An academic family tree can help us visualize the exponential scientific impact of a single professor and his or her research lab. Over the course of his career, Peter Dervan has mentored dozens graduate students and postdoctoral scholars, and together, the Dervan Group became a world leader in the development of chemical biology. As the saying goes, a true leader does not create followers; a true leader creates leaders. And so it goes with Pete Schultz, a Dervan PhD student who went on to a massively impactful career at UC Berkeley and who is now President and CEO of Scripps Research.
Among Schultz's mentees is Kevan Shokat, one of the world's leading chemical geneticists, whose studies of signaling proteins is offering new perspectives and therapeutic breakthroughs on a variety of human diseases, and in particular, cancer. With his dual appointments at UC San Francisco and UC Berkeley, Shokat is intellectually and geographically positioned at the heart of the Bay Area biotech nexus, which combines the resources of academic institutions, philanthropic initiatives, and commercial ventures in the pursuit of understanding and ultimately curing diseases.
In the discussion below, Shokat reflects on the very direct lineage that connects him to the Dervan Group, how and why Caltech became a leading institution in the creation of chemical biology, and why discovery begets discovery in science. And like all great scientists, Shokat conveys excitement in his own role as a mentor, as technologies and new classes of students bring new capabilities and fresh perspective to the most complex and demanding questions at the interface of chemistry and biology.
DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Thursday, November 2, 2023. It's my great pleasure to be here with Professor Kevan Shokat. Kevan, wonderful to be with you. Thanks so much for joining me today.
KEVAN SHOKAT: Thank you, David. This is great. Been looking forward to it.
ZIERLER: To start, please tell me your title and institutional affiliation.
SHOKAT: Yes. I am Professor of Cellular and Molecular Pharmacology at University of California, San Francisco. Also, a Howard Hughes Investigator. And also, a Professor of Chemistry at University of California, Berkeley.
ZIERLER: The duality of the appointments between Berkeley and UC San Francisco, does that just give you wider latitude in terms of research tools and collaborations? What's the interest there for you?
SHOKAT: It was mostly to expand the chemical biology access of students across the two universities. A number of years ago, some students at Berkeley were interested in chemical biology, and there were a few labs. But actually, the departure of Peter Schultz made it a little bit less attractive. When I was recruited to UCSF, I received an appointment at Berkeley to sort of expand that ability of students. It's kind of to help student recruitment and give them more options in one sub-area of chemistry.
ZIERLER: Being a Howard Hughes Investigator, is that more of an honorific, or does that really allow you to do things that wouldn't be possible without that?
SHOKAT: Yeah, the latter. It's basically about $1.5 million in grant support every year for seven years, and then it's renewed. It's the kind of a grant that is given to a person and their lab, not to a project. The money is very flexible in terms of projects, so that gives me huge leeway to do things.
Leukemia Research Breakthrough
ZIERLER: Being in the Bay Area, working at the interface of chemistry and biology, how translational is your overall research agenda now relative to what it might've been a decade or two ago?
SHOKAT: Two decades ago, it was really barely translational. But something happened about 24 years ago, which was the approval of Gleevec, the drug that treats CML, a kinase inhibitor. And that was kind of the first targeted therapy, and we were working on protein kinases. Seeing a drug approved in a family of proteins we were working on all of a sudden kind of had me raise up my head to look around. And then, since that time, it's just gotten more and more translational.
ZIERLER: Does that mean that you have direct interface with biotechnology companies? Are you ever in the hospital? Are you involved at all with the Chan Zuckerberg Initiative, things like that?
SHOKAT: No, I don't do anything in hospitals, and I don't have any affiliation with the Chan Zuckerberg Initiative. As it turns out, Howard Hughes investigators are not allowed to work with Chan Zuckerberg, there's some disagreement on what nonprofit research means, I guess. I don't know exactly what it is. [Laugh] But I do work a lot with biotechs, yeah. We started a number of them and licensed a number of compounds to pharma companies, sit on a number of boards, and things. That sort of helps our molecules get farther down towards the clinic and approval, and it also sort of helps me understand the challenges they're facing, whether there are basic questions we could investigate that would help solve problems that pharma companies are facing. Then, 10 years later, have that product and sell it to them.
ZIERLER: Just as a snapshot in time, November 2023, what are you working on right now? And more broadly, what's interesting to you in the field?
