The Serendipity Mindset: Unlocking Career Opportunities | Caleb Appleton (Part 1/4)

Intro - 00:00:06: Welcome to the Biotech Startups Podcast by Excedr. Join us as we speak with first-time founders, serial entrepreneurs, and experienced investors about the challenges and triumphs of running a biotech startup from pre-seed to IPO with your host, Jon Chee. Our guest today is Caleb Appleton, Partner at Bison Ventures, an early-stage venture capital firm investing in frontier technology across robotics, AI, and biology. At Bison Ventures, Caleb focuses on investments at the intersection of biology and computation, backing companies developing novel therapeutics platforms, data-driven discovery tools, and enabling technologies that reshape how science gets done. He invests from pre-seed through Series B with an average check size of $5 million. Before joining Bison Ventures, Caleb served as Principal at Innovation Endeavors, where he focused on frontier technology investments across synthetic biology and AI-driven drug discovery. His first investment, a surgical robotics company, became his pathway to partnership, and a cold email to a Berkeley professor led to an investment in Eikon Therapeutics, now valued in the multiple billions. Caleb also brings operating experience from TuneIn, where he led a turnaround managing $50 million in revenue during the pandemic, and earlier consulting experience at Bain, advising Fortune 500 companies. With a biomedical engineering degree from Georgia Tech and a track record of identifying transformative companies at the earliest stages, Caleb’s insights on how computation and AI are reshaping drug discovery—combined with his hands-on understanding of scaling breakthrough science—make this a conversation you won't want to miss. Over the next four episodes, Caleb shares how growing up in a university town dominated by Texas A&M impacted him. He reflects on lessons from undergraduate research that pressure-tested whether he actually wanted a PhD, cold emailing researchers about bicycle helmet concussion risk, and why a single Excel error at Bain taught him mistakes were part of learning. Today, we'll hear about Caleb's early days in College Station, how growing up in a university town exalted education, and why professors seemed like the top of the ladder career. We'll also hear about choosing Georgia Tech over Johns Hopkins, diving into undergraduate research in genome editing, and why working at the microliter scale—where experiments worked one day and not the next—made him question pursuing a PhD. Lastly, we'll hear about cold emailing researchers to work on bicycle helmet designs, how two risk plots predicted 90% versus 1% concussion likelihood for the same data, and why that summer convinced him engineering can't solve problems with undefined constraints. Without further ado, let's dive into Part 1 of our conversation with Caleb Appleton.

Jon Chee - 00:03:56: Caleb, it's good to see you again. Thanks for coming on the podcast.

Caleb Appleton - 00:03:59: Yeah. Thanks for having me, Jon.

Jon Chee - 00:04:00: You know, we've been really looking forward to this conversation. I know it's been a long time coming. It's finally here, and we've been really excited to go all the way back and learn about what were some pivotal moments throughout your career and your upbringing that really got you into STEM, investing, and business, and really what influenced your overall philosophy around it. So, take us all the way back. What was baby Caleb like, and what was your upbringing like?

Caleb Appleton - 00:04:22: I was eight pounds, eight ounces.

Jon Chee - 00:04:24: Yeah. Yeah. There we go. There we go. We're going early, baby.

Caleb Appleton - 00:04:27: No. But I grew up in a town called College Station, Texas. It's a university town that not many people, I guess, know of outside of the state, but Houston, Austin, and Dallas make a triangle on the map. And if you're looking at them, College Station is smack dab in the middle. I would describe it—or I do describe it to my friends—as basically a suburb that's just not attached to a big city.

Jon Chee - 00:04:48: Isn't Texas A&M there?

Caleb Appleton - 00:04:50: Yeah. The major employer in town is the university, which is Texas A&M. And so when I was growing up, that was probably like 30,000 to 40,000 students. Today, I think it's something insane, like 80,000 students, but it is the largest university in the state, and you very much feel the presence of it growing up there. When the students were out in the summer, all of a sudden, there were never waits at restaurants. The red lights lasted half as long, etc.

Jon Chee - 00:05:17: Yeah. Yeah.

