M.G. Finn, (BS '80), Organic Chemist, Chemical Biologist, and Explorer of Viral Evolution

In the discussion below, there is a funny and powerful lesson about focus and resilience in the formative years of a scientific career. In Fred Anson's electrochemistry lab, M.G. Finn made a mistake with a vacuum line, causing a small and explosion and a quick trip to the hospital. Finn relates the amusing and poignant image of the very tall Anson and the very short Sunney Chan bounding across the hallway to visit him, where they were relieved to see that his wounds were only superficial. The experience did not alter Finn's love of chemistry that got him to Caltech as an undergraduate, and his experiences - especially his appreciation for the deep partnerships at Caltech between chemistry and biology - have stayed with him for life.

As a graduate student at MIT, Finn joined the lab of Barry Sharpless, and his narration of the revolutionary approach of click chemistry is an immersive and accessible explanation for why this work was so deserving of a Nobel Prize. Finn's highly focused thesis work, which had no biology, benefitted from Sharpless's insistence that one must always follow his or her nose to the next interesting problem, and this was the basis of Finn's increasingly diverse research agenda, first at Penn, then at Scripps in San Diego, and now at Georgia Tech. The Finn Labs pursue questions of viral evolution, and Finn's approach toward viruses serves as a key connecting point between chemistry and biology. From materials science to biological targets, Finn is in constant pursuit of optimizing the best chemical reaction, and his mastery of combinatorial synthesis speaks to the fact molecular design is as much art as it is science - and that it has equally powerful value for fundamental research and for the applications that eventually improve human health.

The discussion concludes on the question of mentorship. Finn has been a major beneficiary of interacting with the best mentors, and the dozens of research projects he has completed or is working on begs the question of breadth and depth. In our modern scientific world and all the pressures it demands, what is the right balance to strike for graduate students who want to cover a lot, or drill down on one specific topic? Without hesitation and with reference to his own experiences, Finn unambiguously advocates for the former. In their professional lives, scientists have all the opportunity and expectations they need to cast a wide net; the process of writing a quality dissertation requires expertise on a very specific research question, and the skills and knowledge gained from that focus have limitless value, regardless of what comes next.

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Friday June 28, 2024. It is my great pleasure to be here with Professor M.G. Finn. M.G., it's wonderful to be with you. Thank you so much for joining me.

M.G. FINN: No, thank you for asking.

ZIERLER: M.G., to start, please tell me your title and institutional affiliation.

FINN: I am currently Professor in the School of Chemistry and Biochemistry and the School of Biological Sciences, and I am currently Chair of the School of Chemistry and Biochemistry at the Georgia Institute of Technology, or Georgia Tech.

ZIERLER: Is there a name that's associated with your chair, as well as the James A. Carlos Family Chair?

FINN: No, that's a different endowed chair which I actually just gave up, but held for eight or nine years. That's an endowed chair referring to other activities.

ZIERLER: That chair—there's always a name behind the chair—pediatric technology, I wonder if you could tell me a little bit about the field, and why specifically pediatrics.

FINN: Georgia Tech, about 12 or 13 years ago, established a wonderful relationship with Children's Healthcare of Atlanta, which is the largest pediatric hospital in the Southeast, and the purpose of that partnership was to stimulate research jointly conducted between those two institutions and Emory University's Department of Pediatrics. The pediatrics in that title refers to a wide variety of research areas having to do with enhancing pediatric healthcare, everything from diagnostics, to treatments, to healthcare data analytics, to patient experience in the hospital, and Georgia Tech investigators have been able to solve a lot of problems for clinicians through this kind of partnership. I became involved in that role a number of years ago through our efforts in vaccine development, and then became administratively involved in helping to lead that partnership. So, that's what that talks about. Georgia Tech also has relationships with other pediatric hospitals across the country that started with the one I spoke about, but now have blossomed, and one of my current roles is to try to grow those interactions to bring science and engineering to help people who are out there trying to help kids.

ZIERLER: So, pediatrics is reflective of your interests? This is a field that you're involved in personally?

FINN: It is one of several. I'm actually, of course, not a doc. I'm not a physician. I'm not a pediatric specialist in any context. My lab develops vaccines, and that's naturally a pediatric application, but really that aspect of my endeavors comes from just being sucked into how wonderful it is to just try to help people get together and solve these problems. I typically don't bring expertise to the table; I just bring a little bit of organizational energy and some cheerleading.

ZIERLER: Administratively, the School of Chemistry and Biochemistry at Georgia Tech, what does that mean? How is it set up? And then where does biology fit in?

FINN: Many departments in the world cover both of these subjects, but at some institutions there are separate departments of chemistry and biochemistry. It really is more of a historical relic than anything else, in the sense that many departments of chemistry include biochemists. But in any case, at Georgia Tech, it is exactly what it says it is. It's a department that covers many fields, as chemists tend to do. There is a separate but of course closely collaborative School of Biological Sciences here, and Georgia Tech is somewhat unique in the prevalence of engineering—or rather, I should say, the importance of science amidst a much larger group of engineering activities that go on. Georgia Tech is an engineering institution primarily, but science here, while relatively small, is highly valued, and it's just a delight to be a scientist in an engineering environment, because as far as I look at it, they all work for me. [David laughs] So, it's just a terrific place to be.

A Chemist in Biology

ZIERLER: M.G., your research is interdisciplinary in so many ways. Fundamentally, working at the interface of chemistry and biology, are you a chemist who does biology, a biologist who does chemistry, or is chemical biology really the perfect term for you?

FINN: Those are all fuzzy boundaries. I am certainly not a biologist. I impersonate one occasionally, but of those I would call myself more a chemist who contributes to biology. A chemical biologist is also a fine title. People argue about this, but it's not a very productive argument, nor is it a very intensive one. If you can bring value and if you can talk to different kinds of people, that's all you really need.

ZIERLER: What then is in the chemist's toolkit? Or what is a chemistry type perspective as it relates to your work on viruses?

FINN: I'll talk about this maybe in two ways. One is a set of skills, which is actually the less important one, but the skills that a chemist would bring, that my group brings, is quite simply the ability to make stuff. Most biologists don't have the ability to go into a laboratory and make a new molecule. The ability to make new molecules means that you can make new function—and function is all we think about—and the ability to not have to rely exclusively on the molecules that biology provides, but instead be able to either tweak them or make new ones to tune the properties and the function that you might like. The more philosophical differences, if you will, are many. Chemists look at problems different than biologists, and I have learned this both painfully and delightfully—much more delightfully than painfully through the years. I can tell you some stories about when we started in this interdisciplinary area. But what chemists bring are a few things. First of all, chemists need to know where the atoms are. We need to know structures and the details of chemical entities to a much more detailed degree than biologists, and that brings some key insights. Chemists also are not afraid to mess things up, to play with things, to functionalize, to make something different in order for the pursuit of answering the question you're interested in or developing the function you're interested in. And biologists tend to do that only in limited ways. Mutation is great, but that's about all they have, all that they can bring. So, it's more of an attitude, as well as the tools that you bring.

One of the things that biology does very well that chemists don't is do control experiments. I learned that in a very intensive way early on when we started to do biology, and it has made me a better chemist to think in terms of control experiments. And what I mean by that, for the uninitiated, is to do an experiment that uses a subset of what you're using to try to achieve the result, to make sure that everything you have brought to bear is necessary to achieve that result. If I'm going out and I'm driving a car, I need to know all the five gears are actually needed before I say, "Hey, I need all five gears to get from here to there." I do a control experiment, leave out third gear, and see if it still works. "Oh okay, maybe I don't need that; maybe I've made a mistaken conclusion about what makes the car go." That's a ridiculous example, but the value of doing control experiments to understand what's going on is something that chemists really do learn from biologists, among many other things.

The Evolution of Viruses

ZIERLER: Your look at evolution of viruses, what is the time scale? Are these geologic periods you're talking about? Or is it the life cycle of one particular virus here and now?

FINN: This really hits into the chemistry versus biology part of the discussion. I am not a virologist, and when I write or talk about evolution of viruses, I'm not talking about that most of the time in the context of viral evolution as a biologist would. However, we do try to take lessons from how viruses evolve in a chemical way. One of the easiest to understand, and the most powerful, is that viruses are highly tolerant of changes in their composition and changes in their structure while maintaining their function. Their function is to encapsulate their genome and get into another cell where that genome can be replicated. And viruses are amazing at the ability to change a lot of their amino acids and a lot of their composition and still have that function. Now, why is that important to me? I want to use a virus because it has some certain advantageous biological properties, but being a chemist, I want to change it, to modify it, to optimize it for the property that I'm interested in. And viruses offer a great test bed because biology already teaches us that viruses are highly tolerant to these kinds of changes, and they still maintain their shape and their form and their function. So, that's an example of a lesson from viral evolution that we use. Now, we've taken a step further, and we've evolved viruses in a very silly way, but that's a chemistry friendly way to create whole new families of structures that we can then use, but those lessons give us more information about what chemists can do than they do about viral evolution.

ZIERLER: Does this put you in the directed evolution field?

FINN: It does. It does, and I'm very much a fan of that field and try to contribute to it and take lessons from it. We evolve viruses in different ways than most people do directed evolution, but I would very much—I would aspire to be seen as a member of that field, shall we say.

ZIERLER: [laughs] M.G., is it a useful distinction for you—specifically thinking about vaccine development, your work in diagnostics—do you approach research always from a basic science, curiosity-driven approach? Or are there times where you're really translational in your motivation, where you have an end goal in mind, and you're looking to reverse engineer to get to where you want to go?

FINN: It's almost always a mix of those; it's very rarely purely one or the other. I tend to be more application driven than perhaps fundamental-chemistry or fundamental-science driven, however it's incredibly important to bring an appreciation of fundamental questions to bear. I can give you some examples. In the context of vaccine development, we started with an appreciation of these virus particles and how immunogenic they are, so we've really focused all of our vaccine development work on those particles. But then we had to learn, talk to a bunch of immunologists, go to school, and do a lot of reading to learn about what are the fundamental questions in immunology that we can help either answer or take advantage of to make better vaccines. The target is always make a better vaccine, but I have to go back to first principles to understand how to do that sometimes. So, it really is a mix, and the danger in doing the kind of science that I like to do, which is to bridge between fields, the danger is to not know enough about the field you're moving into. Basically, you're an idiot; you do stupid stuff. We've certainly done our share of that, but I try to avoid that by both learning the fundamentals, as you just asked about, and really talking to the people who've spent their lives studying those questions and developing those questions so that we don't make idiots of ourselves. But the advantage, of course, when you bring yourself to a new field is you're bringing a perspective that people in that field don't usually have, and occasionally you can make a contribution or ask a question in a way that they haven't thought of, and that's where the magic happens.