SHOKAT: I think the two things we're working hard on are targeted therapies, which are the kinase inhibitors, and now these KRAS inhibitors that we helped make, and then we know targeted therapies in cancer patients can have a great effect, shrink a tumor, but often the tumor comes back. On the other side of immune therapy, we know that can be a cure, but only in a subset of a subset of patients. What we're trying to do is bring those two things together and engage targeted therapies in a way that educates the immune system to also attack the tumor, so that's what we're working on. We work on new targeted therapies if there's no drug, but then the linking of the two things is what we think could be a real breakthrough combination therapy.
ZIERLER: Tell me about the graduate students and the postdocs that are attracted to work in your lab. Do any of them have an MD or have aspirations to work in a clinical atmosphere, given the research focus that you have?
SHOKAT: Starting with one student, Beth Apsel, over 10 years ago, she was the first MSTP, medical science training program, student in the lab. And since then, I've probably had about 8 or 10. There are usually one, two, or three at a time in the lab, and I think they really like the idea that the things they work on can lead to a drug, and there's a real patient population in mind when they're working on that. One of them that worked in the lab was John Ostrem, who's back here now at UCSF as a lung cancer oncologist, and he worked with a postdoc, Ulf Peters, and discovered the first KRAS drug. That's a pretty amazing thing for a student that's going to become an MD/PhD student to have participated in. It's been fantastic to see that.
ZIERLER: The breakthrough you referenced earlier from 24 years ago, was that more of a conceptual eureka moment? Were there breakthrough technologies that made this happen? Was it really just about grinding it out in the lab? What accounted for this?
SHOKAT: It's fascinating, it really, I think, was the brain child of Brian Druker, who's now up at Oregon Health Sciences, and he really just recognized that this BCR-ABL oncogene transforms cells, it's in almost all of his patients that have that disease, and he knew that a chemist at Ciba-Geigy, Nick Lydon, had made a kinase inhibitor of that. And he just said, "We should try this." But Novartis was very resistant because there were only about 10,000 patients, so he had to kind of just keep explaining the logic. [Laugh] Finally, once the trial was there, people from all over the world were just a magnet to Portland to get on this trial. And it made Novartis billions, despite the small number of patients. It overcame so many biases. Small patient population. It's a breakthrough, transforms their life, and they stay on the drug. It's amazing how people didn't see that before, but he really brought that.
ZIERLER: I wonder if you can reflect on how the life sciences, biological research, has really become a big data enterprise over the past 20 or 30 years and how that's affected your lab, your approach to computation, or even more recently, AI and machine learning.
SHOKAT: I'd say that it hasn't yet made a difference in our lab. I'll give you an example. You might think AI is going to tell us about new drug targets, and we can mine so much data. But actually, the target we work on, KRAS, was discovered in 1964, discovered to be a human oncogene, the first one, in 1983, and then subsequent to that, 30% of all cancers have that same mutation. We've known about that, but nobody could make a drug for it. We didn't need AI to tell us about KRAS. [Laugh] And then, whenever we've tried to use computation, it has not helped us with that project because the protein's flexible, and nobody saw the pocket until we had a drug that made the pocket. We kind of tend to work on problems that, at least right now, haven't been a breakthrough there. But it's changing very rapidly. On Monday, AlphaFold people said they have a computational approach for small molecules now. That's what we've been waiting for. I might have a different answer next week. [Laugh]
ZIERLER: Staying on the technology theme, what about instrumentation? Have there been breakthrough advances in microscopy or lab techniques that have really pushed discovery ahead in the course of your career?
SHOKAT: I would say for us, a really good thing is just mass spectroscopy. It's been much more user-friendly, more sensitive. We've got our own mass specs now for proteomics, for small molecules. That's helped us with synthetic chemistry and proteomics. We don't use microscopy a ton. I'd say the biggest thing is NGS, sequencing. It just can't be overestimated. It's so powerful.
The Origins of Chemical Biology
ZIERLER: Let's get to the main topic at hand now. I'm learning about the development of chemical biology as a discrete discipline and the institutional role that Caltech played in it. Let's just start with terminology. What does chemical biology mean to you, and has that term changed since you first encountered it maybe as a graduate student?
SHOKAT: Yeah. I think right now, chemical biology, to me, means using chemistry to study biology. I think the way it started was, the term would've been bio-organic chemistry, which grew out of several sub-disciplines, natural products, and trying to emulate biology with small molecules. Like Ron Breslow's host-guest chemistry. But I think now, chemical biology is now using as much as chemists like to say that chemistry is the central science, I do feel like biology somehow really became the orb that we're trying to understand. I think chemists realize how powerful chemistry is to study that, and that's what chemical biology is. And then, I sort of think of chemical biology as a path to a drug, but it doesn't always have to be. The other term people wonder about is pharmacology because that's using chemistry to perturb biology. What I like to say is, when chemical biology works, it becomes pharmacology. Because if everything all works, you can put it in an animal, put it in anybody. That's kind of the transition point, my borders of things.
