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Patrick Kearney

Patrick Kearney

Director of Medicinal Chemistry, Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, La Jolla, California

By David Zierler, Director of the Caltech Heritage Project

October 16, 2023

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Monday, October 16th, 2023. It is great to be here with Dr. Patrick Kearney. Patrick, great to be with you. Thank you so much for joining me today.

PATRICK KEARNEY: Sure, my pleasure.

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

KEARNEY: Currently, I'm a Director of Medicinal Chemistry at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys in La Jolla, California.

ZIERLER: Let's unpack all of that. First, tell me about Sanford Burnham Prebys. What's its mission? How long has it been in existence?

KEARNEY: Sanford Burnham, I believe, has been here since the '70s. I've only been here since January. It was started in the '70s by couple that came to San Diego to retire, essentially. They had careers in science, and decided, "We don't want to retire," so they started Sanford Burnham as a nonprofit. It is an academic institution. It does have some graduate students here. It's got faculty members that do research. What I do here is basically I work at a core facility that provides medicinal chemistry services and screening services, not only for the researchers on campus but with collaborations basically all over the country. We've got collaborations with the Mayo Clinic, we've got collaborations with USC, and up at Stanford, etc. Basically, if you're in chemical biology or biology, and you want to do a grant, an academic grant, and need certain services that you may not have, like access to medicinal chemistry, that's what we do. It's a really fun job. I worked in industry before I took this job, and I did a bunch of different things there. But it's weird going back. It's weird because I'm now back in academics, and it's all grant-based, and we describe it here as you eat what you kill, and I guess that's academics in general. I work on things that I just never really thought I would ever get to work on. I work on all sorts of different things here. But in industry, I did a lot of kinase work. Here, it's kinases and GPCRs and dehydrogenases, and it's doing traditional medicinal chemistry approaches. It's doing degrader approaches. It's doing computational modeling. It's a great job. I actually really like it so far.

ZIERLER: I'm not sure if you know the history, but we now associate San Diego really as a biotech hub. Was Sanford Burnham sort of part of that founding generation that made San Diego a hub?

KEARNEY: I guess you would have to say it was. Like I said, it's been here since the '70s. Scripps is next door. UCSD is within a mile from here. I guess it certainly did play a role, especially in setting the culture as a place for scientists to work. In terms of the industrial applications, I don't know. I really couldn't say about that. But I think in terms of setting a culture as this is a place where you can actually do science in San Diego, serious science in San Diego, I would say it probably was.

ZIERLER: Now, you calling this an academic position or being in an academic environment, is that to say that you're really not involved in translational research these days? You're doing fundamental research?

KEARNEY: Oh man, that's a toughie. [laugh] I guess I would say it depends. A lot of the projects that I'll be involved in here right now, some of them are really challenging because they have to do that to get grant money. A lot of the stuff we'll be doing is almost too risky for industry to do at this point. I guess how it works here, you know, there are some projects that will be packaged up. It's like, hey, this is going great. We've got a nice candidate here. We'll package those up, and try to partner those off to industry. That does happen. But a lot of the day-to-day is involved like here's this potentially interesting area of research. Here's some initial results that have come out that some biologists have discovered. How do we move that research to the next point where it might be applied to discover new medicines…because some of these things we work on don't necessarily have—even good probe molecules out there. A lot of the things we work on, you know, we do a lot of CNS projects here, at least from what I've seen, in terms of trying to come up with chemical matter that might move a those projects forward. Those projects are really high risk, and so I think there's definitely a role for academics to do that, to keep moving it along into where you may actually go ahead and do it, what I would call a traditional industrial drug discovery program around it.

ZIERLER: Do you have interface with students or postdocs, or do you serve as a mentor in any capacity?

KEARNEY: That's always a good question. I guess the answer here is yes and no. Through some of the collaborations, like, I'm involved with a collaboration up at Stanford right now, and there are grad students on that project. When we have team meetings, you can say like, hey, look, have you tried this? We'll call that that leading without authority kind of interaction, if you will. Directly, no. In my research group here, I have four PhDs that actually work with me, and we direct things that way. It's certainly not like I'm isolated here in my office, not interfacing with anybody. We'll interact with some of the faculty that are here on projects, and work with them. Everything's very team-oriented here. It's actually a great culture, in that sense. It's very, very team-oriented. You will often run into grad students and postdocs working on projects here. But I don't work with them directly.

ZIERLER: Now, eating what you kill, what is the grant structure there? Is it all NIH? Is it private foundations? All of the above?

KEARNEY: I t's all of the above. Just last week, I was putting one in, I was working on a grant for the National Cancer Institute. Earlier, in the end of August, I was working on some that were just local applications, soprivate foundation money. These were for seed money that is for the growth in the local biotech area. It was a Curebound grant that I was working on, and I think that's a fund of money that's designed to help move research in the San Diego area. That would certainly be more private money there. It's anything that might work.

ZIERLER: To go back to the fundamental versus translational question, is Sanford Burnham, I mean, do you have any interface with FDA, or is that sort of too far afield for the kinds of things you're working on now?

KEARNEY: I would say in general, it's too far afield for what we do.

ZIERLER: What would be that next step from the kinds of stuff you do, getting closer to drug development, and trials, and ultimately to market?

KEARNEY: Can you say that again?

ZIERLER: If what you're doing is too fundamental, or the FDA, the regulatory interface is too far afield, what would be that transition connecting point between what you're doing and what ultimately goes to clinical trials and market?

KEARNEY: High risk, high reward, high failure [laugh], so a lot of the grants will go nowhere, for instance. It's OK. But the goal here would certainly be to keep a project alive as long as possible. It's not uncommon to see things start out as a screening grant, and then go into a hit-to-lead grant. Those can actually even move to later stage type grants if it looks that good. But I think a lot of times here too, the idea would be to partner it up, spin it off to industry, and then bring money into the institute that way. There's no clinical trials that get run here, for instance. We don't do that, in general.

ZIERLER: Now, the title Director of Medicinal Chemistry, do you get to be a scientist on a daily basis?

KEARNEY: Oh yeah. [laugh]

ZIERLER: You do?

KEARNEY: Oh yeah.

ZIERLER: It's not all administrative work?

KEARNEY: No. For me there is a career aspect to this role. too. Earlier in my career, I worked at a company called Exelixis for 13 years, eventually, and started out at the bench there. That was like a senior scientist too, and then associate director, director, senior director. Everyone was like, "Oh, you're going to be a VP someday." I have to admit, several jobs later [laugh] I realized I don't really want to be a VP of anything. I actually like what I do. This role's a little different than other ones I've had. This is the first position I've had where I don't actually work in the laboratory. That's not to say I don't do science—I do—but it's certainly more at a slightly higher perspective, where you're looking at the research. You have to understand the project. You have to understand the direction the project's going. It's up to you to work with your team, and say, "Are we making molecules that make sense on the limited budgets we have and in the timeframes we have? What are the most important things we could do?" But you're doing all sorts of things. You're designing new molecules. You're modeling things into proteins and the like. It's very much a science job, and I like it that way,.

ZIERLER: In concentric circles, for the question, what kind of chemist are you, so from the casual dinner conversation among nonspecialists, what would you say that would convey at a general level what it is that you do, your area of expertise?

KEARNEY: I'm a medicinal chemist by training, and that either means something to people or not. Usually, oftentimes, if you're at a dinner party, they'll ask you if it's Breaking Bad

ZIERLER: [laugh]

KEARNEY: —and you're like, "No."

ZIERLER: [laugh]

KEARNEY: My job is to basically try to discover new compounds that would turn into new medicines for various indications. I'm a medicinal chemist, is how I would basically classify myself.

ZIERLER: Then with your own subfield, your professional ecosystem among peers, how does that get more specific?

