew there was a near miss. Those were the countries that I think did the best in the early days of the pandemic, that had that good public health infrastructure, because 20 years ago, they had had a near miss.
ZIERLER: What about some of the takeaways in terms of science communication and building trust about what it is actually that scientists do?
QUAKE: That's a huge issue that is I think separate from the pandemic. We just live in an age where it's hard to figure out what facts and truth are. Misinformation, disinformation, is a part of our life, and it's only going to get more challenging with all of these generative AI tools. How are we going to know what's truth? I think that is like a fundamental challenge of our time, right now. I don't have any answers.
ZIERLER: The question about a universal vaccine for all coronaviruses, what do you think the prospects are for that?
QUAKE: There is some promising scientific work, for sure, and we'll see what happens as they reach the clinic. I don't think you can rule it out.
ZIERLER: A big question—the HIV vaccine remains elusive, and this miraculous mRNA vaccine for COVID happened, as they say, at warp speed. Why? How do we understand these things?
QUAKE: The viruses are very different, in what they do, and the kind of infection. HIV is just so good at hiding from your immune system and it takes over your cells. Its genome integrates there. So it's a very, very different sort of interaction, and strategy for infection.
ZIERLER: As a mentor to graduate students, there was so much difficulty, particularly for international students who couldn't come to the lab, they couldn't go back to their home country. Just on a mentorship, psychological level, what kind of difficulties did your students deal with in those dark days in 2020 and 2021, and how did you help them?
QUAKE: The time when the lab was closed was the hardest, by far. We were having more than weekly Zoom calls with everybody, and you could see that the mental health was deteriorating, as these guys were locked in their apartments, couldn't go out, often very small living spaces, frustrated that they're falling behind in their studies. It was getting hard on people. I did my best to stay in touch and to try to reassure them. I told them, "No one is going to get fired. Everyone can do a longer PhD or postdoc. There will be no time limits. We'll take as much time as it needs. Don't worry about that. Let's just get through this." When the lab reopened, everyone perked up. They could come in, even if it wasn't every day or all day, just they could come in and do things again—that was a real turning point for everybody. Then, we found ways to get together in person. I began to have group meetings in my back yard, outdoors, with chairs that were spaced three feet apart [laughs] and all this kind of spacing stuff that we've forgotten about now. But we were out there with rulers, measuring it! It really meant a lot to people to be able to see each other in person.
ZIERLER: I know how much momentum is important for lab work. Are you concerned that any science was lost during those months, or were you able to pretty much pick back up?
QUAKE: Not my group, but some groups had severe losses. They had to sacrifice all their animals. Nobody could come in and maintain the animals. There were real setbacks for that type of research. For my group, in some ways it was a productivity boost, because people went and analyzed all this data that they had sitting around. There's a little bit of a tendency to take data, then take more data, then take more data, without fully analyzing the last thing. Everybody had to sit down and analyze all the data that had been there, so that was actually good for productivity.
ZIERLER: I want to ask about ethical considerations as they relate to genomics and playing god and gene editing and things like this. Have you dealt with these issues? Have your students? What's the best approach to curiosity-driven research with whatever guardrails you think are appropriate?
QUAKE: These are super important questions. When I sequenced my genome, partly I did mine because I felt like I could take the risk and make an informed choice, and I'm not sure I want to ask other people to do it. At that point it was so new that we didn't know what the implications would be. For my part, I had a little bit of confidence, because the Genetic Nondiscrimination Act, GINA, had just been passed, so at least there was a legal fig leaf of protection. But it was—a non-trivial decision. I spent a bunch of time thinking about it. Then when we did the clinical annotation, we had the genetic counselors there in the room, and it was a very interesting, fun situation, because there were all these people, bioinformatics and genetics experts, trying to annotate my genome, and I was in the room, too. Which is not typical. But I was there because I had the most technical knowledge about the quality of the genome and how it was put together. So that was a very unusual situation that was not typical, and it was fun, we got through it. I think we've now come a long ways. It's a much different time in terms of how you would consent people, and what we know the implications of knowing your genome are. That has become I think much more well defined, and there's I think broadly accepted standards, and that's great. On the genome editing side, it's still earlier days, I would say. I was tangentially caught up in the big CRISPR baby scandal. The fellow who did that in Hong Kong was my former postdoc. When he was in my lab, he didn't work on anything related to genome editing. He worked on bioinformatics of immune repertoire sequencing. When he went and started his faculty position, he decided he wanted to change the direction of his research. He had told me he was interested in doing this, and I had told him in no uncertain terms it was a bad idea.