ZIERLER: The metaphor of biology as the bigger orb, is that to say that biology is just so interesting, so vast, that chemists can't not pay attention to it? Is that the broad story here?
SHOKAT: I like that, but I also like that in a way, it's bounded. We know chemical diversity is more diverse than atoms in the universe. We can make more molecules than we have atoms in the universe. You can just keep making molecules. But if you're really trying to study biology, it really forces you into a box, and you have to make your chemistry work there. And to me, that is a lot more–it creates a different kind of creativity. It really forces you to do it. I think Peter Dervan's work forcing himself to stay in the minor groove of duplex DNA and how to recognize that year after year until he could do it, that's exactly what I mean. It's like, "No, I'm not going to bind to some polymer, I'm going to bind to this polymer."
ZIERLER: I'll ask it as more of a sociology of science question, and that is, who is in the club of chemical biology? In other words, 30 years ago, when it would've been almost exclusively chemists who were interested in solving biological problems, is that more or less true today? Or do we see biologists now reversing that, and they're interested in chemistry, and they're calling themselves chemical biologists also?
SHOKAT: That's a good point. I think there have been biologists who did their PhD in biology, then went into chemistry or chemical biology labs, and then came out as chemical biologists. The person I think of is Craig Crews, who did his PhD with Ray Erikson, kinase signaling pathways, and then did his postdoc with Stuart Schreiber. And now, he does proteolysis targeting chimeras. A real chemical biologist. There are people like that. It's definitely fewer. I still think a lot of people come from a synthetic background, go into chemical biology labs, and then become chemical biologists.
ZIERLER: Because there's always a story behind the administrative decisions of which faculty sit in which departments, where is chemical biology at both UCSF and Berkeley? Where would the chemical biologists sit in the bigger schools?
SHOKAT: The bigger schools, always in chemistry. I honestly still don't think biology departments or molecular biology departments like chemical biology. [Laugh] Biologists are interested in the problem, and they'll use whatever tool they have. Chemical biologists have the tool of chemistry, so they've got to look for problems that match. I think when I looked for my faculty positions, no bites from molecular biology, biology, or anything. That was a long time ago, but I still think it's true.
The Dervan Scientific Lineage
ZIERLER: We'll go back and establish some personal history, but before that, I wonder if you've ever thought about the academic and intellectual lineage that connects you to Peter Dervan through Pete Schultz? What does that look like in your mind?
SHOKAT: It's a definite direct track. I think my career was really changed when I met Pete in my interview for graduate school at Berkeley. Went into the office, heard about his three projects, left the office, and that was the only thing I wanted to do. [Laugh] Then, as I got to know Pete, and then got to know Peter Dervan, and got to know what Pete did in Peter Dervan's lab, and saw Peter Dervan's career and discoveries and their impacts, I could kind of see the strands that connected them. And Peter Dervan was very supportive of me early in my career. Even though I hadn't trained with him, he provided letters and was really, really helpful. It was nice to be in that sort of arena that a student of Schultz's was definitely supported by Peter Dervan.
ZIERLER: Let's establish some context before you get to Berkeley. As an undergraduate at Reed, were you already thinking about chemistry and biology, connecting the disciplines? Or that really only became real for you once you met Pete Schultz?
SHOKAT: I think it was more enzymology at Reed, traditional biochemistry that I was doing. Then, when I heard the projects that Pete was working on, it dawned on me, "Wow, you can do chemistry and manipulate or study biology." I was just like, "Wow, that's not anything I conceived of as an undergraduate." It immediately clicked.
ZIERLER: Coming from a small teaching-focused four-year school to an enormous research university, what was that transition like for you? Did you encounter professors in undergraduate who were engaged in original research?
SHOKAT: Yeah. At Reed, you do an independent thesis, so you actually spend a whole year doing your own research project. And mine was with a professor named Ron McClard, who was very prolific, had his own grants. It was a very intensive research project. I published three papers there, and each month that went by, I got more and more excited about research. I got definitely a lot of exposure there.
ZIERLER: Beyond Berkeley, where else were you considering for grad school?
SHOKAT: MIT. I was thinking of working with either Chris Walsh or Dan Kemp. But once I met Pete, and since I was from the Bay Area, it made sense. Also, visiting MIT in February or March as somebody from California… [Laugh]
Making CRISPR Possible
ZIERLER: You mentioned Pete's three projects that were so compelling to you. What were they? What was he working on at that point?