KEARNEY: I'm not really sure it does. I think that that is specific enough. Within this ecosystem, you're like, OK, are you the guy that's developing the assays? Are you the guy that's developing the compounds, i.e., are you the medicinal chemist – the person who plays a role in physically creating the new molecules that will become drugs? It doesn't really get more specific than that, I would say. There's different levels. Yes, a scientist may say "I'm a bench chemist", "I'm a senior director", "I'm a director", but I think everybody within that groups, from the bench up, would say that they are a medicinal chemist.

ZIERLER: Are there particular maladies that are close to home for you or most interesting to you that motivate the kind of research that you do?

KEARNEY: No, I can't really say there are. I do think, like I said, what's interesting here is that we do seem to work on a lot more neuronal type of problems, problems we need to address by getting drugs across the blood-brain barrier, which is a really hard problem. It's great when you're like, oh yeah, it just has to get into the system. You're like, oh fabulous [laugh], that's easy. But when you have to cross that barrier, there's other things you have to do, and there's far more design restrictions on the types of molecules in terms of the properties they can have to make those valuable. But, no, I wouldn't say there are. I think what I really enjoy about this job is what I said earlier. Like I said, I worked on a lot of kinases before, and those were basically oncology indications, some inflammation indications. I still do a lot of oncology work, but some of these projects are just all over the map. I think that's really great, especially for someone who's a little bit later in their career, and really trying to reposition. No one wants to be old. No one wants to be a fossil. I think, working here, it's definitely—given how fast the field is changing in terms of modeling and AI and all these other tools that we didn't have just even a few years ago, it's a pretty good place to be.

ZIERLER: You anticipated my next question about machine learning and AI. Has that actually made an impact for you? Is this changing your day-to-day already?

KEARNEY: I think where you see it here now, where you see a lot more of it now—you certainly don't ask it to write your reports for you or things like that—but where you think you really start to see it, and I think this is great, you can certainly use it in terms of the design of molecules if you use systems like Reaxys or things like that this. It's these sort of retrosynthetic analyses that you can now get from compounds that you just weren't able to do a couple years ago. Then you go through and you say, OK, which of these make sense, which don't? I think the tools we have now make it a little bit easier for somebody that may not have a very deep background in synthetic organic chemist. I was a physical, organic chemist by training. It's made life easier, and it's made life easier all the way down to just the bench level, people that are just starting out, because now it's easier to learn than it used to be.

ZIERLER: Let's now turn to the research question at hand. I'm trying to understand the history and context of this term "chemical biology" and Caltech's role in it. What does the term mean to you, chemical biology, and has its meaning shifted since the first time you encountered it?

KEARNEY: I still laugh because when we would interview—we'll go back to early 2000s. I got my PhD in '94, and then moved up to the Bay Area in '97. By 2000, you'd interview people, and you'd interview chemists in particular. They all say, like, "Oh, I really want to work at the interface between chemistry and biology," yet their backgrounds were so not that. You're like, "Wait, I have worked at the interface of chemistry and biology [laugh], and it's not what you think it is." I think chemical biology certainly has shifted. I was reading an interview with Peter Dervan, who was featured in C&E News a couple months ago, and even he was saying, "I'm not sure I would consider myself a chemical biologist anymore," because it certainly has shifted. I think when we were starting back then, it was really along the lines of you were using chemistry to approach a specific aspects of biologicalsystems. Thesewere more focused, it seemed like that. You were using chemistry very specifically to try to modify one or two things. I think over time, especially with the rise in computational power, it has shifted. I think it certainly has shifted from going like, OK, I'm making this molecule. I'm going to interact with this one thing. Then I'm going to tell you something about that system, to now I'm going to take these molecules. I'm going to basically generate these massive datasets across the biome, if you will, to answer broader questions. It has shifted.

But, at the same time, there's some other things. The core is still the same. With some of the work I do now in terms of like PROTAC molecules, it's still the same. You're basically modifying biological systems, putting fluorophores on them and the like, and seeing what kind of information you can get on that, very specific molecule changes. I think in some ways, I guess, maybe it has shifted a little bit too. I hadn't really thought about this because no one's ever asked me before. What's easier to do now is it's much easier to put these small probes and these small tags on proteins; not just isolated proteins but proteins in cells. Here's this modified protein where I basically CRISPRed out the original, put in this new one with a small tag, it has a fluorophore, it has a piece of a fluorophore on it, and it's fully functional. That's something that you just couldn't do back then, but you can now. It's still kind of the same. It's still making targeted changes. But the kinds of results you get are very different. It's not just one little thing now; it's just sets of data. It could be massive datasets for all sorts of informatics analyses, which is way beyond what I can do.

ZIERLER: Patrick, what does the term "chemical biology" convey that biochemistry does not?

KEARNEY: I think for me, when I think about biochemistry, to me, it's more of the study of the system as it is. How does metabolism work? How do these natural products that we make, that we use, that we want to avoid sometimes, how do those come to be? What are the mechanisms by which they're presented, and by which they come into being? I think of that as more traditional biochemistry. Like the dehydrogenases, how do they work or things like that? Whereas chemical biology, I think there was a certain way of studying those. But I think chemical biology really comes down to where you have to do an intervention to learn something, you have to do a modification to really learn something, a fluorophore, or something like that, or something that you couldn't easily do otherwise. Maybe that's not quite right, but that's how I would sort of think of it. When I think of biochemistry, I think of classical, the systems as they were, what could you learn that way?

ZIERLER: Now this is perhaps as much a generational as it is a science question, but if chemical biology originated from within chemistry, chemists realizing they could do interesting things in biology—you were mentioning before, you have PhDs that you work with, people at the early stage of their career. Is it still everybody coming from a chemistry background or is it more interdisciplinary now?

KEARNEY: Oh no. It's very different than what it used to be. It's more exciting than it used to be. The way I'd put it is you go where the questions are. There were only going to be so many natural products syntheses that people were interested in. There's only going to be so many mechanisms of putting things together. The idea of the scientist with his lab and his research students working in isolation that you could do even back in the '90s, that's dead. You can't do that anymore. You have to collaborate with people, because the interesting problems at the interfaces, that's where all the interesting stuff is. We mined out a lot of the stuff that didn't require that. Everything is more collaborative. The types of people you get résumés for and you, the backgrounds are much more diverse. A lot of them will have worked in labs that are, I'd say, pretty much doing chemical biology. They'll either have been doing natural product syntheses in collaboration with a biologist to study things later, or their groups themselves will be working in that area. I think what you see a lot more of today is you see a lot more students that are trained in multiple areas. They're not masters of one, but they're pretty good in several, so they will understand biology a little bit. They'll understand biology a little bit more than, say, we needed to in the day. They'll understand computers and programming more than we would've in the day, because they're more available now too. [laugh]

ZIERLER: Right. [laugh]

KEARNEY: Dennis started with punch cards in the '70s, stacks of them, from what I understand, the old stories. But you tend to see people who have a broader skill set. It may not be as deep as it was in certain areas, like in the past, but it's certainly not any less valid, because information and how to learn things has also gotten better, like I said. It's like, oh, I may not be the world's best synthetic chemist, but there's ways you can figure things out, you need to, to get by, or to answer the questions you're really wanting to. You see very different skill sets than you did in the past.

ZIERLER: Patrick, let's establish now some personal history. When you were at Carnegie Mellon in chemistry, were you interested in biology types of questions, even as an undergraduate?