ZIERLER: M.G., your long-term focus on vaccines, are you surprised that vaccines are such a hot button topic in our society? And as an expert in the field, what is your feeling about being involved in those debates, being out in front?

FINN: I wish I had time to be out in front of them more. It's incredibly important. Am I surprised? Perhaps. I'm of course much more chagrined, depressed, gut punched about it than I am surprised, I suppose. But it's incredibly important for scientists to be involved in these discussions, to try to help people understand what these topics are about. And here's one of the key differences. Science is one of the few professions where we train people to say, "I don't know," and we're comfortable with that, and we celebrate those who correctly say "I don't know" because that's the first step to figuring out something new. The public doesn't work that way. In other professions, you don't get paid for saying "I don't know." You get paid for trying to muddle through and do the job. And people who aren't scientists are in general very uncomfortable with nuance, or uncertainty, or non-firm conclusions, where we in science, that's where we live. So, the ability to try to translate scientific information into ways that the public can understand, without dumbing it down, without avoiding the nuance, but while explaining it in such a way that the public can take actionable lessons from, that's both a challenge—it's very rewarding when you get to do that, and I tried to do a bunch of that during COVID and found it to be very rewarding and sometimes very frustrating. But when you can do it, you really can make an impact in a very different way, so we need to do more of this as scientists, and it's hard these days.

ZIERLER: M.G., your collaborations both in clinical environments and in industry, how close do you get? What's the length of the spectrum between the fundamental science that happens to your lab and ultimately where some of these technologies get applied?

FINN: My group in general, we tend not to have taken stuff all the way to commercialization; we hand stuff off. Although I will say right now I have three of the people in my group who have started a company, and they're into it. They're in the entrepreneur game, and they really do want to take things all the way to the clinic. But in my history, I have not gone all the way there. We work a lot with industry, and I love doing that. I especially love it when our industrial funders are also our collaborators, where we actually do work together. It's great because they have a better appreciation for the practical problems than I do in general, and they also can do things that we can't do and vice versa, but they are of course much closer to the application in the marketplace than we are. Some of the stuff we've done has made its way into the marketplace, but not directly through my lab. But it is very enjoyable to work with people who do.

The Power of Combinatorial Synthesis

ZIERLER: Please answer this as technically as you need to: If you can define first, what is combinatorial synthesis? And more broadly, where are the numbers? What's the quantification of the chemistry and biology that you do?

FINN: Combinatorial synthesis is the art and science of making many different variations of molecules using reactions that maximize the number of molecules you make relative to the number of reactions that you do. It is modular in character. Combinatorial assembly means assembling modules in ways where you can change the identity of the module, but the way you connect them is the same. So, that involves certain classes of chemical reactions. Diversity is a very important metric or principle that goes hand in hand with the number question that you posed. In my view, and this is a discussion point in combinatorial science throughout its history, there is an interplay between the number and diversity of molecules you can make. Is it most important to just make as many as possible? Or, is the diversity of those molecules more important: how different do they look? How different do they behave? How different are they in size, polarity, charge, and shape? And as I said, there's an interplay between those. I'm usually on the side of make the most diverse molecules you can even if the numbers aren't there, because that allows you to sample. When you then go and test those molecules for function, it allows you to sample the widest possible array of possible answers to the problem. However, I was just at a wonderful lecture today by a real expert in combinatorial chemistry who says that his laboratory has now eight billion compounds that they've made through a technology called DNA-encoded libraries, and it's really exciting. The challenge is then: Okay, how do you test them? The testing of combinatorial libraries is just as important or more important than the making of combinatorial libraries. In any case, it's a very exciting field. It's now really a tool that is embedded in all sorts of applications and all sorts of fields. I hope I've given you and the listeners some sense of it.

The Origins of Click Chemistry

ZIERLER: One of the most famous terms that you're associated with, of course, is click chemistry. I wonder first if we can establish some narrative boundaries around this. When did that term first come into play? And how has it taken on new meanings over the years, perhaps even in ways that you didn't foresee?

FINN: I obviously can go on and on about this, so I'll try to be as brief as possible.

ZIERLER: Or not. Go ahead! [laughs]

FINN: Click chemistry is really the creation of Barry Sharpless of, now, Scripps Research. Click chemistry was born at Scripps. Barry and his former postdoc and then colleague, Hartmuth Kolb, were the ones who brought that term into being, and that was 25-ish years ago or so. The word "click" actually came from the satisfaction you get, that feeling and that sound you get when you hook buckles together. You know those luggage buckles—

ZIERLER: Oh, yes.

FINN: —that just snap together? Well, that's the "click" in click chemistry. And the reason that's an apt image is it doesn't matter how big the suitcase is, it doesn't matter what those buckles are attached to. It could be attached to a building, a tractor, or whatever, as long as those things are in close enough proximity to snap together, they can make that connection regardless of what they're attached to. The whole message of that image is the ability to make bonds—chemical bonds—between things easily, in a way that allows you the most diversity possible in the things you are connecting. So, click chemistry is all about making ligations, making bonds between a diverse set of things.

I was very fortunate, of course, to be Barry Sharpless's PhD student, went off and established my own career, and then moved to Scripps for reasons that had actually nothing to do with Barry. But when I got there, there he was. We resumed our wonderful relationship, and I had a chance to talk with him often and learn so much chemistry. We started talking about this idea that he had, and I was able to help he and Hartmuth formulate it, articulate it, and work on it, so I was very privileged to be part of the initial announcement in publications of that idea. Because of the chemistry that happened as a result of that idea and that got folded into that idea—think about it—the ability to make a bond no matter what you're attached to, that requires chemistry that is incredibly reliable. It requires bond-forming reactions that are super reliable, and as you develop those, you then have the ability to make all sorts of things in much easier ways than you did before, and that's the power of click chemistry. So, when it started and we published this paper, we knew we were onto something when the first community of scientists that really started to use it were the material scientists—the polymer chemists, the material scientists. And in this first paper that we fondly refer to as "the click manifesto," we actually explicitly drew inspiration from polymer science. You can't make a big molecule like a polymer unless each of those reactions that links the monomers together is a click reaction. By definition, high yield, easy to do, works no matter what it's attached to, click reactions are what you need to make polymers, and the material science people just jumped all over this. It was like, "Oh yeah, this is exactly what we've been doing, but now, look! There are lots of other reactions, or at least a few, that we can use, and I don't need to be an expert chemist to use them!" It took off like wildfire among the material-science community, and then the chemical-biology community, which was nascent then. And bioconjugation chemistry is really the other half, or another component, of click chemistry. Carolyn Bertozzi and others, of course, drove that.

The ability to make bonds, if you're not a trained organic chemist, that has just changed so many fields. So, you asked, Has it gone in directions that I didn't anticipate? And of course the answer is absolutely yes, but the vision—I should say, the realization has not caught up to Barry's vision, even then. Even though click chemistry is applied to things we didn't anticipate, it actually is still pretty much in its infancy in the ability of click reactions to probe to make connections in the context of their environment in ways that inform on their environment. I could go on and on about that, but the idea of reliably making a bond in a way that says, "Hey, I'm going to make it in a certain way if I'm around some things and not around other things." That's chemical information that a molecule provides without you knowing it ahead of time. That's one of the main many areas that click chemistry is going to go, and it needs very special reactivity to do that.

ZIERLER: In the time that it will take to achieve that vision, what you were just explaining, what aspects of that require technological, and what aspects require conceptual breakthroughs?

FINN: Oh, that is such a great question! Very little of the fundamental chemistry that are click reactions is technologically demanding. Most of the click reactions are were discovered 100 years ago, 50 years ago. And in the click manifesto paper, because of Barry's encyclopedic knowledge of the old German chemical literature, we pulled out a dozen chemical reactions that people have been using. And of course, organic chemists were well familiar with these for decades, but we identified them as click reactions because they were so damn good. The insights that were required to invent those reactions really are fundamental chemical insights that don't require technology; they require knowledge and perspective and insight about chemical reactivity. Will a machine learning algorithm ever get there? Maybe. It's possible. But right now, the development of new click chemistry really derives from a deep understanding of chemical reactivity that so far only humans possess and only a very few humans are able to summon. Many click reactions are discovered by accident: I'm trying something and, "Hey, look! That worked really well. Let me explore the limits of this." And lo and behold, you find yourself in possession of a new reaction. So anyway, not technologically driven; however, the application of click chemistry is extraordinarily technologically driven because the ability to make bonds in ever more reliable ways means that you make bonds in ever more challenging environments. A good example of this is an early concept that Barry and I published called "click chemistry in situ", which means "in place", where we gave chemical components building blocks, exposed them to a protein target, and asked them to self-assemble on that target and make a bond only when the target holds them together for long enough for them to make a bond, which is ordinarily very slow. That enterprise required us to use mass-spectrometry technology that at the time was pretty new. Now mass spectrometers are much better, so it's easier to do this, but at the time we were limited by the technology of detecting a very small amount of a molecule in the presence of a large amount of many other molecules that are much bigger or much more abundant. And that's just one very simple example of technological limits, that as you develop them—the field of molecular evolution is full of these, where new technology enables better sequencing, better detection, and better multiplexed information content reporting that click chemistry really helps to accelerate.

Two Labs that Speak to Each Other

ZIERLER: M.G., let's take a verbal tour of your lab. Let's start first with the instruments. What's most important?

FINN: My group has two labs: one where we do chemistry and materials, and the other where we do biochemistry and biology. They happen to be in two different buildings, but they actually are two very different layouts, two different sets of instruments, two different environments so to speak. Let's start in the chemistry materials lab where the main piece of equipment is the chemical fume hood, where if we don't have that, we can't do reactions to make new things. We do lots of separations, so there are instruments that help us separate mixtures of molecules from each other. There are instruments that do chemical characterizations, so nuclear magnetic resonance, which is a core facility in every department, is essential. We do lots of mass spectrometry. We do lots of infrared- and UV-visible spectrometry. We do characterization of polymers. Now, large molecules require a different set of instruments, a different type of chromatography; we do lots of chromatography of various kinds. And then we go to other labs or core facilities for instruments like differential scanning calorimetry and thermogravimetric analysis. So, those are the kinds of instruments making, purifying, and characterizing molecules. That's what that lab is full of. There's a glove box for reactions that need to be kept away from air. There are instruments to purify solvents, instruments to remove solvents, standard organic chemistry synthesis stuff.