SHOKAT: Sequence-specific DNA cleavage by taking a non-specific DNA and attaching an oligo to it to sort of bind and then cleave. And that was Ron Zuckerman and Dave Cory's project. The other one was a natural amino acid mutagenesis, 21st amino acid, stop codon suppressor tRNA. And then, the third one was the one I worked on, which was catalytic antibodies, getting the immune system to make enzymes. And each year that goes by, I think about those three projects. They're mind-blowing. [Laugh] The first one is basically a chemist's version of CRISPR. It's like the thing that…
ZIERLER: I wonder if you can narrate the significance of that comparison.
SHOKAT: Pete realized from working with Peter Dervan that recognizing DNA sequence specifically, and cleaving it, and doing it at resolution that would allow you to be single-site specific in a whole genome, that was the goal. We had to get there. And he knew about sequence non-specific nucleases that could cleave anywhere, but they were misdirected. He, then, attached a new cysteine and an oligonucleotide with a thiol, they made a disulfide. Now, you would direct your DNA non-specific nuclease to where it would hybridize. The thing worked. But the problem was, it's the whole protein with the DNA attachment. CRISPR is basically a nuclease that has a guide RNA that binds non-covalently to the non-specific, and then it cleaves. It Pete had engineered it to bind an oligo non-covalently and redirect, that would've been CRISPR. [Laugh] It's amazing to me. I chastised Doug Clark, the Berkeley dean, when he introduced Pete a number of years ago because he introduced Pete about 21st amino acid and catalytic antibodies. I was like, "Doug, you didn't mention the early CRISPR." [Laugh]
ZIERLER: Your slotting into the catalytic antibodies, was that your choice? Was Pete's style as a mentor such that he assigned you to that group? How did that work out?
SHOKAT: Yeah, I think he just had so many ideas, and Andrea Cochran and I were the two graduate students who joined that year. And he just had six catalytic antibody projects. Andrea got three, I got three. [Laugh] And by the end of it, I had, like, 10 projects. I think he had a very good sense of which projects were right for people to join, where we needed more person power. He also kept a very good eye on the progress, so he could tell, "Are we getting this closer, or are we running into walls?" After about three or four years in the lab, he was like, "Kevan, the projects we started on are just really hard. They're not quite getting there. We have a postdoc who's leaving, and he didn't finish a couple projects. Take those over." And those turned out to be my first really big projects. I was really grateful that he always had a sense of where to move the people and get things done. And it taught me a lot about how to run my lab.
ZIERLER: What were the big research questions that drove your thesis work? What were you after?
SHOKAT: The biggest one was basically a designer protease that could cut amide bonds anywhere we wanted. And the challenge was that antibodies really have never been able to do that. They don't have the flexibility, the catalytic horsepower, if you will, to do that. Every time we tried to isolate one, we had the problem that it could've been contaminated with the protease natural one. And so, I really kind of advocated for trying to cleave a non-natural sequence, I think a lot of us in the lab did, so that there would be no chance that we would be fooled by a contaminant. By the time we kind of worked through that, we just were zero, zero, zero, zero. [Laugh] But at least it taught me, "Okay, that's a good control. Make sure you're not going to get fooled." I loved the time and all the people in the lab. It was a very, very special feeling and just fully engaged. It was great.
ZIERLER: I wonder either through osmosis or explicitly from Pete, did you get a sense of the legend of the Dervan lab, what was going on at Caltech? Or that came later for you?
SHOKAT: I think that came later. I guess it was just so all-consuming for Pete starting his own lab. I was in the third group of students. When I joined the lab, there were, like, nine people. When I left, there were 40 people. [Laugh]
ZIERLER: What explains that explosive growth?
SHOKAT: It's the number of ideas and the ambition, I would say. And the number of good ideas to pursue. Cleave DNA, cleave RNA, make a protease, make a glycosidase, make a chorismate mutase. There was all the 21st amino acid stuff. What I loved about it is, every project had an amazing goal, but he broke it down into such doable steps that actually each step seemed very feasible. [Laugh] By the time you just put them all together, you get up here, and once you get there, there are whole other things you can do. It just accelerated.
ZIERLER: Do you remember the term chemical biology being used as a graduate student? Would you have said you were working in a chemical biology lab, or it was still bio-organics?