ZIERLER: Why? Why was it a bad idea?
QUAKE: It was hard for me to see any clinical benefit in it. It was clear he was interested in it for the scientific notoriety and not because there was going to be great clinical benefit. He was looking for ways to try to find that benefit, but he was struggling. It was clear I wasn't going to be able to dissuade him, after a while. He was just like—tuning me out. I had no control or anything over it. He had been my postdoc ten years earlier. He's in an independent career in another country. So I just told him, "Look, if you're going to go down this path and you're not going to listen to me, make sure that you are being very careful about the consents and the ethics and the institutional, the human subjects review part of it." He said, "Oh, yeah, I'll do that." Later on, he told me he did it. What emerged much, much later was that he had cut corners, and he had broken all kinds of rules, and that's why he went to prison.
ZIERLER: The ethical considerations—if you achieve consent from parents who want a so-called designer baby, what dangerous path does that put us down?
QUAKE: That's not enough. It's not enough just to get consent from the parents. You have to get consent from your institutional review boards, and there's a whole set of criteria that have to be met, from the institutional side, to get permission to do things like that. One of them is clinical benefit. There's others as well. So it's not just a matter of you convincing parents to make a designer baby. There are many other considerations that come into play to get permission to do research like that.
ZIERLER: Just a cultural and policy questions, are institutions by and large resisting this line of research? Is that not a path they want to go down?
QUAKE: Germ line editing? Yeah, I think very few people are doing that, if any. It's more about editing somatic cells that are not going to be put in the next generation. That's where the vast majority of genome editing research is, probably all of it. I think there are a few exceptions, that actually predated what happened with CRISPR, which have to do with mitochondrial transplant. Carl Zimmer wrote a beautiful column about that, that I thought was super interesting, and very thoughtful. So, there's this other funny little corner of mitochondrial replacement therapy that was done before CRISPR and is still being done, and for reasons that are medically justifiable, in my opinion.
ZIERLER: You mentioned institutional resistance. What about at the policy level? What are some of the federal responses to these issues?
QUAKE: There has been quite a bit of work on that. Most countries have put moratoriums in place.
ZIERLER: Is the basic idea there that there's just a cultural revulsion towards what can become considered a quote unquote super race of babies, if we want to select for whatever are considered beneficial genes?
QUAKE: I'm sure that's part of it. There's many considerations; I'm sure that's one of them.
ZIERLER: The idea that if there's no clinical benefit—what about curiosity driven research, just the tenets of basic science? Does that not hold water in this context?
QUAKE: Well, you don't do that to humans. [laughs] There's respect for individuality and there's all kinds of reasons why you would never do that to humans.
ZIERLER: In talking about all the de-siloing, have you talked to bioethicists? Is this important for you?
QUAKE: Oh, absolutely. When the first CRISPR thing happened, we had, at the Biohub, a group of bioethicists come in and talk about it. It was a terrific discussion, really, really interesting, and super thoughtful people, about what's ethical and what's not. Their view is not as dogmatic as most people would think. It's an intellectually I think pretty vibrant area.
ZIERLER: Before we now go back and reflect more on your time at Caltech, I certainly can't burden you with a discussion of all the ways you've been honored and recognized, all of the awards, all of the societies you've been a part of. But I do want to ask, of all the scientific societies that you're a member of, are there any where the membership is not just more than an honorific, where it makes connections, it makes things happen that are actually scientifically useful for you?
QUAKE: That's a great question. My relationship with these societies has changed over time—initially honorific, now more engaged scientifically, especially with the National Academies. It is never just one thing. It definitely evolves with time.
ZIERLER: Two that are recent that I do want to ask you about—the Max Delbrück Prize from the APS—Max Delbrück as a visionary, a pioneer, coming at physics and biology at a time when very few people were—there's obvious connections with your career, your purview. What did that mean for you? What did Max Delbrück mean for you?
QUAKE: Oh, it was just such a terrific honor. When I first started at Caltech, I was trying to put together a biophysics program, and I made Delbrück be the centerpiece of it. I had a little poster with him in it, and was well aware of his wonderful contributions, and that I was fortunate enough to be in his place. To get the Delbrück Prize was just a great way to close the circle there. It felt great.
ZIERLER: Another one—this is an example of a super prestigious prize that's obviously not as well-known as the Nobel—can you talk a little bit about the Sackler Prize, why it's such a great honor, and what you were being recognized for?
QUAKE: There's a Sackler Prize for Biophysics. That's the one you're talking about?