KEARNEY: Oh, that's a toughie. [laugh] I think about this because I had a hard time picking a major. I like biology. I like chemistry. I like math. In retrospect, I probably should have gone with math. [laugh] I think in the day, I liked chemistry. I liked the manipulation of things. I remember I liked biochemistry. But the first things I worked on were porphyrin chemistry, It was porphyrin synthesis when I was just a runt. There was always a derived-from-nature kind of thing but not necessarily with it. In a way, it was studying, look, here's these systems. How do they actually work? It was almost like a dissection, if you will, is what kind of interested me. You extract this one piece of something, so it was somehow related back to nature, and then you'd study it that way. I think I was much more of a chemist-chemist. Then I got to grad school, and Dennis's group was doing a lot of molecular recognition stuff in synthetic systems at the time, when I started. The unnatural amino acids project came later, towards the end of my graduate career. It was still this idea of we were interested in understanding these molecular forces, and what it requires to actually bind an organic molecule to another system, into another system of some organic-based system in water. It still had that chemistry. It was very chemistry focused, but it related back more conceptually to biology. It wasn't as intimate as it is now.

ZIERLER: What was the point of contact with Dennis's group? Was there a professor as an undergraduate that you had that connected you to Dennis? How did that work?

KEARNEY: No. [laugh] My story was—it's really weird. Undergraduate research was not that common back then. I was an undergrad from '83 to '87. At Carnegie Mellon, I was one of the first students to do it within the chemistry department. . I had a professor. There was a professor who took an interest in me after organic chemistry lab, who basically said, "Hey, do you want to come work in my lab?" I did, and I think I was one of the first ones at Carnegie Mellon doing undergraduate research in the chemistry department. Two years later, there were more, there were a few more. But not everyone did it. He was a good mentor. He was horrible [laugh] to his grad students. I have to admit, he was terrible to his grads, but he loved me. [laugh] I just remember he told me, he said, "With your grades, and what you've done here, you'll be able to go wherever you want." I was from Scranton, Pennsylvania, and I knew really early on that I did not want to stay in Scranton, Pennsylvania, so I was at Carnegie Mellon. In my head, it was like, "Just keep going." I applied to all West Coast schools. [laugh] I did the Stanford-Berkeley-Caltech tour. Eventually, I viewed all three of those. Berkeley, I didn't see anyone I really wanted to work for. Stanford, it was shocking that the graduate students that …they brought you in, and you met with the graduate students, and they all complained about how much they hated it there. You're like, "Why would I go there?" Then I came down to Caltech, and it was just different. There were many people at Caltech that I—not many, because it's not a huge place. There were several people I could have easily seen working in their groups, and Dennis's was one of them, and I joined that one. [laugh]

ZIERLER: What was compelling to you about Dennis's group? What was he doing at the time?

KEARNEY: It was the molecular recognition aspects. I really liked the synthetic systems. I liked the fact that it related back to biology. He was instrumental in getting the cation-pi effect, and how it works in biological systems, getting that on people's radar, and understanding how that worked. I liked that aspect of it. Quite honestly [laugh], the group had a really good vibe. [laugh] The Dervan group was hard-ass, and competitive to get in, and there were a lot of people that wanted to get into that group just for the name. But if you went to Dennis's group, you went because you chose to go to Dennis's group. I'll be honest, he was a great guy to work for, so fantastic.

ZIERLER: Tell me about developing your thesis research.

KEARNEY: I certainly didn't blaze out of there, that's for sure.

ZIERLER: [laugh]

KEARNEY: [laugh] How do I think about it? The first thing I worked on the first two years was—you joke later with your friends. You're like, "Oh man, it took so long to get that thesis done." Now you're like, "I could have done that in half the time today."

ZIERLER: [laugh]

KEARNEY: But you've got all your angst and worry and ugh going on. But the first thing [laugh] I worked on—Dennis wanted me to work on this—it was using this cyclophane system. I was going to modify it with ligands to do this copper-catalyzed radical cyclization. Yeah, that didn't pan out. I tried for about two years, and then that didn't really pan out. I moved towards more of the systems, the classical molecular recognition systems he was working on. I took the systems he was working on, and we started modifying with halogens and methoxy groups and ultimately acids to make them a little bit more complicated. It was an education in itself, I tell people, because here it was, these systems that we—it was these simple modifications. At the time, we could not predict what was going to happen. It was just like, here are these systems, and you're just making minuscule comparisons, so you think I should be able to understand this system exactly. There were always surprises in it. Oh look, it collapsed or, oh look, the way we think about reactivity, we always think of electron-rich, electron-poor rings in terms of reactivity, doesn't apply to this molecular recognition sense. Acid, negatively charged acids can have effects over greater distances, but sometimes not even as strong as you would've predicted. I worked on that for a while, and kind of made some progress there. I did have one project I thought was going really well, and then, all of a sudden, it collapsed. I kind of rescued it a little bit later, but it didn't quite work as I wanted it to. That ended up being, I would say, two-thirds to three-quarters of my thesis. The last part was this unnatural amino acid incorporation, and it got in there. How that whole thing started was, I guess, Pete Schultz came down to give a seminar on the method he was using to incorporate unnatural amino acids into proteins, which everyone was like, "Wow, this is amazing."

I'm sitting there the next day after that seminar. I'm working at my hood. [laugh] Dennis comes down into the lab and you're like, "That's strange. He doesn't usually come in here." He's like, "What did you think of that seminar?" I was like, "Oh, that was really amazing. That was really good." He's like, "How would you like to work on that right now?" I said, "Sure, OK." I guess maybe this defines a molecular biology collaboration, because it wasn't something we could do. It was not something we could do in isolation. It had to require a team of people. It required the Lester group, who were experts at ion channels. It required Jeff Sampson and Peggy Saksfrom John Ableson's group, they were experts in creating tRNAs and biomolecule synthesis, and I was the chemist that was making the dinucleotide, and coupling the amino acids to it. I didn't even ligate them onto the tRNAs at that point. That came later. What ended up happening is, the idea was like, OK, we're going to make these things, and we're going to get these unnatural amino acids to incorporate into Xenopus oocytes. We don't care if the failure rate's really high, because we only need a small number of full read-through, because we'll get this massive amplification through electrophysiology. I made these pieces, and they sat there for a couple of months. The project stalled, and the project stalled because we didn't have the tRNA designed quite right, so it wasn't quite working. But then it's getting close to the time I'm about to finish. We figure this out, it starts working, and that's when I really decided, like, I did something that was a little bit unusual, because usually you get your PhD, and you go somewhere else for the postdoc. I went through the back door of the lab into the Lester group, and did a postdoc over there for about a year and a half. I ultimately left that position, because it wasn't quite what I wanted to do at the end. But I basically worked on that system for two years, and it was really fun. You certainly learned. You used a lot of the principles in physical organic chemistry, and a lot of the things you learned about molecular recognition on these artificial systems, and then you were just applying the same types of analyses to these macromolecules. That was pretty new. That was really exciting.

Data collection is data collection, and analyzing data sets is analyzing data sets, so that part was really fun. We started learning about how these nicotinic acetylcholine receptors worked. I studied both the binding site for the acetylcholine and the gate region, and we did learn a couple of things there. That work is really exciting, and I still list it on my NIH [laugh] profile as some of the work I'm most proud of.

ZIERLER: Patrick, to go back to when Pete Schultz came down to give the seminar, and everyone was blown away, what about it, what was so revolutionary about what he was presenting?

KEARNEY: I think the way to put it was because it was a very specific way to modify a protein. Before that, we had like labeling. It's like, OK, yes, you label these lysines, or things like that, or it's like, OK, I'll put a cystine in here, and then I could do an alkylation. But that still carried the risk if there were other cystines on the molecule doing calculations over there. This was a way of being very, very precise in terms of what you put in, and on a level of detail that you could add one methyl group, you could do chiralities that you couldn't put in through natural amino acids. You could put things that were very small in to study with big effects. Here, it made the jump from I'm making a probe tohere's a chemical molecule. Go use it against a known protein. It made this jump to, OK, now I'm going to make these really small changes on macromolecules, and see what we can learn.