ZIERLER: Do the two labs speak to each other?

FINN: All the time. I can give you the verbal tour of the biology laboratory if you want, but this is a much more important question. We have people who go back and forth between those labs. Very often it's more the people who know how to do organic chemistry who learn how to do biology. That arrow is much more intense than the other arrow: people who learn how to do biology tend not to come in and learn how to do synthetic chemistry. And the reason is, you can make progress faster doing basic biology, because there's a lot of kits available, and protocols, and it's easier to get some stuff done than it is to do organic synthesis, which is still largely as much of an art as it is a science, and requires levels of skill and practice that take a lot longer to acquire. So, we have a lot of organic chemists who learn how to do cloning; do protein generation, isolation, and purification; and do immunology, ELISAs, and all that. I've had only one or two students who are biologists who come in and make a molecule, but that's fun.

ZIERLER: The interests and motivations of your graduate students, who goes on to the academy? Who goes on to industry?

FINN: One of my chief joys in being an academic is you get to help people who have all sorts of different career aspirations. In my group, 15 to 20 percent of the folks who've gone through my lab—postdocs and graduate students—wind up in academia. The vast majority of the rest of them wind up in either biotech or pharma, largely, but there's a healthy number who have gone on to be patent attorneys, patent agents, consultants, entrepreneurs—at least a couple—a couple in government labs, of course. So, there have been a variety of destinations for careers.

ZIERLER: All of the healthcare and the biotech around Atlanta, is that an asset for your students, for your research groups?

FINN: It is. What's really an asset for us more specifically is the immunology in Atlanta is phenomenal.

ZIERLER: CDC is right there. [laughs]

FINN: CDC is here. Emory has a vaccine center which is wonderful. The Yerkes Primate Center is here. Georgia Tech has lots and lots of people doing immunology. We have an immunoengineering training grant program. The immunology here is just first rate. We do a lot of material science here, and that's first rate at Georgia Tech. The technology development, engineering—we can get stuff built here that is hard to do a lot of other places. But the biology environment in Atlanta writ large is actually a lot stronger than people realize from elsewhere in the country.

ZIERLER: M.G., let's go back now; let's establish some personal history. Where were you in high school, and how did you hear about Caltech?

FINN: I grew up, I was in high school in Bergen County in northeastern New Jersey, and I owe my career and my development of interest in chemistry to my high school chemistry teacher, as many chemists do. Father Guy Morin was a wonderful, wonderful man and really set me on my course for chemistry, but how I learned about Caltech—I love to tell this story.

ZIERLER: Please.

FINN: There was a set of books by Life Science Library, and I can still see these books in my mind's eye. They were these most elegant, tall, thin volumes, different colors on different subjects of science and technology—the Life Science Library—and there was one called Giant Molecules, and I pulled it and I loved it. I had the whole series, and Giant Molecules was one of my favorites. Pulled it out with these gorgeous—it was about polymers—gorgeous pictures of molecules, and somewhere in that book was a four-page spread about Caltech and people who were working with large molecules at Caltech. And that's how I learned about it! And I then sort of read about it. Nobody in New Jersey knew what Caltech was. In fact, if anybody thought they knew, they mistook it for Cal Poly—California Polytechnic Institute. And the reason they knew about that was Cal Poly had a float in the Rose Parade every year, so New Year's Day you'd turned on the TV and you'd see something from Cal Poly, and people thought that's where I was going. But I applied to Caltech because I loved it. I applied a few other places. Caltech interviewed people back then; I think they still do, and I was very fortunate enough to get in. But that's how I learned about it.

ZIERLER: You must have graduated near the top of your class to get into Caltech.

FINN: That I did, but I still have no idea how I got in.

ZIERLER: What was it like when you first arrived? Was it a bit of a culture shock coming from New Jersey?

FINN: Not really. Caltech is such a small place that it was easy to meet people. I lived off campus because my mother moved out, and to save money we had an apartment there, so I lived close to campus but not on campus, at least initially. And then my second year I moved on campus. Caltech has the house—as those listeners at Caltech will know the house structure; I was a Rudd, so Ruddock House became my home, and it was very easy to kind of fit in and feel like you were part of a community. So, there was really no culture shock per se. I started to do research right away. I can tell you that story because that's one of my favorite Caltech stories. I started to do research before my freshman year and just loved it, so I had a great time. But one of the downsides was there were very few women at the time, and the poor women who were there were just followed all around by a gaggle of guys.

ZIERLER: Yeah, Caltech had only gone coed in 1970, so it was still fairly new at that point.

FINN: It was about 10 or 15 percent women among the undergraduate population, yeah.

Chemistry Kinetics at Caltech

ZIERLER: Did you come in knowing you'd pursue chemistry? Was that the plan from the beginning?

FINN: I did just because I loved it so much, and in hindsight I actually probably wish I would have looked around more. I'll tell a couple of stories because they're wonderful stories to tell. So, when I got to Caltech before my freshman year—I was there in the summer for a month or two—I just knew I was interested in chemistry, so I went to the chemistry department, the building, and I looked up on the organizational chart who the chairman was. I was too nervous to go to the chairman, but there was this thing underneath the chair of the department called the Executive Officer. I didn't know what that was, but there was a name by it named Fred Anson, and they had an office number there. I stumbled my way to that office, and I knocked on the door and I introduced myself. And Fred Anson was this six-foot-seven giant of a man. He somehow opened the door, and I explained I was an incoming freshman, and I was interested in chemistry, and I would love to do research. "I don't care what I do. I'll be happy to wash bottles or whatever. Do you know of anybody who has any position in their laboratory?" And Fred, that instant, took me into his office and spent the next forty-five minutes telling me about his research. And I understood one word in twenty. Fred was an electrochemist, and he just started treating me like a colleague right then and there. And I knew I was being respected. I had no idea what he was saying, but I felt incredibly respected.

At the end of that 45 minutes, when I apparently didn't fall asleep, he said, "Do you want to work in my lab?" And I said, "Sure!" So, he took me by the hand, and he walked me into the lab and introduced me to a Japanese postdoc and introduced me as this Japanese postdoc's new assistant. And this poor Japanese postdoc had no idea what hit him, and he spoke English very badly, so I understood only one word in 10 of his. He wasn't talking over my head, I just couldn't understand him. But he said the words "operational amplifier" in an accent, and I knew what that was, and that was the only thing I understood. So, he handed me a manual for an instrument—in English, thankfully—and I read it, and I learned how to use that instrument. It turned out I would help him do science that summer, and I got a paper out of it! So, here I am, a freshman who doesn't really know anything, and I'm in a lab, and I got a publication, and it was like, "Oh my God, this is heaven! Just heaven." And away I went. So, fine, I'm doing research in Fred's lab, trying to survive freshman physics, not doing too well, and all of that stuff; and then a year later I somehow hear of an opening in Roger Sperry's laboratory. Now, Roger Sperry was creating the field of neuroscience, and I had no idea what that was. I talked with somebody in that lab, and I decided, "Nah, I'm going to stay, still doing chemistry." And I don't regret that choice, but boy! I kind of passed on an opportunity, not knowing it, to help create a whole field of science, because he was doing cat-brain implants and all of that. Nobody was doing anything like that then, and I had no idea what I was looking at. There were so many opportunities, but I stayed doing research my whole four years. I worked for an inorganic chemist named Bob Gagne and blew myself up and had got a visit from Fred Anson and Sunney Chan in the hospital and had a wonderful time.

ZIERLER: [laughs] Looking back, as you came to understand Fred's research, what was he focused on at that point? What were the big questions in Anson's lab?

FINN: The big questions at that time were really electron-transfer kinetics. Fred was interfacing with coordination chemists looking at the fundamentals of how do electrons get from electron surface into an inorganic complex and back again. We were—to the extent that I had anything to do with it—really looking at fundamental kinetics of electron transfer to and from electrodes, and then between molecules in solution. It turns out it's really important stuff to understand these days if you're thinking about batteries and catalysis, but at that time it was really fundamentals of inorganic coordination and electrons.

ZIERLER: You mentioned shying away from what Sperry was doing and being more involved in biology more centrally. We talked about chemical biology at the outset of our conversation. This would have been very early days, but were you aware of what Peter Dervan was doing at that point?

FINN: Oh yes. In fact, Peter was my course advisor. At Caltech you had, not a research advisor, but a faculty member who was assigned to help you navigate through courses. He was a young guy and going great guns, and I was somewhat aware of what was happening, but not in a very deep way, of course. But it was obvious that there were some pretty interesting things going on with DNA and structure and making new molecules. Peter's real developments came much later in terms of specific DNA-binding molecules, much after I was there, but they were starting, and it was obvious it was fun.

ZIERLER: Meaning even as an undergraduate, at a rudimentary level at least, you were aware that there was a chemist's approach to biology that you might pursue one day?

FINN: Yes, but—oh no, I don't know that I would pursue it. But understand, nobody thought this was exotic. It wasn't recognized, or at least I didn't recognize it, as a crossing of any boundaries. This was just somebody making molecules that were reacting with biological molecules and studying how that happened. And keep in mind, Harry Gray was over there studying metalloenzymes and electron transfer in that, and John Baldeschwieler was putting stuff into the gas phase. Yeah, there were divisions, but we didn't look at it that way. Or, again, I didn't look at it that way, and it was probably because I was too ignorant. But it seemed like it was cool science, but not because it was, "Oh! A chemist doing biology!" That never occurred to me.

ZIERLER: Did you stay on campus during the summers for research?

FINN: I did, yeah. Later, I was fortunate enough to get a scholarship from Eastman Kodak, so I spent one summer at Kodak, but the rest of it I was on campus doing research.

Vacuum Lines and Lab Dangers

ZIERLER: You'll have to tell me the full story of how you almost blew yourself up. What happened?