SHOKAT: It was still bio-organic then, yeah. I think chemical biology maybe was more, like, late 90s. Because even then, Stuart Schreiber and K. C. Nicolaou, when they started that early journal, it was called Chemistry & Biology, and then later, when I was one of the editors, we changed the name to Cell Chemical Biology. It kind of had bio-organic chemistry, then it was chemistry and biology for a brief time, because of the journal, I guess, and then chemical biology.
ZIERLER: To connote what? Why does the simplicity of just chemical biology work so well?
SHOKAT: I guess it just captures that idea of using chemistry to study biology. Bio-organic still had that natural product sort of designed-molecules flavor that wouldn't necessarily focus on the biological impact of them. And chemistry and biology wasn't a great name, it just didn't have the staying power.
ZIERLER: As a graduate student, was biotech already a factor? Was that already in train? Were people like Pete Schultz already talking to pharmaceutical companies?
SHOKAT: Yeah, he was always, I think, consulting with Big Pharma companies and then became one of the early people at one of the early combinatorial companies, AffyMax, that was probably one of the–after Genentech and Chiron, then there were a number of biotech companies that were growing, and one of them was AffyMax, which he and Lubert Stryer, as well as others, worked on. That gave rise to, like, five or six companies. That was going on when I was a graduate student. I was peripherally involved.
ZIERLER: Looking now at what Pete's doing at Scripps, I wonder if you could reverse engineer and look back to when you were a graduate student and see that that was where he ultimately was headed.
SHOKAT: I think so, because the jump from Berkeley to Scripps was really motivated by the Novartis Institute that he set up. That was like his lab on steroids. [Laugh] It was clear that he had a lot of great ideas. It was at a time when the genome was completed, so we had the entire list of all proteins. There were a lot of great ideas to go after there. It made a lot of sense right then.
Understanding the Biological Impact of Catalysis
ZIERLER: Looking back on your thesis research, what do you see as its principal conclusions or even contributions to the field?
SHOKAT: I think what we learned was, we were trying to make catalysts that did whatever we wanted, and we understood from Dick Wolfenden and other enzyme chemists that it was the transition state stabilization that helped enzymes catalyze reactions. And antibodies are fantastic at binding. It seemed like an absolute surefire hit. But what we didn't take into account was that you can't make a perfectly stable transition-state mimic. That is by definition impossible because the bonds are not stable, they're at the highest energy. And even when we make a good mimic, it's not perfect. That's probably why it didn't reach its full potential. And then, I think enzymes also are orchestrated to make dynamic changes to help the reaction proceed, and an antibody is just recognized, so they don't help things get across. It was a great vehicle because it took the binding too its maximum, and then we still saw, "Wow, catalysts are still amazing." [Laugh] And I personally still don't think we understand that gap. I still see papers where people say, "Oh, this is how catalysis works." I'm like, "Well, I still don't think we understand." It makes me appreciate how amazing enzymes are. In my own lab, it's interesting that we study really crappy enzymes because that's what evolution picked for signaling. [Laugh] They're not impressive at all, but they do interesting biology, so that's what makes them interesting.
ZIERLER: Was biotech research ever a consideration for you? In other words, could a career in industry have been a viable path for you? Was that available back then?
SHOKAT: I think it was, yeah. A number of people from Pete's lab went to those companies, AffyMax, Affymetrix, Maxigen. And I would've definitely, I think, been happy doing that. I just think that I really liked the creativity I could see Peter Dervan and Pete Schultz apply. And I could see in the companies, they were kind of boxed in, like, "We need to do this." And that wasn't my forte. I liked the thinking of a new thing and then trying to make that happen. I think at companies, you have to really have a lot of stamina to bring things all the way to the clinic, and I'm not the best at that level of detail for that long on one thing.
ZIERLER: After you defended, were you looking at postdocs and faculty positions in tandem? What did the job market look like then?
SHOKAT: No, I went to a postdoc, and I did it in immunology because I was working on catalytic antibodies. I looked around, and I thought, "There aren't that many chemical biology labs. There's Stuart Schreiber, there's Chris Walsh. It would be more training like I have now in Pete's lab, so I should learn biology," so that's what I did.
ZIERLER: Did you ever consider Caltech for a postdoc? Did you meet Peter Dervan as a graduate student?
SHOKAT: Yeah, I met Peter as a graduate student because we Pete was getting recruited to Caltech. I went down with Andrea and another student, and we looked at Caltech that day to kind of see if our lab would be good there. We thought it would, but ultimately, Pete stayed at Berkeley. That's where I met Peter Dervan.
ZIERLER: Where did you do your postdoc in immunology?