I think even my boss here says, "Oh, this is one of the best examples ever of physical organic chemistry and biology." I think it was one of the grad students in the lab, he was coming through as I was a postdoc, and he was basically putting these little fluorine, replacing a hydrogen with a fluorine, which is about as small a change as you can make. But it has big electronic changes in terms of cation-pi effects, and how did those affect the binding site? He was able to map out which of these aromatic regions in the agonist binding site mattered. Couldn't do that before, or proline shifts, like prolines be able to change that from tertiary amide, very hindered rotation, to an ester, which has high rotation. Being able to see how those effects, you were able to learn a lot about things that you just couldn't get through structures at the time.

ZIERLER: As you narrated it, when Dennis came down to the lab, and had this conversation with you, how formative was that in terms of what ultimately you got out of Caltech, and all the research that you did? Was that a real turning point?

KEARNEY: Yeah. It continued a trend. Like I said, I was interested in chemistry. I was interested in physical organic chemistry. You knew that you wanted to work in biological type systems. Once you decide you don't want to be an academic, and you think maybe I want a job in industry, you're really aiming towards pharmaceuticals, especially in those days too. You're really aiming towards that, and how do I fit into that sort of world? I think what that made you do is you had to look beyond just how you made things, but you had to consider the systems as a whole, and how would you go about exploring those without information if you didn't have all the information you needed? One of the things I was interested in, in those days, I'll call it the first iteration of combinatorial chemistry, which is the idea where you can make a lot of molecules. You make a lot of these close pairs of molecules, and really learn about systems somewhat rapidly if you can make things happen that way. I don't know if there was like, oh my god, a light bulb went off, but it more progressed along a continuum is what I would say. I knew the area I wanted to be in, in terms of you want to do chemistry that has biological applications, and that kind of meant pharma, and it still does.

ZIERLER: The idea behind going to Lester's group, is that because there was unfinished work, and you just couldn't stay with Dennis?

KEARNEY: I don't think I would quite put it that way. No, I wouldn't quite put it that way. I'm not even sure how—I think it really came about as it started to work, and it wasn't I couldn't stay; it was more like I wanted to see it through, and it was a really good opportunity. It wasn't I couldn't stay. It was I wanted to see it through, and wanted to explore this realm of what happens in biology? When I go in there, I went through the door, and the electrophysiology part was great. I liked doing that. Molecular biology, for me personally, I didn't love it. I really loved the manipulation of chemicals like in the flask more, and what happens, and the art of working things up, and putting things together. Ultimately, after that postdoc, which I left early because some of it was personal reasons (relationship), and wanting to be in the Bay Area, where most of my friends had moved, and wanting to move out of academia. It was finding out what works for you, and how do you want to fit in this mix of chemistry and biology, and shaping your career to fit in that sort of space.

ZIERLER: Were Dennis and Henry, were they deep into their collaboration at that point?

KEARNEY: Oh, absolutely. One of the things that was really interesting is there was a real commitment to making this work, because everybody believed in it, and everyone knew that if we got this to work—and listen to me being all excited and everything—that if we got this to work, that would be a breakthrough. This would be a new way of studying ion channels in a way they hadn't been done, and other membrane-bound neurological proteins that hadn't been done before. You were able to do it because we're doing all these Xenopus oocytes. You would inject the mRNA into the Xenopus oocytes. They're huge, and they didn't die when you poke them with a big glass needle. [laugh] They sometimes didn't like it, and these things are huge. I think we all knew it was going to be something, that it was going to be amazing if we got it to work. I think really here, there was just a commitment. I think it was a really good example of just how the three different teams got that to come together. Ultimately, we even involved Pete Schultz in it—and he said like, "Don't put me on the paper"—because we couldn't get our tRNA that we had designed to work. We ended up borrowing his, and it did work, and then we redesigned ours to make it more specific for the applications we needed. There was a real commitment to getting it to work, and then it started to work, and it was like, OK, what do I want to do? It made sense to go through and see that through.

ZIERLER: If you could narrate experimentally, making it work, what does that mean? What does it look like? How do you know when it works?

KEARNEY: Oh, it was obvi…it would be very, very easy. [laugh] In this case, you were inserting a stop codon in the middle of the messenger RNA. What you would do is you would say, we've made our tRNA to read through that stop codon in protein synthesis. We think it's right. We ligated the unnatural amino acid onto the end. We think this is going to work. Now, Schultz's group was a cell-free system. We're going to inject it into these Xenopus oocytes. If you just took a pen, and made a big period on a page, that's about the size of the oocyte. It's like a millimeter, so you can easily see these things. You'd draw out these long glass needles, you'd draw up the solution of the tRNA and mRNA mixture, and you would inject it into these oocytes, and you would let it incubate for 24 hours.

Then at the end of that time, you would then examine the oocytes to see if your protein expressed on the surface of the cells. You would take them over to the electrophysiology equipment, two-electron volt patch-clamp that we were doing, and you would basically apply acetylcholine. If you saw nothing, it didn't work [laugh] because you didn't express the full-length ion channel to get to the surface. I think I was a little too simplistic there. We were doing a four-subunit, or two alphas, a beta, gamma, delta, so you had to put the full-length mRNAs for the beta, gamma, delta subunits. We were doing the alpha subunits. If you didn't get a full-length expression of the alpha subunits, you would not get a functioning receptor, so you would see nothing. That's what we were seeing, a lot of nothing. Then all of a sudden one day, we got a system. Now we had to also make sure that—and this was where we had to move from Schultz's tRNA. It's amazing how much of this I remember.

ZIERLER: [laugh]

KEARNEY: The thing that didn't work about Schultz's tRNA is once it dumped the original amino acid, you're in a functioning cell, it could get recharged and start putting something else you don't want in there. I forget, I think maybe it might've been a phenylalanine or something. But it was very possible that you would see a signal, but [laugh] some of it might be from your unnatural amino acid, and some of it might be from when it got recharged. That's when after we got our tRNA to work that it didn't have the recharge issue. It was designed to avoid that problem. As a result, when you were studying something, you knew if I'm seeing that signal, it's because what I wanted to put in there is in there. If it didn't work, then maybe I put something too big or something that's best off folding that didn't enable it to work. But that's how you knew it was working. You were seeing signals. You were putting an unnatural amino acid to see a shift in the—EC 50s (Effective concentrations that elicit half of the maximal responseof these things. Then when you just did a blank with no tRNA, it's like did you see anything or not? (You should see nothing with a blank tRNA.) We did run blank controls in those days. That's how you knew was working.

ZIERLER: Patrick, when it was time for you to go on the job market, were you equally toggling between industry and academia, or did this research really put you more on the industry path?

KEARNEY: Unrelated, to be honest with you, you know, life's complicated, and I kind of knew. [laugh] One of the things that was pretty clear to me is I remember talking to Henry one day. He was just like, oh yes. The thing that was interesting is there was a very big difference between a chemistry postdoc and a biology postdoc. Chemistry postdocs in those days, two years tops, done. Not uncommon to leave early. They were very specific in terms of amounts of time. Biology postdocs, on the other hand, the trap had been set. [laugh] I remember Henry was like, yes, you should stay here for four years, and then if you want an academic job, you'll have to do another postdoc for another four years. [laugh] You're like, oh, hell no.

ZIERLER: [laugh]

KEARNEY: No, no, no, absolutely not. It was very clear [laugh], I did not want to be a biology academic. You're like, dear Lord, I'll be like 35 before I get my first real job. [laugh] It's like no. Yeah, that was a big no. Like I said, I was seeing somebody who I met at Caltech, and then I wanted to be up in the Bay Area, and there were a lot of opportunities up there, so I just started looking up there.

ZIERLER: Was the biotech world in San Francisco already in full bloom at that point?