Caleb Appleton - 00:05:17: But more practically, it meant that I grew up surrounded by higher education. And that had, I think, a couple of really profound impacts on both how I view the world and then, two, how I thought about education myself. I think that the first—how I view the world question—was, you think of a town of about a quarter-million people in Central Eastern Texas, and you probably have some hypotheses of what that might be like. I think in many ways, College Station was not that because of the university. Actually, you had this incredibly diverse—both ethnically, from a religious perspective, and from a socioeconomic perspective—community that was really there because of the university. You had professors from around the world. You had many of my friends; their parents were graduate students getting their PhDs or doing a postdoc in a lab. So I had all of these friends with pretty radically different backgrounds from myself in this tiny town—or not tiny, but mid-sized town—in Texas. And so I think that was a real blessing growing up. It's something that I wouldn't have gotten. Even most suburbs of large cities tend to be very homogeneous.

Jon Chee - 00:06:27: Yep. Yep. Absolutely.

Caleb Appleton - 00:06:29: So that was, uh, I think, a really exceptional thing. But the second piece is education, I think, was exalted as a result. Right? At least this is my perception of it. Neither of my parents at the time were directly affiliated with the university. My mom's a surgeon. She's an obstetrician and gynecologist. My father's been a lifelong engineer. Actually, after I left Texas, he started working as a Professor of Practice at the university, but that was never the case when I was there; he was working for the State Department of Transportation. And so the people I looked up most to—my friends' parents, family friends, etc.—were professors. I saw that as kind of like the ultimate career. Like, you get to learn really deeply about one or two specific things and you really push out the world's knowledge graph in some domain where you are the expert. I felt like, wow, what a cool thing to be able to say: "I'm changing the world in this very tangible and discrete way." And so, yeah, from a very early age, I think those were the people I looked up to the most. I would say that it shifted. The people aren't always professors today.

Jon Chee - 00:07:38: Yeah. Yeah.

Caleb Appleton - 00:07:39: Yeah. Largely still the case. I really admire and enjoy the fact that I get to spend my time talking with people who are the experts in the thing that they're doing—to have this relentless pursuit of expanding humanity's knowledge. And so I would say that was very much rooted in growing up in a town where the dominant employer was a higher education institution.

Jon Chee - 00:08:02: That really resonates with me too because growing up in Berkeley, it was the same exact thing. Going through the Berkeley Unified School District, it's just like... as much as I think Berkeley is—there's much more to it than just the university. But it plays a dominant role.

Caleb Appleton - 00:08:18: For sure.

Jon Chee - 00:08:19: Yeah. Like, a dominant role. And as of late, UC Berkeley has an even larger growing presence. But yeah, that was the same thing too. And I actually think about this podcast as—I don't think I've ever explained this on the podcast—but kind of my conversation style reminds me of when I was a child just annoying the hell out of my friends' parents. Just asking really deep, probing questions about what kind of got them into what they got into. Because a family friend of mine's parents came to Berkeley for grad school and did the Lawrence Berkeley National Labs for a very, very long time and does lithium-ion batteries. He's actually one of the earlier guests on the podcast, but I would just pester the hell out of him. Like, just like, "Okay. Tell me more about this and that." So it was a really interesting—exactly—I can empathize with getting exposed to that. Especially as a child, that's amazing that a kid could have the opportunity to just kind of soak this up to very much fill that in. Did your parents come to College Station for grad school as well?

Caleb Appleton - 00:09:17: No. So they both went to Texas A&M as undergrads. My dad studied Civil Engineering. My mom actually—it's a good question. I don't know what her—

Jon Chee - 00:09:26: No. I'll just put you on the spot.

Caleb Appleton - 00:09:26: She's basically pre-med. Her technical degree was in... They got married directly out of college. My father actually joined the military. Texas A&M, for those who don't know, has—I think it's probably the largest outside of the military academies—for ROTC and people joining the military as commissioned officers. And so he did that for four years while my mother was going to med school and got into Texas A&M's med school, which is actually not in College Station. And then, she went to residency, had my sister, and then later me. It didn't make sense for him to be in the military. And one, both, it's much harder to move a surgical practice around every couple of years.

Jon Chee - 00:10:05: For sure.