QUAKE: Again—well, Sackler is a very complicated story these days, and I think that Prize may be changing its name like so many other of the Sackler philanthropic things.
ZIERLER: Because of the opioid crisis?
QUAKE: Exactly, yeah. But, again, administered by Tel Aviv University in Israel, an international prize, and just wonderful to see biophysics get recognized. Because there's not that many prizes in the field. To share that with the other laureates was also a real pleasure.
ZIERLER: Just to bring the story right up to the present, right now, June 2023, what's the most important things you're working on? What's on your plate these days?
QUAKE: I have this new career in science philanthropy, so making sure that we're doing the best we can do for global science at CZI is the biggest part of my day. I still have a small research group that I run, and that's like oxygen, to be able to do research. But for sure the vast majority of my attention is seeing what I can do to help scientists around the world achieve their dreams and have breakthrough discoveries. It's an awesome, awesome thing.
ZIERLER: Is that to say that you will cling to the science as a mental health issue for as long as you can, even if you get pulled further and further into science leadership?
QUAKE: Absolutely, absolutely. I am never giving it up. I am never giving it up! I'll put it that way.
ZIERLER: Good, good, good.
QUAKE: It may get smaller, but it's never going away!
ZIERLER: As time becomes an increasingly valuable resource, what are the kinds of science issues that no matter how busy you are, no matter how many directions you're getting pulled in, that's going to be the thing that grounds you?
QUAKE: These days, what I'm really honing in on is evolutionary questions, in particular the evolution of multicellular organisms. We spent all this work building these cell atlases. We understand cell type now with detail never before seen. We've done this across many different animals now—fly, mouse, human, lemur—and we're starting to apply those same techniques to early animals. The belief I have is that it will help us understand the evolution of multicellularity in a very deep way, so I'm fascinated by that right now.
ZIERLER: Let's now go back for some more reflections on Caltech. One thing I've been meaning to ask you about—you're so uniquely positioned to discuss this—as you well know, Caltech's tenacious insistence on remaining small—so here we are, in the era of big science, which obviously has now gone on to biology. How does Caltech retain its smallness but also do world-leading research? How do you see, from your experiences, Caltech continuing to square that circle?
QUAKE: Caltech has been very good at that. I think part of it is because it's just very good at finding excellent scientists. Whether they're working on big projects or small ones, that's the key to the success. For example, astronomers, LIGO folks—they work on very big projects at a small place, and they do that through large consortia, and that works really well, and Caltech has displayed a lot of leadership in that field. That's awesome. A lot of science is still driven by small groups. Not all science is big science. Many discoveries come out of smaller groups, and Caltech, by having just absolutely terrific faculty—Frances Arnold never ran a huge group, won her Nobel Prize for her amazing work in molecular evolution. Classic Caltech story.
ZIERLER: What about from a faculty recruitment perspective? Obviously Caltech wants the best, Stanford wants the best. But at Stanford, a prospective professor can look and say, "There's eight or nine other people that are working generally in this area," whereas Caltech, that might not be the case. Just generationally, do you think the next generation of younger professors, assistant professors, do they need that sort of similarity, or is that not necessarily the case?
QUAKE: I don't think so. I think some of them may like being "the person" in their field at a place. That kind of personality goes well at Caltech. I also just think, Stanford has got a lot of great people, but they're all competing for the same graduate students. So if you're starting out [laughs], you receive less attention, as a place to land graduate students, whereas at Caltech, everyone wants to come work for the young people, and the fact that you don't have eight people in your area means that people who are interested in your area, they'll come to you.
ZIERLER: What about the way Caltech supports its junior faculty? From your own experiences, from what you see at Stanford, where is some overlap, where is some real distinction?
QUAKE: The great thing about Caltech from my perspective is it lets you alone to do your thing. They don't overmentor you, and that's a positive, I think, that you're not caught up in lots of bureaucratic mechanisms of one sort or another. When I started at Caltech, I was invited to meet the division chair, John Seinfeld, a kind of welcome-to-Caltech meeting. Went to his office. I asked him, "What do I need to do to be promoted here? I want to be successful." He said, "Just do the best science you can." I thought he'd say, "Be on committees, be a great teacher," duh-duh-duh-duh. He said, "Just do the best science you can." That is the only career advice I got at Caltech! [laughs]
ZIERLER: [laughs] It's good advice!