KEARNEY: Oh yeah, Genentech was already a success story. There were a lot of companies starting up there. In terms of biotech, it was set far longer than before San Diego was. It's the proximity to money, and good research institutes, and ideas, and things like that. Just before I leave this behind, one other thing that was kind of strange, I remember going to a biophysics conference. It was a huge conference, much larger than American Chemical Society conferences. I remember looking out over this auditorium full of people, and I was just thinking like, man, that's a lot of electrophysiologists out there. [laugh] I was like, you know what? There just aren't enough jobs for all of them. It was something like, OK, let's go back to doing a little bit more chemistry, and going back to something that we want to do.

ZIERLER: Jobs were plentiful? You had options?

KEARNEY: [laugh] There is a downside of working in Dennis's group, but it's also an upside. I remember him giving me this piece of advice, and I remember he told me, he said, "If they're looking for a traditional synthetic organic chemistry, the phone isn't going to ring. But if they're looking for someone that's a little more off the wall, your phone will ring." That's actually pretty much been true throughout my entire career.

ZIERLER: [laugh]

KEARNEY: I think it's really good advice, because in Dennis's group, you worked hard, you studied hard, you had to understand a lot of different things, but there was going to be this question that sort of followed you around a little bit that is "What are you?" That exists, like, even for a long time. That still exists even to some extent today in some of these entry-level industry positions, but a little less now because I think there are so many more different types of positions open. I think actually, for instance, like today, with the background I had, I could have easily probably shifted over towards more assay development type work, working more with biological systems, and designing chemical probes for those systems. That would've been a very viable career path. I didn't think about it at the time. Sorry, I talk too much. I forgot what the question was..

ZIERLER: No, that's fine. When you were on the market, would you use the term "chemical biology"? Was that the hot thing to describe what you were doing?

KEARNEY: No. You really wouldn't use that term in those days. What you were trying to do is you're trying to land those jobs as a medicinal chemist. You would even get this criticism sometimes. They would want you to emphasize your synthetic work, and you're like, OK, it's not going to bowl you over, because there were so many traditionalists in those days. There were just so many people that just couldn't break out of that old thinking in terms of what it took to be a medicinal chemist. In those days, it was certainly like, "You must have a deep background in natural product synthesis, and we'll teach you the rest. We'll teach you the biology." You even hear it to some extent today. You can teach a chemist the biology, but you can't teach the biologist the chemistry—not entirely true. For entry, there was definitely this bias towards like synthetic prowess. However, coming from Caltech opens a lot of doors. What you have working for you is you have like smart guy, so a little off the wall but smart guy. That's how you basically would get in. To be honest with you, it self-selects. It's like you find the jobs you want as opposed to the jobs you don't want. You had to work a little harder, but I think you ended up with jobs you probably wanted.

ZIERLER: What was your first position in the Bay Area?

KEARNEY: I ended up doing an industrial postdoc at Tularik, which was ultimately bought up by Amgen a couple years later. Like I said, I didn't want to stay in Henry's group, and I wanted to move up to the Bay Area for personal reasons. I guess one of the things I learned there is it's OK to change directions, if you really want to change directions. You don't have to stick with everything because you chose it once. Here, I was making an adjustment, and I was looking for what I want…I was looking for things. At that time, it was not exactly the—I think it was a little bit of a tough time. I ultimately took this industrial postdoc, which paid OK, and it was doing combinatorial chemistry. It was working with these—trying to use one of these Rainin peptide synthesizers, which was really a robust machine, actually, and they made those things for decades, because they were really good. We were trying to make libraries of compounds on that machine using different chemistries. I ended up inventing a reagent there that's used in peptide chemistry even today, I think, a little bit. That was it, but it was only a two-year gig. They had a policy of not hiring their postdocs, and I don't know why. Actually, that was OK. Then I went to this company called Metaxen, which was over in Hayward. I was there for about a year and a half, and then we got bought by Exelixis. Metaxen was circling the drain. They had this sort of computational technology that was not exactly well developed. But we got bought because we were sharing a building with Exelixis, and they had a lot of genomics money. They had a lot of genomics money, and they were smart enough to realize that we have this money here, but we need to be over there, and we need to be a drug discovery company, and we need to have drugs on the market. The idea that they were just—that vision that they set out was set in stone, and so 20 of us were like the first chemists in the buildings there, and that was fast. At that time, the job market was really hot. I remember they were like, "Oh, we really want you to stay." I'm like, "I've got five interviews lined up. What are you going to do for me?"

Then the job market had been that good for chemists, then it cooled and I think, hasn't been that good for chemists again until the last few years, like now. They had a technology. Within three years, I went from being a scientist one at the bench, to basically an associate director leading their library synthesis group that they had, and ultimately became a senior director of that. I think within five years of starting at that company, I had a group of about 30 people. Part of what e were doing was collaborative contract research …we were doing collaborations with Merck and Schering-Plough and other companies. I learned a lot real fast. I think one of the things that really ended up helping in that job was, you know what, that's not a job that you would've succeeded in as a natural products guy. They required being a little off the wall. That's how I got into the Bay Area, and I was at that company for about 13 years.

ZIERLER: Patrick, at the turn of the century, how much did the so-called dot-com boom and bust register with you? Was that a big deal in biotech?

KEARNEY: No, not outside of general recession concerns. My partner at the time worked at Yahoo! when it was good, and cashed most of that out, and bought a house. It didn't because there are difference…I mean, if investment's down, investment's down, and that affects biotech one way. But in terms of would you invest in biotech, it has its own life a little bit. But there are different considerations because they're very different businesses.

ZIERLER: Now, during this time through, throughout these 13 years, to go back to the fundamental versus the translational aspect, were you working on things where obviously the end goal was to bring drugs to market, to make money for the company?

KEARNEY: Oh yeah. I had a bifurcated career there. First half of it, I was doing this library development. I was doing these combinatorial library collaborations, because what they knew, they took a strategy of they wanted a huge compound collection kinase-focused for high-throughput screening. How they were going to find their drugs was high-throughput screening, and so they wanted several million compounds, and they wanted a way to do it. We had this collaboration with BMS at first, because we were going to copy their system that they were using. We set it up. I was in charge of bringing that technology in, and getting it set up. We realized this is a great technology if you've got a large workforce, with each chemist contributing a thousand compounds here or there, or a couple hundred here or there.

It was a terrible system if you want to build a large collection with few chemists. This was really, I think, another one of the really good lessons here, because the only way to make that work was—so we ended up redesigning the plates we used, simplifying the software we used, simplifying the process we used, so that we would be able to do that. There were some technological advancements that had to happen there, but there were also business things that had to happen there, because it's really expensive, and you're not going to be able to do that yourself. I think we built a four million compound collection, and I think it cost $30 million to do it. What we were able to do is we were able to offset half of the costs by doing collaborations with outside companies, because they all wanted compounds too. We would basically do these design collaborations. We said, "OK, Schering-Plough, let's design 100,000 compounds together for this year." You'd sit down, and you would come up with the things you wanted to do. They were great to work with, good chemists, very practical, easy to pivot when chemistry provided obstacles. You'd say, "OK, here's the thing. We'll get you 100,000 compounds, and we'll make 100,000 compounds. We'll give you half the volume, and we'll take half the volume, and whoever gets to the patent office first with whatever you discover out of it, fine." We were able to offset the cost of that library like $15 million worth. Basically, it was this really smart mix of business and science to really make that happen. They were using it as a hook too, because Exelixis did not have a reputation for chemistry. This was one of the ways they were able to say, "Hey, look what we can do here."