Immunology Interlude at Stanford
ZIERLER: What were the big exciting things happening in immunology at Stanford at that point?
SHOKAT: That was the era of signaling coming into the immune cells. I worked in a tolerance lab, B-cell tolerance, and how the signal comes in, and the cells evolve in germinal centers to make new antibodies, and when they recognize self-antigens, they undergo apoptosis, so that's when the apoptotic genes were discovered, that's when cell trafficking was found to be so important. It was a good intersection. It was kind of like more, I would say, molecular biology and signaling thinking in the immune system. But then, there was a ton of cell biology and organismal biology, which I wasn't that interested in. That's why, when I started my lab at Princeton, I went back to more chemistry approaches.
ZIERLER: Looking back, were you something of an early crossover, coming from a chemistry or chemical biology background into an immunology program? Had that been done frequently before?
SHOKAT: No, that was a very odd thing. And in fact, Pete said, "Kevan, that's a mistake. [Laugh] When you then apply for a faculty position, nobody's going to know your postdoc advisor, Chris Goodnow, and they're not going to know what to do. It's going to be very hard to get a job." And it was very hard. There were not many people that understood the projects I was doing. But I really lucked out at Princeton because Dan Kahne, Martin Semmelhack, Arnie Levine were able to understand what I was trying to do and gave me the opportunity.
ZIERLER: Tell me about Chris Goodnow, what is he known for?
SHOKAT: Basically, studying B-cell tolerance. He created a really elegant mouse model of tolerance by introducing a neo-antigen from hen eggs into the genome, and then he could study how that hen protein was recognized. And that really was a powerful model for me, and he and Pete both had projects that took something outside and brought it in, that let you study the thing. For Pete, the 21st amino acid, he could take a stop codon and then use it to expand the genetic code. Chris could study biology of self-recognition by taking a non-self protein, put it in, and make it be self. I think that's where I trace back our ideas of our early projects in the lab to change kinases to recognize non-natural substrates. Even though they were in chemistry, chemical biology, and immunology, that kind of experimental style or whatever was very cool.
ZIERLER: The conceptualization of outside and inside is very fascinating. Outside relative to what? What does that mean exactly?
SHOKAT: There were no tRNAs that recognized the stop codon. He took that and repurposed it to deliver an amino acid when the stop codon was there. That's outside of natural biosynthesis of proteins. And then, Chris, it was a hen protein put into a mouse. [Laugh] Now, the mouse thought this hen protein was itself. And because it's so precise, and you could follow it, it enabled a lot of things. Both of them, once you do that, it immediately gives you a lens and some tweezers to grab things that otherwise would be too obscured by the normal system going on.
ZIERLER: Was your time at Stanford instrumental in your developing interests in cancer biology? Or that came later?
SHOKAT: Yeah, that came later. In immunology, we were studying tyrosine kinases, so I picked up that area, and then at Princeton, I just wanted to study kinases, I didn't care where they worked. And then, when the Gleevec approval happened, I was like, "Wow, tyrosine kinases are in cancer. What are those doing?" When I moved to UCSF, that's when I met Frank McCormick, and he really said, "Study the oncogenes." He was a real pioneer in the oncogene field. He said, "Study PI3 kinase, study RAS, make a RAS drug." That really was my shift towards more oncology.
ZIERLER: Thinking back on Pete's advice not to do immunology, when you safely landed at Princeton, did you feel like you had proved him wrong? Or is that really a credit to Princeton, that they were so versatile in their thinking that they were excited about you?
SHOKAT: I interviewed all over the country, everywhere, and that was the one offer I had. I was very fortunate and traumatized. [Laugh] I remember we walked around Princeton one day, and I said, "You were right, I shouldn't have done that. [Laugh] But I'm going to try to make it happen."
ZIERLER: And this is really a signal for how unique your decision-making was. When you were applying to faculty positions, how many people really came from chemistry and did a biology postdoc, and all the problems that that must've created? How did you square that circle in job talks? What did you explain as your unique approach or viewpoints?
SHOKAT: I did it terribly. I now look back at the talks, and those were days where you wouldn't even give a practice talk. You would just go give your job talk. Now, I practice with my students for any 10-minute talk at a meeting. I think if I had done that, I would've been able to package it better. I wasn't able to package it well. I just had two discrete things, my graduate work and my postdoc, and almost no audience was interested in both. They were just too far apart. I think the other person who did what I did was Carolyn Bertozzi, who was in graduate school in Berkeley at the same time in a different lab, and she came to UCSF to work in an immunology lab. She had the sort of carbohydrate focus, both in graduate school and as a postdoc, so there was an easier continuum. We did very similar jumps, but hers has the carbohydrate consistency. Mine had bigger jumps, so it was harder.