FINN: [laughs] I won't talk about the actual mistake I made, but it was a vacuum line. Imagine a very elaborate rack of glassware with valves and taps and all the things. That was the way we did air-sensitive chemistry then. This was in Bob Gagne's laboratory. I made a mistake working with liquid nitrogen which condensed liquid air, and it was a pressure explosion. The real heart-thumping aspect of it was I was not wearing safety glasses when this blew up. I had turned away and turned back, and this little glass chamber blew up, basically, in my face. I had cuts all over my face, and nothing hit my eyes. So, blood's pouring off me. They rushed me to the hospital. Turns out I'm fine, just little stitches or little—I don't even think it was stitches, just little bandages. So, I'm in there, and then I see coming down the hallway—and this is my enduring image of this—Sunney Chan, who was just a wonderful mentor and professor. I was lucky to take a couple of courses from him and therefore knew him. Sunney, who is like four foot eight, and Fred who's six foot seven, coming down the hallway together, looking like—I don't know what the allusion is—but I just remember these two wonderful people coming down to see me in the hospital, and then walking away that way with the height difference. And they couldn't have been nicer, except that—who was it? It might have been Sunney. Somebody wanted to put a picture of my face, with all the bandages, on the safety magazine as a cautionary tale of what not to do, and I wouldn't let them take my picture for this reason. [David laughs] But yeah, I was really lucky.

ZIERLER: M.G., did you ever think about going into industry? Were you always on the graduate-school track?

FINN: When I interviewed for my first academic job, I also did industrial interviews at the time because I wasn't sure if I would get an academic job. I always knew I wanted to go to academia, but I had this experience at Kodak, which was quite fun and I enjoyed it, but there were some things about it that I realized were not quite my cup of tea, so that reinforced my desire to go to academia. But I figured I don't know where my job's going to be, so I will do both interviews. I had a really lovely offer from GlaxoSmithKline—then, Glaxo—and they were starting to set up their research facility in Research Triangle Park. I would have been like the second wave of hires there, and it was an amazing opportunity. They basically said, "We'll give you a few million dollars to do what you want while we set this up." But then I also simultaneously got an offer from University of Virginia, and I knew that was a great place, and I knew I wanted to do academia. But I did do industrial interviews and had a great time.

ZIERLER: Did you have any professors who guided you, who encouraged you one way or the other, or suggested once you were set on the academic track what labs to join, what professors to work with?

FINN: That's a great question. In terms of as an undergraduate or as a graduate student?

ZIERLER: As an undergraduate, about what labs to join, what professors to work with.

FINN: No, that was pure random walk. There was no guidance. It's not that it didn't exist. It may have existed, but I didn't know about it. So, there wasn't, "Oh you should think about going to work in that laboratory," or whatever. Caltech is such a small place, there's just no barriers to this kind of thing, so you didn't really need that navigational assistance. If you took a few chemistry courses, you started to know who the faculty were anyway, so that wasn't an issue.

Barry Sharpless at MIT

ZIERLER: Was Barry Sharpless a name you knew before you got to MIT?

FINN: Oh yes! Oh yes, yes, yes. I went to MIT to work with Barry. I applied to a bunch of different places and got into a few of them, but I knew about the Sharpless laboratory, knew about their work, and just fell in love with it, so when MIT admitted me—and Barry had just recently moved there from Stanford—I knew that's where I was going to go.

ZIERLER: Was Barry the deciding factor for you to go to MIT?

FINN: Yes. MIT was a great place, and I may very well have gone there if Barry hadn't been there. If I wasn't going to go work for Sharpless, I might very well have gone there, but there were other places that were also very exciting. So, I loved MIT in every respect, but I went there to work for Barry.

ZIERLER: Do you know the broader story of Barry's recruitment to MIT and what that represented for where MIT wanted to go?

FINN: I'm not sure I know the broader story. He was clearly a hot ticket, and he had ties in Boston and was obviously very well-known there. I don't know if there is a story about MIT making a strategic move that Barry was a part of. Barry is not one that you would build a long-term strategic vision around—around anything other than excellence. But certainly not a particular subject, because he also went where his chemical intuition told him to go, and that might not be the same thing that he was doing the year before. And there's a through line to Barry's work which is quite instructive, but perhaps not apparent to casual observers. So, I don't know if there was a broader story. He was just one of the best there was and pretty obviously a great recruit.

ZIERLER: Was he there long enough where it was basically an established lab that you joined, or were you part of the building up process?

FINN: I wasn't part of the move-in process, no. They had been there for a year or two when I got there, maybe even a little bit longer, but a couple years, say. So, it was an established group, and I walked in, and things were humming. So yeah, I wasn't part of the unpacking.

ZIERLER: Do you remember meeting Barry for the first time and what that was like?

FINN: I remember it vividly. The first part of his anatomy I saw was his rear end sticking up, because I walked into his office and he was reaching behind or under his desk for something. He straightened up, and I introduced myself, and it was delight to meet him. I don't know that we had a long conversation the first meeting, but pretty soon I became part of the lab and started to just have this life changing experience of talking chemistry with the man.

ZIERLER: How big and variegated was the Sharpless lab, and where did you slot in?

FINN: It was not the biggest group at MIT, but it was a pretty good size. When I joined there were maybe 12-ish people there. We were in Building 18, and Fred Greene was next door; Sat Masamune was the other side. Gobind Khorana was two floors up leaking P-31 down the walls. [David laughs] It was an amazing time. So yeah, I slotted in. There were a number of postdocs there, and they became my mentors and lifelong friends. And wonderful graduate students. I think there were maybe two other students that entered the Sharpless Lab in my year. But yeah, it was just a terrific environment.

ZIERLER: What were the big questions he was pursuing at that point?

FINN: This was asymmetric catalysis days, so asymmetric epoxidation was hot. It was before asymmetric dihydroxylation. So, I came in and my project was to take over from a wonderful pioneering student named Scott Woodard to learn the mechanism of the titanium-tartrate asymmetric epoxidation reaction. And I was officially an inorganic chemist because those were the qualifying exams that I passed. Nobody cared, but those are the ones that I passed first, so that was the label they gave you. And it turns out it was an inorganic chemistry problem to some degree, so that was it. It was the days of the hexose syntheses with the Masamune lab; that was going hot and heavy. Disparlure natural product synthesis had happened just before I got there. It was super exciting times. We would have meetings with Alan Davison on their inorganic chemistry, but it was mostly on asymmetric catalysis and learning how that worked.

ZIERLER: M.G., once you got your bearings at MIT you were sort of familiar with campus. Obviously this is a different stage in your educational trajectory, but I wonder if you thought about the differences or similarities in the research cultures at MIT and Caltech.

FINN: Yeah, it was little things. Like, in my head, there was a West Coast way to do air-sensitive chemistry, and there was an East Coast way. In the West Coast, that was that rack of—the vacuum line that I talked about that blew up in my face. In the East Coast, we use glove boxes. And you didn't have a lot of West Coast air-sensitive chemistry people using glove boxes at that time. Of course that all changed later. So, there were technique differences. There was a clear, obvious difference in the institutions. MIT, a lot bigger. Not a very big place, but compared to Caltech, of course, a lot bigger and a lot more confusing. I love Boston. I'm a city boy, so that was a very happy environment for me. Pasadena was Pasadena, and I was wrapped up in Caltech anyway, so I didn't really pay attention to the environment that much. But the differences in the institutions were more cosmetic than anything else, and just size.

ZIERLER: What about the fluidity from lab to lab? That, as you explained, you could easily at Caltech meet faculty, you could float in and out of labs. That was present at MIT as well?

FINN: It was a different experience being a graduate student than an undergraduate, and therefore it was less fluid at MIT, but I would venture that graduate students at Caltech would find it less fluid in a sense. It was much easier to meet faculty at Caltech and get to know them as people. At MIT that was harder, because it was just larger and you didn't run into people that much, in a way. MIT did have a wonderful pub, so that was a good barrier breaker, although I didn't drink, so I didn't make as much use of that as some others did. Caltech had the Athenaeum, again a nice ice breaker. So, it was more a graduate student versus undergraduate.

ZIERLER: What was Barry's style like as a mentor, and how did that factor into how you put your initial ideas for a dissertation topic together?

FINN: Barry's style was very much peer to peer. Barry loved talking chemistry with people who loved talking chemistry and didn't care what rank you were. He would have the same level of conversation with an undergraduate as with a senior colleague—you know, with those levels of understanding. So, that was how interacted with Barry, was talking science. He wasn't a mentor in the way that he didn't do a lot of the mentor things that we now ask mentors to do, but he was all about encouraging when you were working hard; and when you were into it, he was into it. And that was really the coin of the realm there. My thesis topic was really decided right away because there was this open-ended question about how this reaction worked. I was an inorganic chemist, so it was an obvious question that I should have the skill set to answer. And I was fascinated by it, so I had no problem picking a thesis topic.

Chirality and the Nobel Prize

ZIERLER: What was the reaction? What was the question?

FINN: This is the titanium-tartrate catalyzed asymmetric epoxidation. It's the reaction for which Barry won the Nobel Prize in 2001. The question was: How does it work to generate one-handedness or the other-handedness of the product? That had not been done before by a man-made catalyst before Noyori and Sharpless's different catalysis, and nobody knew how this happened. So, it was really an inorganic and organic mechanism question. Again, Scott Woodard really paved the way for my work in the laboratory. It was a lot of, How do we figure out what the structures of these things are? How do we figure out—I spent years doing chemical kinetics. I did lots and lots of kinetics to find out the change in the composition of the catalyst; change in the composition of the substrate; how does that influence the rate; work out how many molecules have to get together to make this reaction work; and then figure out how the structure is made since. It was a wonderful problem, and with the tools of the day, we did okay.

ZIERLER: To clarify was the chirality understood at the outset? Or was this discovered along the way?

FINN: The fact that chiral enrichment happened, that was known because that was the value of the reaction. That's why it got such wide notoriety and such wide use. It was the first way in which it laboratory scientists could make one-handedness or the other of a particular class of molecules. And they happen to be a very useful class of molecules for making other things. So, the chirality fact was known, but what was not known was how did the catalyst make that happen, so that was what we had to work out.

ZIERLER: Tell me what the experimental setup looked like. What were you doing at the bench?

FINN: A good 60 to 70 percent of it was chemical kinetics: How fast does a reaction go when you change the structure of one or more of its components? I liken this to a game of Battleship. You know the Battleship game where you have the wall, and you want to know where your opponent's ships are, but you can't see them, so you lob a bomb over, and they tell you if you hit it or not. Working out a mechanism of a reaction where you can't see it operate is a lot like playing Battleship. You change one thing; you determine how fast it goes. If the thing you've changed makes it slow down or stop, then that position that you've changed has to be important. If it changes the chirality, the handedness, okay, now you know that's important in a different way. If you change the catalyst in a way where you make it more electron rich or electron poor, you get an answer as to what that does to the reaction, and you begin to formulate hypothesis about how this works. So, that was a good chunk; the majority of what I did was kinetics.