They were able to entice other companies to do deals with them. But it was a subset of what they were doing. There was a large chemistry group, and then part of it was doing this library work. I did that for five years until the collection got large, and then we said stop. The other half was doing traditional medicinal chemistry. After five years, we said, OK, I think the library's big enough. We don't need to do this anymore. We've got lots of targets we're working on. We're getting really good hits out of this. Then we downsized my group from about 30 to about 15, and we went over and did traditional medicinal chemistry, which was again, like, taking these hits that we were getting, and developing basically what we thought would be clinical candidates. My team, within five years, I think, we developed three of them. We basically came up with three development candidates, one for JAK2, one for kinase called CDC7, and one for PI3K Delta. Most of those programs, I think, one of them we tried to develop internally kind of, I'd say, bombed in phase 1, because I think neutropenia was an issue. The other two were basically partnered out. Those programs were sold. I think the Delta program was sold for—CDC7, I think, was sold for 20 million, I think. I think Delta was sold for about 12. What they needed, what Exelixis ended up having was this massive pipeline, and then it was one of these cycles where things were going down, you know, investment was going down. There was a recession. This was 2010–2011. The investors were like, "Push something over the finish line." At all points, actually even before that, some of these programs that you would develop would be sold off to bring in money so that you can move some of your other programs through clinical, because clinical is just so expensive. The amount that you spend in discovery is so small compared to what it takes to move something through development. That's kind of what I did. In a way, I ultimately got what I wanted, which was a career doing medicinal chemistry, developing drugs through this really backdoor way of doing molecular recognition and then ion channel work and combinatorial libraries. But you pick up things along the way, and you eventually get there.

ZIERLER: How close did you get to these drugs ultimately moving to market? Did you see anything get that far?

KEARNEY: Actually, there is one drug on the market that my group touched. [laugh] We were not driving it. Most chemists, if you get a drug on the market, you're like, "Yes, I did it!," because most chemists, medicinal chemists will never get there. You're just not going to do it. It's hard to do. Things drop out for a number of reasons: some of them are commercial; some of them are scientific. But we worked on one, and my group worked on one. It was Cobimetinib from Exelixis, and it's their MEK2 inhibitor. What was interesting is that program was stalled in discovery, and they were like, "We're not sure what to do." They sent it over to my group, and we said, "OK, we'll make a library of compounds around this," and so we did. We took the fragment they gave us, we made a library of compounds around it, and it gave insight into a new direction that ultimately broke the logjam that ultimately got that compound into a development candidate, into the clinic, and out. I guess I did touch it. I touched one, in a way. It wasn't like I made the final molecule. But what my group ended up doing is I think I calculated it once, and realized they had already put about $2 million of drug discovery effort into this program, and just this simple thing broke the logjam that allowed it to go forward. That was pretty cool.

ZIERLER: Does that accord with however you would quantify or qualify satisfaction in terms of having a part in getting something to market that actually helps people, or is it really all about whatever the most interesting science is, regardless of where ultimately it ends up?

KEARNEY: It's a career thing too. You ultimately have to say, like, where do I fit in or where do I want to fit in? One of the things you see—it's pretty common actually—is that most chemists that will start out in doing medicinal chemistry at the bench, they're gone after about a decade, 15 years. Most people want to migrate away from the bench, away from doing drug discovery work. What you often see, and I saw it with a lot of people I know, is that they migrate into drug development work, technical writing, clinical trials, management. They move away. I don't think you see a lot of people stay in drug discovery their entire careers. Most leave, and for perfectly valid reasons. It doesn't say anything about they're not committed enough or anything; nothing of the sort. People evolve. I think, for me, I don't want to say [laugh] I didn't evolve. That would not be true. But I think, for me, I like the hunt aspect of drug discovery work. It's fun. It's the fun part, and when it's not fun, then you shouldn't do it anymore. But it's the part you're like, I don't know what will solve this problem. What will give me the biochemical activity, the cell activity, and what do I think will survive metabolism and elimination, provide an effect long, and it can be dosed long enough, all really challenging problems. The hunt is the fun part. Once you're like, OK, I've identified the candidate, and here's a route to make it on a large scale, I never wanted to do drug development work myself. It's just not the thing that gets me up in the morning. I don't have this idea of like, oh, I want to fill out reports all day long. It's just not the thing for me. I really wanted to stay in the drug discovery part, which is the part I really like, so that's what I did.

ZIERLER: What was the next—?

KEARNEY: I'm not sure I answered your question.

ZIERLER: What was the next move for you?

KEARNEY: [laugh] It isn't always an upward trajectory.


KEARNEY: What happened was Exelixis did pretty well. But in 2011, early 2011, they jettisoned—and this was really common—they jettisoned most of their drug discovery unit. It was like save cash, push something over the finish line. They ultimately did, got two things through, and now they've sort of rebuilt their discovery effort up on a different kind of model. But it was a hard time, that time. At that time, the industry was changing so much, and the job market was terrible. At that time, big pharma was flushing hundreds of people every week into the job market. It's always hard to compete against those guys because they're the traditionalists. If you're looking for someone, if you're looking for someone standard, you go for a big pharma guy. If you're looking for someone off the wall—but it was a really conservative t…then you call me. [laugh] But it was a really conservative time because it was one of those down cycles we talked about, where no one wanted to invest in drug discovery. Everyone wanted clinical candidates. You'd apply for these jobs, and it would be like, "Oh yeah, we want a director of drug discovery, VP of drug discovery," but they didn't. What they really wanted was somebody to direct clinical research. You're like, "That's not me." Things that were really popular in that timeframe were repurposing things that were already on the shelf, failed drugs with new applications. It was all about, because investment was low, it was all about pushing developed things into the clinic, and getting results. I looked for a job for a while, and then ultimately what I decided I wanted to do, I did really well at Exelixis. I realized it's like this could take a while. I cashed out all the options. I ended up having eight years of salary banked, and I was paid really well. I had this idea of starting my own company. I wasn't sure exactly what, but I found myself in the Midwest, for personal reasons, again. I'm not from there; I'm from Pennsylvania.

Then I tried starting a company, because there were certain things I had learned at my time at Exelixis. I had this idea that if I was able to miniaturize chemical synthesis to like a submicromolar scale that you'd allow a discovery researcher to basically explore a region of chemical space really quickly within a period of a couple of weeks that would've taken months through traditional means. It was going to be a technology company, and so what I ended up doing was I had a lot of friends in the Bay Area. I had friends and I knew people who had started companies, so I would go talk to them, and say, "What did you do?" One of the other things that was really popular in this high unemployment time, this difficult employment time, a lot of academic institutions were all about start. Everyone was like, start something, start something, start something. A lot of universities were adding sort of these incubator type things. I would go talk to people in the Bay Area, and then I would go back to Kansas City. The University of Kansas is like 40 miles away, so it's like right in Eastern Kansas, so it's pretty much in the Kansas City metro area. Ultimately, I was able to get into the incubator there. I was the first person ever to walk off the street, and get in there. It was one of these things. I was networking around the area, and I knew what I wanted to do. I had a collaborator who was in the chem…I had a champion in the chemistry department there, who I accidentally got roomed with at a conference. I ended up trying to start this company doing this microscale synthesis. I had no idea what I was doing, not scientifically, because I put a lot of thought into that, but just like in terms of how you start something, I didn't know. But I gave myself a certain amount of money. I said, "You can spend this amount of money to try to get this idea to work." The day I spent that last dollar, I said, "OK, I'm done." But it kind of came close. Five grant applications went in, and the technology got better and better. It was kind of weird, the more I would send ideas out to people in industry to look over these proposals, and be like, "These are amazing," the worst they would score.

It was frustrating that way. I had a position over in the incubator. I was able to use excess space in the chemistry department. I was paying a postdoc to help do some of the work. That was a bad investment. I should have just outsourced it all, but it was part of the deal. I don't regret doing. It didn't work. I still think, one of these days, someone's going to do it. One of these days, someone's going to do it. I did that from 2011 to 2017. The idea of starting something came at the end of 2011 when the job search just wasn't going anywhere. I was like, well, you can do what you want to do, so go do what you want to do for a while. Try starting this. Talk to people for like, you know, ACS was good about resources in those days, American Chemical Society, in terms of just not money resources but people to talk to, groups, conferences. They were really good about that, so really made a serious go at it, and then close it down. Then you get bitten with that bug, that entrepreneurial bug. It's really addicting, to be honest with you. I wasn't sure what I wanted to do, kind of realized that if you want to stay in the Kansas City area—which I didn't really want to do but, again, personal reasons—I didn't want to feel like a fossil, so I was trying to think of new ideas and things I could do. I realized at that point, I was like, the last programming course you took was like in Pascal in 1984.