Kinases Focus at Princeton
ZIERLER: As an assistant professor at Princeton, your focus on kinases, what were you looking at? How did you set up your lab to answer those questions?
SHOKAT: Basically, we wanted to sort of engineer a kinase to recognize an at that point analog that no wild-type kinase could recognize, so that when we put that one mutant into the cell, and we put our ATP analog in, we could identify the direct substrates of the kinase. That's what we were working on, protein engineering chemical synthesis of analogs, and then also pairing that with inhibitors of the enzyme. We were really doing, I think, what Stuart Schreiber calls bump-hole chemistry.
ZIERLER: How long did you stay at Princeton, and what were your decision factors for moving to UCSF?
SHOKAT: I was there for five years, and I was actually thinking of moving with Pete to Scripps. I accepted an offer at Scripps to do that and be a GNF as well. And then, the wife my job wanted in San Diego didn't come through, so we rethought. I had turned down an offer at UCSF, and they resent me an offer, and we decided to come here. My family's on the West Coast, so we were going to move back once the offers started coming in and we started thinking about it.
ZIERLER: You mentioned the influence of Frank McCormick. Did you meet him before you got to UCSF?
SHOKAT: No, I'd only met him on one of my interviews here.
ZIERLER: What was so compelling about his research? How did that turn you on in this new direction?
SHOKAT: It was just very compelling. I think the reason was that here I was at Princeton, synthetically engineering enzymes to control them, and I think what I appreciated with Frank was that, he was like, "In cancer, these proteins get mutated. If you can do what you did with an engineered enzyme and make a specific inhibitor, what if you could make an inhibitor of a naturally occurring, disease-causing protein?" I was like, "Yeah, that's not different from what we did, it's just now, the cancer made the mutation, not us." I think the other interesting thing was, right around 2000, when the first patients became resistant to Gleevec, the prime resistance mutation in the kinase was the site we engineered. We'd actually discovered the importance of this recognition site before the patient trials read out. That also taught me, "Wow, we're playing with these enzymes, and cancer cells are also playing at the same exact residue. They did a different kind of substitution." I was like, "Wow, okay." That was an easy jump and made a lot of sense to the lab.
New Chemistry for Translational Research
ZIERLER: Intellectually, even stylistically, how much was it a pivot for you to think about translational research, to think about clinical applications? Was it basically the same science, the same process with a different result? Or do you really transform your lab thinking about potential applications?
SHOKAT: It was the same thinking. Projects kind of either–we'd do it in the style of Pete, which is you engineer it, and you can study it, or we'd do it in the style of translational work, which is, "Biology made this protein. Now, we've got to attack that." It's always been about the small molecules, binding, exploiting new chemistry, and the box of the biology and forcing us to make new chemical solutions. The one I'm most excited about now is, we just made a covalent inhibitor for the most common KRAS oncogene, the glycine 12 to aspartate that causes 80% of pancreatic cancer. And it's a covalent bond to an aspartate. A year ago, I thought that was going to take us 10 years, and then it just came in one of the projects.
ZIERLER: To come back to the history of the term chemical biology, by the time you'd joined the faculty at UCSF, was chemical biology already in use at that point? Was it no longer a unique niche term?
SHOKAT: Yeah, I think so. I think also, Harvard, around that time, changed their department name from chemistry to the Department of Chemistry and Chemical Biology, and we named our graduate program here Chemistry and Chemical Biology.
ZIERLER: Given the importance of what you accomplished with Gleevec, did you start out with Gleevec thinking that this would have clinical value, or that was sort of a happy surprise along the way?
SHOKAT: We didn't work on Gleevec ourselves, we just saw its success and realized, "These are molecules that are very easy to make now that we know have a clinical impact." It was more observing that from a distance. The thing that really struck me was, I was at Thanksgiving at my in-laws' in Portland, and after the dinner, somebody came in the house, and he was from India. And his eyes were very jaundiced and yellow. And I sat down at the table with my father-in-law, talked to him, and I said, "Wow, who are you?" He was a friend of a friend, and he said, "I'm here in Portland to go on a clinical trial." I said, "What do you have?" And he had CML. I was like, "God, this person traveled from India to get this drug. And I know how it works." Since then, I've seen drugs we've made go to companies, get into clinical trials. You hear about the clinical benefit. That really was a real game-changer for us, I think.