Then there was characterizing the catalyst. What is it made of? We knew what we added to the pot, but we didn't know what got together to make the molecule that actually did the catalysis. So, that was measuring its molecular weight. It turned out we had to find some new ways to do that. These were moisture-sensitive compounds, so they had to be worked with in a certain way. And then trying to work out the structure. When you figured out the composition, then what was the structure? I tried and tried and tried, and never could get, at that time an atomic resolution, what we call an X-ray crystal structure. We couldn't grow crystals of this thing, so we had to work it out from NMR, from nuclear magnetic resonance spectra. So, I did a lot of that as well. I did synthesis of isotopically labeled compounds to illuminate what the NMR was showing us. So, there's a variety of different ways we tried to get an insight into the shape, dynamics, and behavior of this molecule.

ZIERLER: If I'm hearing correctly, there's not so much biology or biochemistry for you in graduate school.

FINN: No, none.

ZIERLER: Is there an intellectual seed? Is there a foreshadowing that happens at MIT that sort of helps to explain what you went on to do?

FINN: Nope, not at all. No, that came much later. There is actually an important intellectual seed in my relationship with Sharpless. What I learned by osmosis from Barry, if nothing else, along with other ways, was the only thing that mattered was reactivity. And when you're a chemist looking at that, that divorces you from worrying about all sorts of other stuff. Like, what is this good for? Or, how can I apply it? And oddly, that opened me up intellectually to all sorts of applications. I wasn't invested in any particular goal. I learned from Barry that all that matters is reactivity; if you've got good reactivity, you can do all sorts of things. And that set the stage for me being able to either contribute to or at least appreciate the application of chemistry to other fields.

ZIERLER: What did you want to do after graduate school? Were you looking at postdocs? Culturally, were their faculty positions available at that point?

FINN: No, I really wanted to do a postdoc, and Barry actually steered me in this case—you asked about people steering you—so, Barry steered me to Jim Collman at Stanford. And Collman was doing—did for his whole career—porphyrin chemistry, and that was the first whiff of biologically relevant molecules that I got a taste of. Anyway, Barry hooked me up with Jim Collman, and I applied and got an NIH postdoctoral fellowship, and almost lost that fellowship because I was having such a good time in graduate school that I actually never moved. I didn't leave. The NIH contacted me and they said—I got the fellowship and didn't use it for like a year or a year and a half—and they said, "You've got to start, or we're going to take this away." So, I said, "Okay, I'll write up my thesis and I'll go." So, I went to Stanford with this NIH postdoctoral fellowship and started to learn organometallic chemistry, which I really didn't know before then, and porphyrin chemistry. And there, there was not really a biological emphasis of application to biology, but it was taking a class of molecules from biology and using that for other purposes. So, the Collman laboratory was all about doing catalysis using porphyrin complexes, which is the essence of the heme molecule to do oxygen fixation. In other words, take oxygen from the air and use it for catalytic reactions, and do some electrochemistry and other things. It was all about catalysis using those complexes.

ZIERLER: Did you specifically want the postdoc to be an opportunity for exposure to new stuff, for it not to be an extension of the PhD?

FINN: Yes, very much so. I wanted to learn a new branch of chemistry, and for me it was organometallic chemistry and porphyrin chemistry at that time. It was a nice sweet spot, because I could bring skills, I could bring value. I knew how to do things that they needed to do and that they were already doing, but it was a whole new area of chemistry for me, so it was a very nice opportunity to learn new things.

ZIERLER: What was most exciting branching out into these new areas?

FINN: Two things, one from a craft perspective. One of the beauties of doing chemistry, at least making stuff, is it's a craft. You actually make new things. You make new matter. So, I was making new stuff, new complexes, and it didn't hurt that they were all nicely colored. I love colors. They were all these beautiful colors, and you could really have a lot of fun making those. So, there was different craft, different making of those molecules which was lovely to learn. And then the other thing was just thinking about or being exposed to new chemical reactivity, which was important to me, and new catalysis, new ways of thinking. But really what turned out to be the most important was meeting new people. If you go to someplace new, if you go to a new area, you meet new people who think in different ways, who can help you in different ways, and that is the magic sauce.

ZIERLER: What did you accomplish at Stanford?

FINN: Very little. I didn't publish a paper from Collman's lab, actually. I contributed to some things; I think I helped some people do some things. I didn't publish a first-author paper there, but I learned a hell of a lot, and I made a lot of different kinds of complexes. I also got married, so there was some personal things happening there. But yeah, I learned a lot. And Jim is ever gracious. He never begrudged me the fact that I didn't contribute a lot to his publication list. He was always very supportive and always was a mentor and a supporter.

ZIERLER: Did the things you picked up in Collman's lab affect the kinds of jobs you applied to once you went on the market?

FINN: It was a very different time then. You could be seen as being a relevant candidate for, let's say, a pharmaceutical company without having made pharmaceuticals. As I said, I had this offer from Glaxo, and I was not published at all in making biologically relevant compounds. I think they were interested in me because of my asymmetric epoxidation experience and that work. But it was a very different time, so I was less constrained in what I was able to apply for because the constraints were less. So, I felt empowered to just see what was out there. I had an offer from Kodak, and I knew I didn't want to go there, not because they weren't great, but it wasn't the kind of work I wanted to do. But then I interviewed, as I said, in a couple of other areas. But I was really most interested in the academic pursuit.

Appointment at UVA

ZIERLER: What ultimately worked out? Where was your first academic appointment?

FINN: University of Virginia in Charlottesville, and it was just a terrific place to start. I got hired by Bob Ireland who is wonderful, a legend, and a legendary personality. Bob hired me and then hired my great good friend Dean Harman the year after that, who I convinced to apply to UVA. And it's the best thing I ever did for UVA, to get Dean there. Bob hired us both and then spent the next few years ragging on us because we thought about these elements in the middle of the periodic table that he didn't care about, and it was great fun.

ZIERLER: [laughs] And at UVA, this is a chemistry department?

FINN: Yes.

ZIERLER: Tell me about setting up your lab. What was most important to you?

FINN: When you're starting out as a faculty member, you're in the lab, so what's most important initially is getting the lab set up, getting the mechanics done, and we had a lot of fun doing that. I moved into some lab space that was tucked in the back of the building and kind of hadn't been used for a while, so we unearthed some really old equipment, which was fun, and got that shaped up. And then it was the students. I started an organometallic club which hadn't existed, just to get my name out there amongst the students and get some interactions going. And then I was doing organometallic mechanistic chemistry, and that had nothing to do with biology. We were doing synthetic methods and mechanism work in the same style that I had been doing previously, and I started to get the group together.

ZIERLER: What were the most important funding sources for you as an assistant faculty member?

FINN: NSF was really crucial. I didn't get NIH funding for the longest time, so it was the NSF, the American Chemical Society, the PRF, Petroleum Research Fund. Those are the most important funding sources for a young faculty member like me. And then some odd and assorted foundation grants, that kind of thing; but the NSF was key.

ZIERLER: When did your lab start to feel like it was really going well, that you were going in the right direction?

FINN: We were doing okay. When we started to publish, we established a little bit of a name in two areas of organometallic chemistry: Fischer carbene chemistry, and when we invented a new synthetic method for allenes and did some that was early metal high oxidation state chemistry. So, we were doing fine; we were publishing papers. But then I kind of woke up one day—this is a true story—I literally woke up one day, and I was maybe seven years in, and I realized nobody's going to read these papers 30 years from now. There's going to be 10 people who care about what we do 30 years from now.

ZIERLER: Why did you think that?

FINN: I don't really know for sure. Things bump around in an academic environment, but maybe I was just a little frustrated with the pace or something—I don't know. But I said, "Okay, we've got to do something different." That's actually when I had the idea, let's do—and because of what was out there, I was reading a little bit about combinatorial stuff, and I said, "Let's do combinatorial catalysis." We started to think about that a little bit, and we started to do some things in it. We started to make polymers for the first time, and do polymer supported catalysis. We weren't very successful, but it got me talking to a different group of people in the combinatorial game. That was very early on, so people were just starting to work out combinatorial synthetic methods; split-pool chemistry had not been invented yet. So, we started to do resin-based chemical reactions to make things, and we started to try to think about catalysis and how you assay for catalytic activity in a combinatorial library. And that got us into analytical questions which turned out to be really important, so we started to think about mass spectrometry and how we do analytical work there. So, it got me into a whole new area, or combination of areas, and my wonderful students came along for the ride, and we started to do this stuff. Okay, it wasn't very successful writ large, but we started to carve our way into this field.

Then, Richard Lerner shows up to give a seminar at UVA, and in hindsight this is really unusual; Richard very rarely gave academic seminars. I don't know who invited him. I never knew, or forgot. So, Richard gives this talk about catalytic antibodies, and I'm in the audience. I had a sabbatical coming up, and I had no idea what I was going to do. And I said, okay—I didn't know what Scripps was, but Richard described a little bit—and I ran, literally ran, down to the front of the room after he was done, introduced myself, and said, "I have a sabbatical coming up. I've done some catalysis and stuff. I want to learn some new things. You think I could come to Scripps and do a sabbatical?" And he said yes! After some discussion or whatever, he hooked me up with Carlos Barbas at Scripps, and I went to work with Carlos and Richard on catalytic antibodies. That was a year later. We found funding and all of that, and it worked out. And because I had done combinatorials, Richard was very interested in this kind of concept, although he was far ahead of me in thinking about it conceptually. But that, I think, kind of helped me connect with him. And then because I had done analytical, we started thinking about analyzing the results of combinatorial reactions. That got me connected to the mass spectroscopists at Scripps, a guy by the name of Gary Siuzdak who became a good friend. So, I got, in a way that was totally lucky, plugged in at Scripps faster than I would have otherwise, because I could, again, bring a little bit of value to the proposition. So, I spent a year in the laboratory, in Carlos's lab, and I had never touched a protein before. Basically, my mission was to see if any metal ions made a difference in catalytic antibody reactivity. What a stupid idea! But it got me playing with proteins. I'd never touched one before. I didn't know the first thing to do. I'd never done a bioconjugation reaction. So, they taught me how to do this stuff, and I started to play with proteins. We actually got a paper out of it because we stumbled on some interesting observation. And again, much more importantly than that: the people.