QUAKE: And it turns out, it's pretty good advice! Right? I pass that on all the time to the young professors we hire here and the ones I talk to elsewhere. It's really quite simple. Don't get caught up in all this other stuff. Do the best science you can. It tends to work out. Applied Physics hadn't hired—that was my department at Caltech—they hadn't hired a new faculty member in a decade. They didn't know what to do with me. There was no one to talk to or anything. I had a few senior faculty who went out of their way to mentor me, research-wise, and we collaborated—Axel Scherer, Frances Arnold. They were awesome. They acted as mentors and collaborators. But as a department, there was no structure. The secretaries taught me how to write grant proposals. [laughs] I'm very grateful to them for that. But that's the kind of place it was. And that wasn't a bad thing. It really wasn't.
ZIERLER: When you were there, was there any rumblings or attempts at making Los Angeles a biotech hub, or was that before your time, really?
QUAKE: There was. Larry Gilbert, who ran the Tech Transfer Office, spent a lot of effort trying to pull things like that together. He was very active about matching faculty entrepreneurs with investors. He was good at doing that on a one-off basis. A lot of good things came out of that.
ZIERLER: You mentioned of course your current pleasures at having the clinical environment right there, getting to schmooze with doctors. Obviously Caltech does not have a hospital or any affiliation like that. Do you see that as a strategic blind spot, or is that just another way that Caltech can punch above its weight?
QUAKE: I think it's just different, and it makes Caltech—it gives it certain opportunities that it wouldn't have if it had a medical school. They tend to be big. They suck the air out of the room. They're financially very challenging to deal with. They're positive in some ways, negative in others. Caltech is good at taking advantage of not having a medical school. They just partnered with the Carnegie Institute for Science, for example, which is a great match. I'm now a trustee of the Carnegie Institute, and I'm so thrilled to see those two institutions come together, both of which are great at doing science, being small institutions and punching above their weight in different ways.
ZIERLER: What are some of the exciting things that could happen as a result of this partnership?
QUAKE: On every front. Carnegie has a great history in astronomy, on Las Campanas Observatory in Chile, and Caltech has great astronomy, so there's going to be tremendous resonance there. Carnegie is consolidating all of its biology operation in Caltech, and figuring out that frontier in the absence of a medical school I think is going to be great. Choosing biology that is not related to humans but other aspects of the biological world, to find excellence. That's going to be awesome.
ZIERLER: As a faculty member at Caltech where you were just given this advice to do great science, do you think this is like a road not traveled—would you have pursued the same science more or less if you were at any institution, or was there something specific about that freedom at Caltech that put you on the path that it did?
QUAKE: It's hard to do the counterfactual, but I will say that it's also hard for me to imagine doing the things I did at Caltech, had I been elsewhere. I have another story about that. When I was an assistant professor, I remember we had a speaker come through; it might have been Tom Cech, Nobel laureate, discovering ribozymes, and running HHMI at the time. I was in applied physics, and yet they put me on his schedule because they knew I was interested in biophysics. He met me, and I got the benefit of talking to him, and I was invited to the dinner. And it was one of these boozy dinners, with a couple of bottles of wine into it, a bunch of people—must have been 12 people there—and I was sitting next to Peter Dervan. As the dessert course was coming around, and it was all a little like this, he turns to me and says, "You know, the great thing about Caltech is, you can do whatever you want, as long as you're good at it!" [laughs]
ZIERLER: [laughs] That's great!
QUAKE: There was some deep truth there! Because there are many stories of Caltech faculty members who changed directions radically and went on to do great things in other fields. There was this sense that you could do that there, but you're being held at a very high standard. I took that to heart. There's something special about Caltech.
ZIERLER: That gets me to the point of our connection. Rob Phillips talks so really lovingly about how he got to Caltech and you were just so profoundly important. He mused that he had never touched a pipette before, and there you were, showing him the ropes. I wonder if you can talk about what Rob Phillips meant for you, and how you got him on this path that he's on now.