ZIERLER: [laugh]

KEARNEY: I took a programming course, of all things. It was a full stack web-design coding class, web platform coding, and it was great. I really enjoyed it. But then, ultimately, it turns out one of the guys who was reviewing my proposals, my research proposals, had a company in Lawrence, Kansas, doing kinase work. I worked there for two years, but ultimately realized I just didn't want to be in Missouri/Kansas anymore, and I wanted to get back to California. I started looking around.

It pays to be nice to people earlier in your careers, because somebody I knew said, "Hey, I'm looking for basically a head of early R&D at this company I'm starting here in San Diego." I took that, and I got here in July 2021. [laugh] It was an awful place to work. The people were nice, but we had no money, so it was like being in an unfunded grad school lab a lot of the time. But then tried to make that work, but it got me to San Diego, and then it got me to this job. A lot of the times in this field, back in the day, people would fly you all over the country to interview for a job. Today they look for people that are already here. That's true in the Bay Area. It's true here. It's true most places. You look for people that already are there. Then I got this job, and it's kind of a godsend in a way.

ZIERLER: What did you learn about yourself in the start-up space, and do you think it made you a better scientist?

KEARNEY: Yes [laugh], the answer is absolutely yes, because you were totally responsible for yourself. But the other thing was you—one of the things I never really had done—and I guess maybe I want to say the failure of mentorship or something. Networking is really important, and I think in the sciences, we sometimes undervalue how important that is. In retrospect, I look back at some of the people that were like the most prolific networkers as graduate students, and they became some of the most successful people that are out there. I won't name names. But at the time you're like, oh, look at that person schmoozing. But they were onto something. It was interesting, the Midwest is like the greatest place to learn how to network because, unlike the Bay Area, where people are like, "Oh, I'm too busy, I don't have time for you," in the Midwest it's part of the culture to basically—it was a very easy network.

You called anyone up, and they all called you back, like, everybody. It could be like the CEO or whatever, and they would call you back. If they couldn't help you—one of my old career coaches says it's part of the agrarian tradition. If you can't help someone, you still have to offer them something. You're like, "I can't help you, but you should talk to so-and-so, or you should talk to so-and-so," so you would always get something. You're networking around, and then you realize that all these little pebbles of things that you're collecting, all of a sudden one day, you can just cash them all in, and make something happen. It was like two years of networking and, all of a sudden, boom, I was able to—this deal I needed to be able to do the work at the University of Kansas in their incubator and in the labs there, it all came together like that because I had had all these things. I had made all these connections. I had done all this pre-work from networking, and then realizing that networking is really just thought experiments. You're like, I'm just going to try this, and see what happens. I really learned about that then. It made me a different person, I think, than who I was before. Coming up with new ideas is super fun. You would talk to somebody else that was trying to start their own thing, and you would hit it off with them, and you could be sustained for weeks on just—like two week…you'd have a good conversation with somebody, and you're just rededicated to what you're doing for a couple of weeks, because you're like, yeah, someone else gets it. Whereas your family is like, "When are you getting a job or something?" You're like, "I have a job." But that part was really—I don't regret it, I don't, because it was really fun. I never worked harder in my life. I never failed more spectacularly either, but I don't regret it. But then when it was time to do something else, and it was like, OK, I think I'll still probably always be looking for new opportunities because of that.

ZIERLER: Bringing the story closer to the present, what was COVID like working in biotech? Did you get involved at all in trying to understand COVID, or develop therapies?

KEARNEY: No, I didn't. If you want someone who does who's a Caltech person, I suggest you talk to Jason Perry. He works at Gilead, and I have never been prouder of somebody in my life who I've gone to grad school with. He's done amazing work modeling just the COVID virus, and how it assembles, and what the pieces do. It's astonishingly brilliant work. But, no, for me, we didn't. I was working at Deciphera in Lawrence, Kansas, at the time. We never shut down the labs. Anybody that was nonessential didn't have to come in. The person who's doing HR or the person who's doing accounting, they all worked from home. But those of us that were in the lab still worked in the lab. We spaced out a little bit more. But especially when you think about what we know now, not getting COVID, a lot of it's about ventilation. If you're in a chemistry lab, you're working in a room that has one pass air. It comes in, it goes out the hood, and that's it, the end. Being in a chemistry lab is actually pretty darn safe from a COVID point of view. It was a weird time, of course, but overall, except for the social aspects, my day-to-day was largely the same, because I was working in the lab at the time. From a career point of view, it wasn't that different.

ZIERLER: Then bringing it right up to your current job, what was exciting to you? Why was this the right job for you at this point?

KEARNEY: For me, I'd certainly had enough of Midwest living and, in particular, Red state living. As a gay man, within the confines of Kansas City, great. A little Blue island. Fantastic. People that stay there and live there and are fighting the good fight, great, I support you and the like. But it's a very different mentality, and it's a very different mentality from California in terms of I was in Pasadena. I was up for grad school and postdoc. I was in the Bay Area for 17 years. The Bay Area is nerd heaven up there in a way. There's so many smart people, and it's just very sophisticated, and it's fantastic. When I moved to the Midwest, I did the best I could, but I always felt like a fish out of water there, like, this isn't where I should be. I wanted to come back to California, and I realized I didn't want to go back to the Bay Area. I enjoyed it while I was there, and still have a lot of friends up there, but I wanted something different.

So I said, OK, where else can we go? It was like San Diego was the choice. That was like the number one thing, for me, moving from the Midwest, and coming back to California, I wanted to be in San Diego. I took that job at this one company, and it was like, meh, not great. It went out of business after about 15 months after I was there. They were all about, "We'll get our series A," and then they never could, because it was also a down cycle last year in terms of biotech investment. [unrelated conversation] After that company shut down, it was like, OK, what else can I do? I looked around and, again, it's where networking saves you, and basically this job—there weren't a lot of opportunities for me here, and this one came up. There were a lot of opportunities back in the Bay Area, and a couple up in the LA area. But I wanted to stay down here. The people are friendly. It's a great environment. Basically it turned out that I knew people from my old job, said, "Hey, talk to this person." People I knew from Exelixis said, "Hey, talk to the same person." It's a very different environment. It's going back from industry to academia, and then the very different early stage. It's got different problems in terms of is there enough money? In industry, it's like we just throw a lot of money at this problem, and solve it. Here you have to be a lot more careful about how you spend resources. Then when I was interviewing here, they would be like, "We don't have a lot of money." Then I'd be like, "Have you seen my last job?"

ZIERLER: [laugh]

KEARNEY: "Seriously, this place looks great compared to that one." Then it was just like the work they do. One of the things I wanted to do was, again, I realized I wasn't looking for a VP type job. I wanted a director of chemistry type job where you could have a hand in management and the lab, and hands in both worlds, if you will. That was important to me. Also what I really liked about this job is I wanted to branch out. I'm 58 years old. I'll probably work till I'm 70, if not longer. I could say what I said, no one wants to be a fossil. I realized that the way chemistry was done, the way medicinal chemistry's done is changing again a lot. The idea of doing high-throughput screening is definitely more falling out of favor than it was. No one's ever going to build these massive collections ever again. Computational methods to do drug discovery are so much better than they were back in the day. It's changing again, and I think this is a perfect job to sort of reposition where you could be. It's an academic institution, so you have access to all the literature, all the good modeling tools. I wanted to branch out from kinases because it was always kinases, kinases, kinases. Let's do something else. Here, I basically am involved in 12 different programs, and they could be G protein-coupled receptors, one or two of them is a kinase, hydrogenases. In different types of chemistry, some of it's more modeling-focused. Some of it's more to come up with traditional small molecules. Some of it's more coming up with degraders, which is a new way of doing medicinal chemistry, which is very different from PK/PD requirements, because it's a very different way of doing things. It was a great way to get a lot of experience, and it was a good way to refresh the career. The culture here is fantastic. Industry [laugh] can be a little cold sometimes and a little harsh. The thing that's nice about academics, in a way, it's a very professional, very supportive environment to do work. That part's really great.