The Move to Scripps

I tell this story all the time, and it is the truth. I didn't know how to read a paper about antibodies. I didn't know anything. I'd never taken a course in molecular biology. Knew nothing. Didn't know the language or anything. So, every few weeks I would grab a postdoc—and this was in this wonderful Beckman building where you could walk around, and it was all the people walking in a common atrium area, so you can't avoid bumping into people. I would grab a postdoc and then tell them who I was or somebody I'd met, and I said, "I will buy you lunch, but here's a paper I'm trying to understand. The deal is, I buy you lunch, but we don't get up from the table until I understand the paper." I would obviously try to pick the person appropriate to the paper. I did this, I don't know, six, eight, ten times, and these lunches went on a while because I knew nothing about the underlying language, or abbreviations, or concepts, or whatever. I started slowly to be able to understand what a molecular biology exercise was, how you do all sorts of stuff, and more importantly, what are the concepts underlying biomolecule manipulation. And that just changed my worldview. So, I go back to UVA, Virginia, not knowing at all what I'm going to do, but I know I'm going to do something in biology now. And I couldn't figure it out, and we're thinking about all sorts of things. Then, Scripps offers me a job the next year, so I said, "Sure. If I crash and burn, I'll go teach high school." That was my backup plan. I moved out to Scripps with just a few people, a couple people. I had temporary space, actually, in Barry's lab, because they had some extra space, and then they found some other space, and away we go. Okay, what am I going to do? Well, I still had no clear idea. We started to do a little bit, and then, again through this mass-spec connection, I met a man named Jack Johnson who was at the time the premier structural virologist in the world. Jack's group had done X-ray crystal structures on more viruses than anybody else—him and his mentor Michael Rossmann. And I walked into Jack's office because Jack was interested in mass spec. I was doing mass spectrometry with Gary Siuzdak, and Gary introduced us and said, "You guys ought to meet each other. You'd like each other." And I walked into Jack's office, and he had these 3D models of viruses hanging from the ceiling. And understand: nobody had printed 3D models back then. I had never seen one, and here they were, these beautiful structures. I love structure. As an inorganic chemist, I love X-ray crystal structures. And here are these models of these enormous molecules, but they are these beautiful spherical icosahedral things. "What are those?"

"Oh, those are viruses."

"How do you get them?"

"Oh, they're structures. We do X-ray crystallography."

"And how do you get at them?"

"Oh, we express them. We make them in the lab."

"Has anybody done chemistry with them?" I ask, and Jack says, "Well, funny enough, I've been looking for somebody to help me do that." Jack turned out to be a bachelor's—BS chemist—and then he turned to structural biology. But he always loved chemistry, and nobody had walked in the door and said, "Hey, do you want to do some chemistry with this stuff?" So, because of my startup package at Scripps, I had some extra money. I had some undesignated funds, so we could afford to put some people on it. We were doing other chemistry. I asked my group who wants to learn how to express protein, and a wonderful postdoc named Qian Wang stuck his hand up and said, "I'll do it." He went to Jack's lab, and they taught him how to do molecular biology, and protein expression, and to do rudimentary cloning, and away we went, hand in glove with Jack's group to do chemistry on these particles. And that's how I got into that, into biology.

ZIERLER: Do you think this never would have happened had you not made the leap, had you stayed at UVA?

FINN: Never would have happened, never ever, ever. I am a product of my environment as most of us are, but I perhaps go overboard in that regard. And again I bring a philosophy of, if I've got good chemistry to bring, I can make bonds to viruses. I can go figure out how to label a molecule to detect chirality by mass spectrometry, which is, again, what we did. I didn't talk about that, but that's where we got to. Good reactivity enables you to do all sorts of stuff, so why be afraid? If you're willing to admit to people that you don't know anything, and you're willing to learn, and as long as you can say, "I'm an idiot, teach me," and you can bring bond making to the table, you can do a lot of great things with a lot of great people.

ZIERLER: So, being a product of your environment, what does that say about Scripps?

FINN: It was, and remains, but at the time, a magical, magical environment for pursuing crazy ideas. And it was that for a couple of reasons. The first is Richard Lerner had established this aura, this environment, and it brought a lot of money to the table. So, there was a significant amount of money floating around which meant you could explore some things without having to get a grant. But then you had to get the grant, because Scripps is a soft money institution. So, everybody's paying their own salaries, and that means that you have to collaborate. Because at least for somebody like me, there's no way I could raise enough money if I only did stuff by myself. I had to go in with lots of other people to get lots of different grants, and that makes for a spirit of, "Hey, let's get together and do stuff." It also means you're chasing important problems, because that's how you get paid. So, it was this unique environment of some money available to start stuff, but then an environment that was relentlessly targeted toward fundraising, which means you had to get going with other people and get it done. And then the students were amazing, and there's so much biology floating around that it's a chemist's paradise if you want to do work in biological areas.

Immunology and the Biotech Sector

ZIERLER: M.G., what about at the turn of the century—the late '90s, the early 2000s—biotech in San Diego? Was that already up and running? Was that relevant for you?

FINN: It was at that particular time not terribly relevant, but it was very relevant to Scripps, so by extension then relevant to me. Johnson & Johnson had an early relationship with Scripps, and the interplay of Scripps with J&J—Scripps was initially an immunology institution in its bones, and there had been longstanding relationships with vaccine developers and that kind of thing. But then J&J and Pharma came in. Historically there was a funding relationship between J&J, and subsequently Novartis and then Pfizer, where Scripps got a lot of money from these companies essentially for the right of first refusal of intellectual property. At the time that was totally groundbreaking and quite controversial, and Richard just made it happen because he saw that this was both a way to get money to the institution, but also the way to get the institution's discoveries out into the world. Those relationships worked or didn't work in varying levels of success, but they were revolutionary, and now everybody does this. Everybody tries to partner with big pharma and big biotech because of these very benefits. Now, later in my Scripps career it became very important. We became very close partners with Pfizer, and that lasted for a long time, and we did some wonderful work with them. So, that industrial relationship was important to me, but at the time—the early 2000s or late '90s—it was more the zeitgeist than anything else.

ZIERLER: When Sharpless won the Nobel Prize, what was that like for Scripps, and what was that like for you personally?

FINN: Oh, it was just wonderful! It was just delightful! I remember I was in the back of the press conference, a huge hullabaloo, hundreds of people on campus, lots and lots of press interviewing Barry; and he's up in the front of the room and answering questions and being Barry. He's talking about what he loves. He's talking about science and chemistry and how ideas connected to him. And one of the reporters turned to me—and we were in the back of the room—turned to me, this woman, and she said, "He's delicious!" [laughs] Well, yeah, he's pretty charming, and his kind of enthusiasm is just infectious, and everybody got it. Everybody understood the essence of the man, and it was just wonderful.

ZIERLER: We talked about click chemistry in the beginning, but now let's orient it in the narrative. What was happening with click chemistry around this time?

FINN: Barry had announced to his group that he wasn't doing asymmetric catalysis anymore, and he was going to do this thing called click chemistry, and his group was shocked. Nobody knew—he had people coming with postdoctoral fellowships to do osmium chemistry for asymmetric catalysis, and nobody understood what was going on. So, Barry and a wonderful postdoc at the time, and then lab manager, Valery Fokin, started to do all this. Hartmuth of course was deeply involved earlier on, but Hartmuth was there for a time. And they just started to do this stuff. I was there talking science with Barry and got involved in various ways with the chemistry, but it was really a Sharpless group operation. Recruiting people early on was difficult because nobody understood what he was trying to do. He was laughed at, literally laughed at. I was in the room on several occasions when he would get up there and talk and people would start laughing. Organic chemists would start laughing because, "What is he talking about? He's talking about simple chemistry. We know this stuff already. It's just good reactions. What are you doing?" And then Albert Eschenmoser came to talk to us. Albert is a giant in organic chemistry and one of the two or three smartest people I've ever met. Albert would spend summers at Scripps, and he and Barry of course were fast friends because they are both amazingly insightful chemists. And Albert got it. Albert understood what Barry was doing and trying to do and was an enormously influential supporter. When Albert came and started to talk to people about this, at least some people started to listen. And then of course Barry carried on, and the copper reaction then came along—this is all mixed in time-wise—and when the copper reaction hit, then people picked it up. As I mentioned, the material scientists started to pick it up, et cetera. And then it became pretty obvious that this was a powerful concept, so the laughter went away. This was now over five or six or seven years; the laughter went away, and the rocket ship got ignited. My group started to do bioconjugation right away, and we published that work. We worked on the mechanism of the copper reaction, and it was all hands on deck. It was fantastic fun.

From Copper to Viruses

ZIERLER: So Sharpless's pivot affected your lab significantly and immediately?

FINN: Not immediately. I was not on the discovery of the copper reaction. That was Barry's lab. But as soon as that reaction was discovered I realized we needed this reaction to do what we were trying to do with viruses. We needed a superlative, high-rate, high-tolerant, water-friendly reaction to make the kinds of bond connections to viruses that we needed to make in order to tailor the viruses to what we wanted to do. So, it was purely utilitarian from my point of view. Hey, we've got to use this reaction because nothing else worked! We had tried everything. So, we started to do it, and it worked like a champ. We worked out methods to optimize it, and because I'm a mechanistic chemist, we then started to work on the mechanism of the reaction, because I just love that stuff. So, it didn't change our group immediately, but pretty shortly thereafter it was revolutionary for me.

ZIERLER: Let's go a little deeper into the science. Why is this reaction so important for the viruses that you want to work on?

FINN: Viruses are a repetitive structure. At the time, the virus we were working on was an assembly of 60 identical copies of a protein that self-assembles into this little nanostructure, big from a chemistry point of view. Because it's a protein, you don't make a one-molar solution of it. When you put it in solution, you're working with micromolar—at most, low millimolar—concentrations. And because it's repetitive, when we wanted to functionalize—we wanted to attach chemical entities to that virus—we needed to make at least 60 attachments. If we wanted to functionalize each of those 60 building blocks to make this structure that showed out these functional units all over the structure. So, we have a molecule at low concentration, relatively speaking, and we need to make a lot of bonds to it. If you think about that for a minute, you need a reaction that is incredibly fast. The next thing you need is a reactant that is going to do that fast-connection chemistry, and that reactant can't be very disturbing. It can't interact with very many things or it's going to interact with the protein and denature the protein or disrupt its structure. It's got to be pretty innocuous. It's got to be pretty invisible.