QUAKE: Rob is an extraordinarily close friend of mine and someone I respect enormously as a scientist. He is the best scholar I know. I mean, he has read more of the primary literature of all of science, never mind the fields he's expert in, than anybody I know! It's truly remarkable. They just—they don't make them like that anymore. He's an example to all of us. Again, the example of Caltech—the strength of a small place—they were recruiting him in Mechanical Engineering, because he had been collaborating with Michael Ortiz, and Ortiz had brought him in. Again, I was on his visiting schedule, because he was interested in biophysics, and he asked. That was when I met him. He said, "Hey, my little secret is, they're bringing me here for solid mechanics—that's what I've been doing for years—but I think this biology stuff is interesting. I want to change my direction." I said, "Great! Let's talk about it." One thing led to another. So, when he came, I offered to let him hang out in my lab, to learn how to do wet bench biology and biophysics. In part, I was passing it onward, because Axel Scherer and Frances Arnold had helped me out when I started, and made their labs available to me. It was my turn to pay it back a little bit. To help Rob understand what it was to do experiments, because he had been a theorist before that, and a computational person, I let him hang out in the lab and work with an undergraduate for the summer. He learned how to pipette. He was really interested in these single-molecule biophysics experiments, so I said, "All right, go do them yourself." That set him on a trajectory that has been profoundly impactful for science and great for his career. He has written several books, published beautiful papers. We still talk, a whole bunch. It has been one of the great pleasures of my career to count him as a friend and a collaborator.
ZIERLER: Do you remember specifically what your lab was involved in when he became an honorary student in there?
QUAKE: [laughs] I remember he was working with an undergrad named Vincent Auyeung. I don't remember the details of the project but it probably involved sticking molecules to beads, because Rob was wanting to do these single-molecule force measurements, and that was sort of the key thing for that.
ZIERLER: Given his wide-ranging interests and background, what does that tell us about what makes a great scientist, as you see what he has accomplished?
QUAKE: It's that wide ranging curiosity, and a relentless dedication. He is absolutely relentless intellectually, and that is such an important piece of the puzzle.
ZIERLER: I bet he was one of the reasons why it was so difficult for you when you decided to leave Caltech.
ZIERLER: Have you ever collaborated, or you just more informally keep in touch?
QUAKE: We've written things together, more along the lines of review articles, opinion pieces. We're collaborating right now on a project to understand the regulatory structure of E. coli, so we actually have weekly calls with our postdocs and students, and I'm enjoying that. He is helping me out at CZI with the theory program, and we're going to see where that goes. He has helped me organize a conference every year on Frontiers in Biophysics. That has been a ton of fun. So, we talk a lot about science. I've given him feedback on his books, especially as—he's trying to bridge from the biophysical view to the genomic view, and so we have very fun conversations about that.
ZIERLER: To wrap up our portion just talking about Caltech, have you kept up with Caltech research over the years? Have you followed what's going on?
QUAKE: I have. Absolutely. At a distance, but it has been awesome to see the continued success. Caltech continues to hire great faculty members. I was just on the call before this talking to one of my former students, who is now a postdoc at Caltech and is working with Michael Elowitz and doing great things. They've got an awesome paper. He was telling me about it. I'm super happy for him. He's going to go on and be a great faculty member somewhere, there's no doubt.
ZIERLER: For the last part of our talk I want to ask a few broadly retrospective questions about your career, and then we'll end looking to the future. I want to start first by asking, what has been most fun for you? Between all of the students and the papers, was there a discovery or an aha moment that was just more exhilarating than anything else, that really sticks out in your memory?
QUAKE: Oh! There has been so many. What's the most fun is being there in the lab when there is a new discovery and we figure something out. I've been fortunate to have many of those through my career. When you find something like that, and you've made some discovery ahead of the rest of the world, and your head is spinning with the implications, it's great. There have been times when that has happened in the single molecule field, in the microfluidics area, in the single-cell genomics area, in the diagnostics, liquid biopsy stuff. All of those, there have been moments that—it's addictive. You want to find more of those.
ZIERLER: Between instrumentation, computation, and materials, what have been the real game-changing technologies for you?
QUAKE: Over the course of my career, it has been the ability to manipulate and image molecules. The ability to sequence molecules. The ability to automate biology with valves and pumps and the chips. All of those have been so important, technologically.
ZIERLER: In the clinical world, not being a medical doctor, being a basic scientist, what have you learned that has advanced fundamental research for you?
QUAKE: It's interesting, that when I came into this being a physicist, not being a biologist, I thought the biologists were defining the problems that were important for medicine. But it turns out, the biologists are picking certain problems, but doctors have another set of problems that they think are important. That is why it has been so fun to talk to them, about the stuff that really matters for patients, and where there's diagnostic or therapeutic—that has been very enriching for me intellectually.
ZIERLER: You have so much experience working with philanthropists and of course government grants. What's the best way to deploy funds from both of those sources, and is there any difference, or are dollars dollars?