ZIERLER: Tell me about taking on that additional appointment at Berkeley. Why was that important for you?
SHOKAT: At that time, it wasn't that important. But one of the students who was admitted that year, a guy named Matt Simon, had been thinking about Berkeley or UCSF, and he wanted to be at Berkeley for the chemistry, but he wanted to join my lab. And so, when Paul Bartlett offered me the joint appointment, I accepted it because I could have Matt join the lab. Now, Matt is a faculty member at Yale and working on epigenetics. I would've missed out on three very, very great students from Berkeley if I had not taken that appointment.
ZIERLER: In our remaining time together, I want to focus on Caltech institutionally, then we'll end looking to the future. Have you spent time at Caltech? Have you ever thought about yourself, as a Pete Schultz student, where Caltech fits into this overall story of the development of chemical biology? How do you think about those things institutionally?
SHOKAT: Yeah, Dennis Dougherty, Linda Hsieh-Wilson, who was a grad student with Pete. Just the environment that chemistry there has created for chemical biology. And being a small campus and seeing how people in the biology side are so close and can interact. I know a friend of Ray Deshaies who was there but now is the head of research at Amgen. I knew a lot of the immunologists there like Pamela Bjorkman, who discovered the T-cell receptor MHC peptide complex and now works on HIV antibodies. Everybody there is very mechanistic and molecular, even when they're in the biology side. To me, there's always a flavor of the chemical there. I don't know why that came about, but institutions have a certain appeal of a certain kind of science, and they diversify, but there's a core shared molecular part there.
ZIERLER: It's such an interesting word, what do you mean by mechanistic?
SHOKAT: I kind of think of Pamela Bjorkman's work on figuring out that the way HIV avoids antibodies is that it spreads apart the antigens on the viral surface so that the bivalent antibody can't bridge. She's worked in detail to understand which antibodies are special so that they can get the chelate effect and recognize. Not a lot of immunologists think at that level of molecular, and it's fantastic.
The Role of Chemical Biology in the Quest to Cure Cancer
ZIERLER: Finally, looking to the future, if there's a grand ambition to cure cancer, however we define that, whatever that means meaningfully in people's lives, what role as a discrete discipline will chemical biology play in it? In other words, if it's an all-hands-on-deck scenario to cure cancer, where will the chemical biologists help in that effort?
SHOKAT: I think in the getting out of the dogma that drugs look a certain way. There's a lot of pharma that will not touch a molecule outside of 500 molecular weight and things. But from bio-organic chemistry, understanding natural products and molecular glues like rapamycin, and covalent chemistry, and seeing how important that can be, I think what chemical biology did is realize we don't get to choose the chemistry we use. We have to choose the chemistry for the biology. Whereas at pharma companies, in the 80s and 90s, they just kept screening. And then, they abandoned RAS and said it wasn't possible. And I think chemical biologists, because we were saying, "Let's study biology," we were willing to take a risk that what we were making chemically would never be a drug. But surprisingly, in our case, it did become a drug. [Laugh] Even though most people told us, "Wow, KRAS G12C, that's rare. And it's a covalent drug. And it binds to the off state," all these things that are no-go's. It's still got a long way to go, like you said. I'm glad you said, "The cure." And that's where, I think, really combining the immune system will be so important.
ZIERLER: You're emphasizing perspective here, that's really important. A different way of looking at drugs.
SHOKAT: Yeah. You look at Ben Cravatt's work, just the sheer technology application towards discovery of covalent fragments, and now, there's no drug company in the world that doesn't have some kind of a covalent effort. 10 years ago, nothing. [Laugh]
ZIERLER: It's exciting then, how much things can change, given what's happened.
SHOKAT: Yeah. The number of modalities. Coming back to Pete, it really makes me realize that the creativity he had, the things that seemed outlandish, now, that's just normal everyday. Chimeric antigen receptor T-cell, that's Carl June. But that kind of creativity, that was a Pete-like idea. And now, that's a breakthrough therapy. The things we thought about at Berkeley back in the 90s, you see them. David Liu came out of Pete's lab, and you see base editing now. It's this week in the news. It's just amazing. [Laugh]
ZIERLER: On that note, this has been a wonderful conversation. I'm so grateful for you to share your perspective with me. Thank you so much.
- Leukemia Research Breakthrough
- The Origins of Chemical Biology
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- Immunology Interlude at Stanford
- Kinases Focus at Princeton
- New Chemistry for Translational Research
- The Role of Chemical Biology in the Quest to Cure Cancer