So, the combination of a fast reaction that's invisible, that doesn't react with everything that's on the protein—and there are lots of reactive functional groups on proteins, and these particles had RNA inside. There's lots of reactive functional groups on RNA. It had to completely ignore those and yet be reactive enough that we do very fast chemistry so we can cover these things with chemical entities at low concentration. There was no reaction known before the copper reaction came along that had all of those qualities, so it was a complete revolution for us. We had done the best chemistry there was known there, and we couldn't make all of the bonds we needed to make. It was messy, the yields were terrible, so there's clearly something else was needed.

ZIERLER: How much did this change your lab as a whole? What was an incremental change? And what was really a new direction, things that even your students needed to change?

FINN: The idea of playing with viruses, that was the change. If the copper reaction hadn't come along, we would have continued to play with viruses; we just wouldn't have been as good at it. But we would have proceeded on that route because there was so much to do there. But the copper reaction changed our effectiveness and therefore the speed at which we were able to operate. Then, the mechanistic work that we started to do, that took up two or three of my wonderful students for years, and that's because it was such an important process. It was immediately recognized to be a revolutionary process. That also was very important to us and very important to the field. So, that was also a change, but all of that happened over a period of a couple of years. Click chemistry itself, for me the best part was just talking chemistry with Barry all the time. And that was in the vehicle of click chemistry because we were thinking about that. The in situ click chemistry was really important fundamentally. It hasn't gotten a lot of play—as much play—because it's harder to do, but conceptually that was a foundational component of click chemistry overall, and really, really, really just got my reactivity juices flowing, as it did with Barry's. It changed my life immeasurably. But it all was just being on the rocket ship, on the Sharpless rocket ship. That was it.

ZIERLER: Once you start thinking about viruses, is viral evolution there for you in the beginning, or that sort of develops later on?

FINN: What comes pretty quickly is immunology. Initially I didn't know anything about immunology. Our initial focus was viruses are polyvalent, this repetitive structure I was talking about, so we knew that interactions with cells—cell-to-cell communication—was all about polyvalent interactions, and, it turns out, carbohydrates. So, that started our interest in carbohydrates. We were thinking of making particles that displayed ligands, or displayed molecules, that interacted with cells in multivalent ways, and we could program those structures in ways that weren't known before; because viruses had regular structures and we knew where the atoms were, so we could put things in precise distances. We were starting to think about all that, and every time I would talk about it or we would start to talk about it, we published a couple papers and people would say, "Hey, don't you know they're immunogenic? What about the immune response?" We were thinking about putting them in—finding target cells in the body. "Immune response? What? They're immunogenic? Tell me about this."

Okay, so now we have chemical-modification control over something that's immunogenic. What do I need to exploit this? I need to learn immunology. Or more importantly, I need to find immunologists who are willing to work with me and talk to me and teach me. So, that then started a relationship that persists to this day with Luc Teyton, a wonderful immunologist at Scripps, and other immunologists there. And that's what got us into biology in a real way, was the immunology part of it. Evolution came later, although my interests in evolution are wrapped up all in chemistry. And this is a story that people have heard Barry and I tell about this book, Out of Control, which is all about evolution. So, I was thinking about evolution, and that seeded my appreciation for viruses, but we didn't start to think about trying to evolve viruses or modify them with those techniques until much later.

ZIERLER: Are you thinking at Scripps about biotech yourself, about translational biology? Or does that not yet come until you get to Georgia Tech?

FINN: No, that definitely was at Scripps, and that was you start thinking about immunology, you start thinking about that kind of thing. But again, I wasn't known. I didn't have experience in translation, and there were people around who had much more experience in it than I, so I didn't try to step into that world in a major way. I was happy to try to talk with people who did, and hand off and learn what you had to do to think about it, but it wasn't a concern of our lab at the time.

Lab Funding and the Business of Grants

ZIERLER: What was the decision making to transfer over to Georgia Tech?

FINN: It was a couple things. I love Scripps and still to this day. It became a point where my group was large enough—was rather large—and because of Scripps financial structure at the time, I was just spending a poisonous amount of time writing grants. And though I love writing, and I actually like writing grants, but it just became, "Okay, is there some way I can carve out—I can make this a little easier?" So, that was what kind of got me looking around a little bit. Georgia Tech had actually contacted me years before, so I had known them and I got to know some of them. But also with click chemistry came an interest—or actually preceding click chemistry—in material science. I had long wanted to do materials chemistry, and that was almost impossible to do it at Scripps because there was nobody around doing it, and you need an environment for that. I had the only GPC at Scripps for years. I had the only NSF grant at Scripps for years, for this. And Georgia Tech is the Scripps of material science, so coming here fed that aspect. Then I learned about the immunology in Atlanta, and I realized I didn't have to give up very much in the immunology space when I moved here, in terms of expertise and just energy around me in that space. And then Georgia Tech had some opportunities that Scripps didn't in terms of leadership and doing other things. I didn't come here to be department chair, but that came shortly thereafter. So, it was a friendly move; it was a pull, not a push in any sense. As I say, I'm incredibly grateful to Scripps. Changed my life. But this was a good move.

ZIERLER: If you could explain it just to clarify, why was the burden of grants reduced at Georgia Tech? It's the same research.

FINN: For those who aren't in the biz, the overhead rate (at Georgia Tech) — at that time, Scripps has brought its overhead rate down since — was half that of Scripps, which means that your money goes much farther. And I didn't have to pay my salary, so I didn't have to raise that money, so that could go into the laboratory. So, it's primarily overhead and salary, and most of the other costs are pretty comparable.

ZIERLER: Did you bring most of your students? Did you basically pack up your lab? Or, to what extent was there an opportunity to build anew?

FINN: My senior students finished out at Scripps. One of them transferred to another laboratory that was a collaborative lab and finished out her work there. Another couple came with me to Georgia Tech to finish out their work, but they got Scripps degrees. Both institutions were just very, very helpful in that regard. And then a couple postdocs moved with me. So, I moved six people when I came to Georgia Tech, and a couple stayed behind. And then others—I had known I was going to move, so they had moved on by the time we made the move.

ZIERLER: The dominance of engineering at Georgia Tech, was that just a fun thing for you, or did that really become useful?

FINN: Oh, it was always a plus; I love engineers. I'm half an engineer myself in the sense of having a focus on trying to make things practically work, making things work at scale, and making things work as simply as possible. But the engineering mindset is just a very happy one to be around, so it was always a plus for me. I'm a scientist. I'm a basic scientist. But again, I really play well with engineers.

ZIERLER: In making the move, where was there an opportunity to push into new research?

FINN: That was really in the materials space for us. We immediately got involved in a wonderful collaboration, which again, was going on great guns with a young faculty member at the time named Ryan Lively. This was in membranes, and I had an idea I wanted to do water purification with some click-chemistry-enabled materials. I got to Georgia Tech and called up the eminence in this field, this guy named Bill Koros who is a wonderful fellow and part of collaborative projects to this day. Bill is the founder of a lot of membrane-separation science. I introduced who I was, and told Bill, "I have this idea." And Bill said, "Well, I'm pretty full up with collaborations right now, so why don't you go talk to this guy, Ryan Lively?" I talked to Ryan, and six months later we had funding, and away we went. And it was like, Oh my goodness! I'm in an environment in material science just like Scripps was in immunology and biology. You can't swing a cat here without hitting somebody who does materials in some sense, or does modeling, and does all the things that I don't know how to do that is relevant to this kind of work.

Recent Advances in Materials Science

ZIERLER: So, again, being a product of your environment, the material science was very much an outgrowth of what was happening around campus?

FINN: Yeah. Now, in that case, I brought the desire to do it, so I knew what I was getting into, but the specifics of what we were doing, or what we wound up doing, that was very much a product of the environment.

ZIERLER: What changed your lab, now thinking about material science? What were the new techniques? What were the new concepts to look at?

FINN: Again, kind of rooted in we can bring bond-making value, then the question is, To what are you going to apply that bond-making value? And from a basic science position, what we were very good at was, at the time, modifying pre-existing polymers, and I was looking for what an application area would take advantage of that. What could I do that would have a good outcome in terms of bringing some value to the world, but that could test and take advantage of our ability to functionalize polymers in ways that people weren't doing very much with a diversity of functional groups? And that's how this connection with the Lively lab with Ryan became important, because I had no idea that the world of separation science had need of new materials, and how important it was. So, here's a stat: one percent of the energy that humans use on the planet and ten percent of all of the industrial energy that we use as a species is in the separation of the components of crude oil. Park that in your brain for a minute. The scale is unimaginably large, and of course it has enormous consequences for the environment and the planet. The more energy you use by burning fossil fuels, the worse off we, are and we use a hell of a lot of energy just to refine petroleum. It turns out the world of separation science had no way to separate the molecules of petroleum just using filtration rather than distillation. And that was the problem that Ryan was working on. We brought new chemistry to that enterprise, and we've actually made some really nice advances in that field. And again, it was again product of the environment. What are we going to apply it to? And what a phenomenally interesting problem. Sounds boring, but it turns out to be really interesting to separate molecules on the basis of their size and shape.

ZIERLER: It's another area to get involved in, sustainability. It's as important as anything.

FINN: Exactly right.

ZIERLER: M.G. tell me when COVID hit your work on vaccines and viruses was there a chance for you to contribute?

ZIERLER: Yeah, we really were lucky, in a sense, there. The CDC is here. The Centers for Disease Control is in Atlanta, and we had been working with them for a few years prior on doing immunology to help them generate antibodies to molecules of interest. One thing you need to understand about the CDC, which not many of the public knows, is the CDC is the world's diagnostic laboratory. So, no matter where in the world you are, if you have an unusual disease, something pops up and you don't know what it is, you basically call the CDC to see: Is this an infectious agent we've never seen before? Is this a toxin we've never seen before? And the CDC will send people out there, collect it, analyze it, and figure out what it is. There's a whole branch, whole divisions of the CDC that need diagnostic tools to help do this, and it turns out that antibodies are really helpful in this regard. So, by various ways we had partnered up with a core facility at the CDC to help them develop antibodies against red-tide toxins and other things. And then COVID hits. So, we're right there; we know them; they know us; and they need antibodies for diagnostics against COVID. So we pivoted in March of 2020. We started to work with them, and with their partnership, the antibodies that we developed were the standards that the CDC used for the first year and a half of the pandemic came from the partnership with our lab. They were not commercially available, but they were really very, very useful to them, and I'm very proud of that and very grateful to them for giving us the chance to do that. So, we work now continuously with them on variance on antibodies to variances that pop up, and we have an ongoing program with them on that and other things.