QUAKE: Oh, there's a huge difference. This is something I deal with as Head of Science at CZI, that we have this amazing, amazing endowment. I mean, $20 billion, right? We are as big as the Howard Hughes Medical Institute, bigger than all but five universities in endowment. And yet it's a drop in the bucket. Our annual spend on science is like 1% of the NIH budget. So, what we do could never replace government funding, ever. It's so important, what the NIH does, and other government agencies. That's really what makes science happen in this country. A few months into the job, I was having a conversation with Francis Collins, who was the head of the NIH at that point, and he reached out to me. He said, "I'd like to partner with you, and figure out what we can do together." I pointed that out to him. I said, "Francis, why do you even bother with us? We're such a small part of what you do." He said, "Yes, but you can do things that we can't do. You can take bigger risks than us, and you can be more nimble. It's for that, that I think we can have a really good partnership." I think there's a lot of wisdom in that. That philanthropy, even though the dollars are smaller, we can take gigantic risks, we can derisk areas where it becomes then justifiable to spent taxpayer dollars on them, and we can move very quickly in ways that larger institutions struggle to do. That's our special niche.
ZIERLER: Operating at the frontier, there are so many of the things that you do that have a long future ahead, in terms of potentials and clinical applications. What have been some of the things that you've been involved in where you really see it as a closed chapter? You did the research, you made the discovery, it made its impact, and it's sort of a complete story?
QUAKE: That's a great question. Single-molecule biophysics, measuring forces on molecules; I'm done with that. The field has still interesting things going, but my part of that story is done. In microfluidics, my part of that story is done. They just had the Gordon Conference in Italy this year, and I felt a little envious of my colleagues who were going there. But I'm not really contributing to that field anymore. My part of it is done, There's great things still happening, but I'm moving on to other things. I think NIPT and many other aspects of diagnostics, my research contributions to that are done, and my contribution is now my involvement in companies that are doing clinical trials to try to bring new tests to the market. Those are the areas that I think are bookended for me.
ZIERLER: It raises the question, what are those decision points for you? Obviously the work continues, there's always more science to be done. When do you make that call that your time is to move on to something else?
QUAKE: I like to get into a field early, before other people realize it's important. I've been able to do this multiple times in my career. We do work that helps people appreciate, "Hey, there is something really awesome here," and the field then catches fire, and lots of people jump into it, and then it's time for me to leave. [laughs]
ZIERLER: Do you think that style has attracted a particular personality type of student that wants to work with you, based on that?
QUAKE: A little bit, yeah. They tend to come, though, because they're excited about what I was doing, and I convince them, "This new thing is going to be even better."
ZIERLER: Of all the things that you currently have in the air that are poised for success and discovery in the future, what are you most excited about? What has the greatest prospects, as far as you can tell?
QUAKE: Uch! What I'm going to do next week is try to finally write up this paper on evolution of the box camera eye in octopus and humans. That, I'm super jazzed about. We've been sitting on the data for a while. I've been busy with my day job at CZI. But I finally carved out a lot of time to write a paper that's going to be a labor love for me and I'm super excited about.
ZIERLER: If you could share some details pre-publication, what's the impact? Why are you so excited?
QUAKE: It comes back to this question of understanding evolution from the perspective of cell type and not from the perspective of gene. You look at the literature, especially around convergent evolution, when nature has evolved the same things twice, and you say, "How can that happen? The odds seem astronomically small. There must be some constraints we don't know about, and what's the nature of those constraints?" We're going to start to get at that now. One of the textbook examples is the physics of the box camera eye, which both humans and octopus share without having a common ancestor that shares it. So it has evolved twice. We have some ideas about why that has happened, even though it seems like it should be very improbable.
ZIERLER: That's to say that the field of cellular evolution is really at an early stage? There's a lot to learn?
QUAKE: Correct, yeah.
ZIERLER: What are some of the open questions that might be answered in the future?
QUAKE: How do we evolve different cell types? How are they repurposed? What are shared ancestors, and what are new ones that have evolved that are different between organisms?
ZIERLER: Finally, last question, looking to the future. As you indicated, it sounds like an increasingly bigger part of your overall portfolio is going to be supporting other scientists. What's most important to you? How can you serve as a force multiplier with deploying these funds, with deploying all of your wisdom and experience, so that the next generation of science is as well prepared as possible for success and discovery?
QUAKE: Part of it is finding those high-risk areas, emerging areas, that we were talking about earlier, and being selective about those. Part of it is just finding great scientists, and resourcing them and empowering them to chase their dreams. That's important.
ZIERLER: This has been an excellent series of discussions. I'm so glad we connected through Rob Phillips. I want to thank you so much for doing this.
QUAKE: It was a ton of fun. Thanks for spending the time.