ZIERLER: Sounds like the perfect place for you to do science.

KEARNEY: Yeah. I can honestly see myself being here for five years, if not longer. The only thing that may entice me to leave would be another opportunity at a company, because it's academia, so salaries are a little lower than what they would be in industry. But I get paid great, so it's not a huge—and I'm not a money-motivated person. I mean, I don't like being broke, I mean, no one does. But I get paid well enough that I could live comfortably and do exciting work, so planning on staying there for quite a while. Sometimes you think like, oh, you don't get to help people. Like, in academia, there's this idea of professor and student. You get to help people all over the place. In industry, you help people all the time. One of the things I found was you get to mentor people, whether they're people in the lab, people you work with. When I was doing the entrepreneurial stuff, the grad students that were in the lab knew nothing of industry, so they were always asking me like, "What about my résumé? What's out there for me?" You can actually help people. There's lots of ways to help people. You don't have to be a professor helping someone get a PhD to help them, and it's just as satisfying.

ZIERLER: Patrick, now that we've worked right up to the present, for the last part of our talk, just a few sort of retrospective questions. Then we'll end looking to the future. The point of this project, of course, is to talk about and explore Caltech's role in the creation of chemical biology. I don't want Caltech to be the center of the universe, but I really do want to center in on what was advanced, what was innovated at Caltech in the space of chemical biology. In the grand sweep of history, what's your perspective on that? What was really new that came out of Caltech?

KEARNEY: Some of it might be a little dated but—

ZIERLER: This is a history discussion. [laugh] It's all dated.

KEARNEY: Yeah. I'll think about my time there. You had Peter Dervan working with ways to cleave DNA, making molecules that would be very specific to DNA to study DNA. You had people like Dennis, and Henry Lester. Dennis was a intermolecular forces kind of guy, who basically put this piece in place to, you know, working with Henry had this way of studying ion channels that no one had done before, really making very targeted things to macromolecules. You had Frances Arnold, who's still there, I believe. Her chemical evolution of proteins is just brilliant work. Jackie [sp] Barton, who I think is now close to retirement, is what I read, in terms of DNA as a wire. There was a lot of interest in terms of saying, OK, we know a lot about chemistry. But all these things we know about chemistry from the things we learned in the '60s, '70s, and '80s about redox, electron transfer, hydrophobic effects, whatever, how do we apply those to these problems? There was never this feeling that, oh, Caltech's stuck in the past here. I've only named a few groups. I can probably think of a few more if I put my head to it. But, actually, that's not entirely true. [laugh] I forget the guy's name. Jack? Actually, Jack—

ZIERLER: Beauchamp?

KEARNEY: No. Basically invented the DNA synthesizer—not the DNA synthesizer, but he came up with some of the original DNA sequencers, was done over in Braun, a professor who used to be over in Braun.

ZIERLER: You don't mean Lee Hood?

KEARNEY: I think, yeah, I think it was him. But there's another guy too I'm thinking about. The name escapes me or something. But all those things, if you think about sequencing, Jesus, everything relies on sequencing. That was the gasoline that accelerated everything. There was never this feeling like, oh, we're just stuck in the past here. No. It was always a very exciting place. There are times sometimes I wish I could go back because it would just be like, oh man, grad school without all the angst would be so much easier.

ZIERLER: [laugh]

KEARNEY: You could've enjoyed it a lot more.

ZIERLER: On the positive side, Patrick, minus all the angst, what has stayed with you from your Caltech education, the way you approach the science, the way you approach your colleagues? What has remained with you from Caltech?

KEARNEY: Here's what I would say. From Dennis, in particular, the thing about Dennis that was so great about working for him was you could walk into his office with the worst idea ever, like, terrible. I'm not saying I did. I'm sure some of them were terrible. You would never leave that office feeling bad. He would just be like, "That's interesting. Have you thought about this?" There was always this collaboration when you worked with him that you always came out feeling like you were going to move forward. I think I've tried to do that in my career. [laugh] Another thing—and, I'll be honest, I used this in a meeting once—Dennis would just always ask this question. He'd be like, "Why not?" The other thing I liked about Dennis was he always took this point of view. He's like, "If I can understand this, you can understand this." He's a freaking genius, and you're like, I'm not a genius. But he always took you on that story. He's like, "If I can understand this, you can too." I kind of incorporated that. The other thing too is he would just ask like, "Why not? Why can't we do this?" I used it in a meeting once. I had a meeting with Merck, and we had a collaboration—this was Exelixis—and it was terrible.

The terms of the agreement to do this library work were so bad that we just could not succeed at this. I remember going into a meeting, and I'm like, "I've got to figure out a way to save this." I had this idea like if they would only pay us for this much compound, if these compounds met these elaborate criteria, would they pay us less? I remember saying, "We had this many molecules that came close, and yet we got nothing for this." I said, "What if we just said we'll discount these for you? Would you take them then?" I remember the guy across the table was like, "No, we can't do that." I just pulled out my best Dennis impersonation, and I was like, "Why not?" Then I saw it across the table, he's like, "Yeah, why not?" [laugh] They took it. They took it. I came out of that meeting, and I'm like, "I cannot believe they took that. I cannot believe that they did that." I guess the lesson there was don't take no for an answer, if you will, but that there are other possibilities, multiple ways of thinking. I took that away from there too. What was the second half of your question? I forgot.

ZIERLER: Just what has stayed with you?

KEARNEY: What has stayed with you? I think there was that in terms of how you treat people, ultimately. Again, and you still have to use it today, the number one way to be successful in this business is you have to look at the details. A lot of people don't look at details. If you're very detail-oriented in terms of designing good experiments to get data, designing close pairs of molecules, things that will really tell you something, that's hard. It's remarkable how something so basic can be so important to getting ahead. That was done really well there at Caltech, really, really well there. I took that part away, especially now we've got computational things. Dennis's group always had a computational chemistry component to it. You learned to question the models on which things were made. Is this model appropriate for what we're doing? I can get an answer, but is it an answer that's meaningful? Again, for a lot of that work too, it comes down to doing the appropriate control experiments to make that work, not at this level but at this level.

ZIERLER: Finally, Patrick, for you, looking to the future, you've already said you want to work till 70, you want to stay close to the science, and nobody wants to be a fossil.

KEARNEY: Yeah. [laugh]

ZIERLER: How are you going to make that happen?

KEARNEY: I think I'm actually positioned pretty well for this. Things we're seeing now, especially in terms of chemistry, we're definitely in the second age of computational chemistry, so those kinds of modeling is going to be much more important to what we do going forward. It's important to understand what those tools are, and to be able to use those tools. I think it's important to understand a lot of the types of drug discovery programs that are out there in terms of what's important and what's not. Like I said, a lot of my career was in kinases, but a lot of that's been mined out. It's done. Where are we now in terms of small molecule chemistry? We're not just necessarily going after things that are binding sites. We're looking at things that are like molecular glues that if they bind, the degradation machinery comes in and takes them away. That's a different kind of chemistry. I think it's important to understand how modern medicinal chemistry is being done. It's not just all this traditional way of doing it. That's still there, but there's new things that are coming about. I think it's important to be able to do that. Like I said, I think I'm really well positioned here to be able to do that.

ZIERLER: Patrick, it's been a great conversation. I'm so grateful for the time. I want to thank you so much.