ZIERLER: Had you worked on mRNA technology at all prior to COVID?

FINN: No, and we still don't—well, with some small exceptions. No, we're not developing mRNA vaccines. And that work with the CDC wasn't in developing vaccines; that was developing antibodies as reagents, so it was a very different process, again, using our virus particles, actually. So, no, we haven't worked on mRNA delivery.

ZIERLER: What was your first thought about the pandemic? What stuck out in your mind? What was new for you as you were experiencing this?

FINN: What was new? That's a great question. Hmm...

ZIERLER: As in, this is a global emergency early on.

FINN: Well, yeah... I wasn't—you spend time thinking about evolution, and you read a little bit about it; this wasn't a surprise. It was a surprise in the sense, "Okay, which virus is it?" Or, whatever. "Hey, we're having a pandemic." It was a surprise, but not a shock. This is coming; we all know this is coming, so it wasn't conceptually a surprise. It was, "How does the society respond?" That was shocking. I started to become known as somebody who could explain this stuff, so I had a number of interviews on local TV, et cetera, to try to explain. And on campus, what's going on? Our connection with the CDC meant that I was informed fairly well about what was coming. So, throughout the two years, or two and a half years of the pandemic, I would help explain what was going on. But the surprise was really, How do we deal with all this? And I was also an administrator, a department chair, so there was a lot of time and effort in helping our department get through this. What do we do? How do we keep people safe? How do we get people who need to work safely working? Graduate students, what are they going to do? Because they can't do their research. How are we going to support them? There was a lot. Everybody was dealing with this. How do we teach class? How do we in remote mode, and what does that mean? Of course, I was just trying to help people figure this out, but people did an incredible job. It was a lot of mechanics as well. What was surprising was, How does society deal with this? And it was just a crazy time, as we all know.

ZIERLER: Did the pandemic change your perspective on viruses? Did it change your perspective on how to research viruses?

FINN: No, really not. As I say, it was scientifically not a surprise at all. It of course supercharged a lot of great science, and the mRNA vaccines are of course the prime examples of that, but there's been some wonderful science done. Scientific communication is way better. The vaccine came about because the genome of SARS-CoV-2 became instantly publicly known. That hadn't happened before. So, there's a lot of—I hate to say—a lot of good stuff, in a sense, came out of it. But no, it didn't change our perspective—didn't change my perspective—on viruses or on the problems that we wanted to attack. We were already trying to do immunology.

ZIERLER: M.G., we'll bring the story right to the present. What are you currently focused on?

FINN: As is normal with our group, we're doing a lot of different things. We are getting deeper and deeper into mechanistic immunology with the help of some wonderful colleagues at Emory and at Georgia Tech. We're actually delving farther now into HIV vaccines than we have before, with some interesting new approaches. We're combining chemistry that we've been developing over the past decade, which is click chemistry, but also reversible chemistry. So, highly reliable, but reversible, releasable chemistry. We're doing a lot of drug delivery stuff there, and I'm most excited about how that impacts making vaccines and delivering vaccines. We're really beginning to dive deeply into the timing of vaccine delivery and how that impacts the immune response, so that's an area of great continuing interest. We're doing more and more continuing the work on membranes for different kinds of applications, and there, machine learning is becoming now very exciting.

We've partnered with an amazing group here that does AI on polymer properties. The name is Rampi Ramprasad. The Ramprasad group is one of the world leaders in predicting the properties of polymers using machine learning algorithms, so we're working with them to help them test those algorithms and use their expertise to predict properties of membranes and of materials and make those materials. So, that's super exciting. And lots of little stuff happening. We have a tradition in my lab called the Friday Afternoon Experiment, which doesn't have to happen on Friday afternoon, but it's a crazy idea you're going to test. You don't have to tell me about it; you don't have to tell anybody about it if you want to give it a shot. And if it works then you talk about it, and if it doesn't you don't have to. So, we've got a bunch of stuff that comes out of Friday Afternoon Experiments that we're trying to nurture.

ZIERLER: M.G., for the last part of our talk I'd like to ask if you retrospective questions, and then we'll end looking to the future. Of course what brought us together is your time at Caltech, those very formative years as an undergraduate. What has stayed with you since? What has served as a guiding light for all of the science you've done in your career?

FINN: The way that Caltech made being a nerd okay. It's a community of the nerdiest nerds in the world, [David laughs] and it is such a special place. I've never been anywhere else like it, and it is such a welcoming place for thinking crazy thoughts and being a nerd in the best sense of that word: caring about knowledge and caring about the stuff that you don't want to show if you're in other company because you look like a nerd. Anyway, it was that. It was that joy and realizing that there are other people around who were just as clueless, who were super smart—way smarter than you—and just as clueless as you are. That was also an enduring lesson. There were these Putnam Award guys in math—or gals—that ran rings around me at math when they were asleep. And they had trouble with chemistry! So, it's like, "Oh my God! Okay, I can hold my own here." That was an enduring help to me. And then the other lesson was the fact that faculty treated you like a person, like a colleague. I told that story about Fred Anson starting out treating me that way before I was a freshman. That was a constant theme at Caltech, and that has stayed with me. I hope it has informed the way that I deal with people. It's certainly a model to try to emulate.

Amplifying the Scientific Method

ZIERLER: In reviewing or reflecting on your scientific accomplishments, I wonder if you can explain the different satisfactions in a discovery that happens in your lab that's just about fundamental research, basic science; and the satisfaction of, if not from you directly, the application, the taking of that discovery ultimately, hopefully, for helping people.

FINN: They are equally as rewarding, I'll say, at least in my head. To our new graduate students, I give a talk every year about strong inference, which is actually a subject that Barry and I both love. This wonderful paper by John Platt in the '60s about how you do science is basically really amplifying on the scientific method. And in that lecture I talk about what is science, and what is—I'll put in the bin of engineering—but it's really fundamental stuff or applications. Science is when you're trying to answer a question to which you don't know the answer, where an unexpected result is what you're looking for. Engineering is when you're trying to make something, where an unexpected result sometimes is a pain in the ass, because you're not making what you need to make in order to have the function that you want to have the impact on the world that you're looking for. So, the lesson there is don't delude yourself. When you're doing engineering, call it engineering; think about it that way. When you're doing science, think about it that way. But neither one is better than the other, and neither one of them is actually more satisfying to me than the other. In the very rare cases where we come up with a fundamental insight, that is that's the mountain top. When we have a great vaccine candidate, that's an equally high mountain top; it's just the mountain range next door. So, it's a lovely profession to be in.

ZIERLER: M.G., you joked earlier that you're half an engineer, so this is as much a philosophical question as a scientific question: In the creation of ideas and discovery, where does the technology enable the discovery, and where does the imagination require new technology?

FINN: As with many of the answers to your penetrating questions, the answer really is a continuum. I know of discoveries—and again Barry is my exemplar in this regard—that really come from deep insight and knitting together a career of knowledge in a way that has nothing to do with the technology, but has everything to do with what's going on in synthesizing these complex these concepts. But there's a hell of a lot that goes on that depends on the technology where the discoveries are just as important, or more so, because the technology existed. DNA sequencing: if that hadn't happened biology would be dead, pretty much, or we would be still drawing pictures of organisms out there in nature and that's about it. So, that technology obviously made all sorts of other things possible, and that happens again and again and again and again. Combinatorial science, I often say—and click chemistry—takes the challenge away from making stuff and gets it into the area of finding out what that stuff does.

That is very often technology limited and technology driven, so there are more discoveries made on the backs of technology than there are on the backs of pure insight, but they're, again, a continuum. You can have a weird idea, and if you don't have the technology to verify it or extend it or whatever, then you'll it'll never go anywhere. That's kind of somewhere in the middle. You need an insight in order to know what to do with these great instruments. That's definitely in the middle. You need to know what questions to ask. So, for me—and I should have mentioned this before—one of my chief joys about interacting with people in industry is they ask questions that we don't ask in academia typically. And finding out where the important questions are in a field is the most important thing you need to know when you're getting into a new field. Where are the boundaries? What questions are people trying to grapple with? What can't they do that they want to do? And that is hard-won knowledge. It typically takes you years of reading, but if I can find that out by working with people, sharing credit, collaborating, and finding out where those questions are sooner, I'm all for that. So, technology helps when you know where the questions are, and enough to ask the right questions, then technology can really help.

Graduate School is for Singular Focus

ZIERLER: M.G., for my last question I want to make it student-centric, looking to the future. The trajectory of your career is so emblematic of one of the great convergences in science: the chemistry, the biology, the material science, the engineering, the fundamentals, the translational, it all sort of comes together; but that is also reflective of generationally, how you're a part of that wave. For graduate students today who recognize that this is what's required, how do you as a mentor balance the classic breadth-versus-depth question, where there obviously is the expectation for their own careers to be involved in all of these different areas, but at this moment in their life they really still need to drill down on a specific problem? How do you deal with that?

FINN: This is the reason why we give PhD degrees and the reason why the PhD is structured the way it is. A PhD is an exercise in becoming expert at something. You're diving deep, but much more importantly, it's an exercise in experiencing how to become an expert, feeling what that's like, and understanding the level of mastery that you need so that you can do it again on something else, faster. And you can do it again and again and again. Maybe not become the world's expert, but become enough of an expert not to make an idiot out of yourself when you're trying to solve the next problem or whatever it is. That's the message I give to graduate students. Don't worry about breadth so much in your PhD, but remember that once you're done being so narrowly focused, then take a step back and say, Okay, I'm never going to do that again—that particular subject—but I'm going to be able then to go to the next-door field, or who knows how far away, and figure out how to make it work. That's the message. From an operational point of view, do your PhD, whatever it is. It almost doesn't matter. And then for the next stage in your career, do what I did: go find a postdoc that's in a different field to which you can contribute—so you bring value; always bring value—but that is enough far afield so that you have another base of knowledge now that you can then operate from. When your feet are spread far apart, you're more stable than when they're close together, so get as far apart as you can in areas that interest you.

Here's my last homily for the day: I hate the word "passion" when you're trying to advise people. That's just—I hate that. My advice is: Don't find what you're passionate about; find what you want to work hard at. That's the key. That's the key question. And if you can find more than one thing that you want to work hard at so the next thing you go is that mountain top next door, then you're on your way. That's the message I try to transmit.

ZIERLER: M.G., this has been a phenomenal conversation. I want to thank you so much for spending the time.

FINN: Thank you for asking me.

[END]

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