Caleb Appleton - 00:10:06: And so they ended up moving back to College Station basically right as I was born. My mom helped to start a large physician practice in town. My dad was working for the State Department of Transportation, which had a large office in the area. And I think they just liked the things that being in a university town brought. Because of the university, a lot of things came to town that you wouldn't otherwise have in a 200,000-person town. George H.W. Bush, the older Bush, put his presidential library there, which meant world leaders would come to town to give lectures. You know, obviously, diversity attracted really interesting people. And so is it, all in all, a great place to grow up? One of the things that it didn't have though, which I think we'll come back to as it relates to my own career, is I talked a little bit about thinking of professor and academic being the tip of the career pyramid. A lot of that was because I also didn't have exposure to what is it that people did other than that?

Jon Chee - 00:11:06: Yeah. Yeah. Yeah.

Caleb Appleton - 00:11:08: The best jobs in town were doctor, engineer, academic, right? You didn't do a lot of industry and business and tech and all of these other things that I think you get exposure to. It's like, wow, actually it takes a lot to make the economy go round. I just had no idea that any of them were career options or, candidly, even existed. I remember whenever in middle school you take one of these career aptitude tests. It's just like an online survey, essentially. Yeah. My friends figured out how to game it such that they got, "You will be a physician," and people were like, "Yes, I make so much money."

Jon Chee - 00:11:42: Yeah. Yeah. Yeah. Sweet. This is my calling. This is perfect. It's fate.

Caleb Appleton - 00:11:46: But I don't think I knew what an accountant did or what a consultant was. I just had no idea and no exposure to those types of industries.

Jon Chee - 00:11:54: Interesting. And as you're starting to think about your college—your undergraduate college decision—were you like, "I kinda wanna leave Texas," or were you contemplating staying in Texas as well? Where were you at in that headspace?

Caleb Appleton - 00:12:08: Yeah. It's interesting. So the state of Texas has this rule that if you're in the top 10% of your graduating class, you're guaranteed admission to any state university. I grew up, because I lived in College Station, as a huge fan of the sports teams related to Texas A&M. The Aggies is their mascot. We had season football tickets, soccer, women's basketball, etc. And so I was too much of a fan of that university to apply for the University of Texas, that rival school. I was too convinced I didn't want to go to school in my hometown. And so I think I applied because it was a free option with the top 10% rule. Never had any real ambition or intention of going to school in the state of Texas. So how I ended up where I did—I ended up going to Georgia Tech—was first, it started with—and I imagine this is a pretty similar process for a lot of people—it's like, "What do I wanna major in?" I'm 16. I have no idea. I don't really even know the full spectrum of jobs I could have. I know what I'm good at. I'm very good at math and science, and I really enjoy that. My dad's an engineer. My mom's a physician. What's the mash-up of those three things? You know what I'm good at? You don't wanna know. Biomedical engineering. Okay. I've convinced myself that I want to get a degree in biomedical engineering. I don't think I even had any idea what a biomedical engineer could potentially do other than it was engineering and it was impacting human health, which I thought was meaningful. And so I convinced myself, "Okay, I'll get a degree in biomedical engineering." And so then I did the next logical thing, which is I logged on to the U.S. News & World Report website. Actually, I think it might've been a book back then.

Jon Chee - 00:13:49: Yeah. Yeah.

Caleb Appleton - 00:13:50: Right? And you go to biomedical engineering and it's like, "Okay, here's the top 10 undergraduate schools." And I basically applied to half of those. I think at the time, Hopkins was number one. Duke and Georgia Tech were second and third in some order. Rice was in the state of Texas and also in the top five. Applied to those, maybe one or two others. It ended up coming down to Georgia Tech and Johns Hopkins. Visited both and really for two reasons ended up choosing Georgia Tech. The first being, I went to a high school that was about 3,000 students. At the time, I think Johns Hopkins' undergraduate student population was like 1,800 students. It was 60% the size of my high school.

Jon Chee - 00:14:34: No way. I did not know. I thought Johns Hopkins was way bigger.

Caleb Appleton - 00:14:37: Oh, and I think it's still today only a couple thousand students. It's a pretty small university. So obviously punches up in terms of number of students to notoriety. But I already felt like my high school was too small of a place and I knew everyone. And so going somewhere smaller seemed constraining. And then two, I was fairly convinced I wanted to be an engineer. You know, I thought biomedical is where I would stay. Georgia Tech provided the opportunity where all of their engineering schools are ranked in the top 10. Hopkins Biomedical is really the engineering degree. And otherwise, they have an incredible liberal arts school, but it was not as necessarily aligned with what I thought I wanted to do categorically. And then the final piece was Georgia Tech, which is kind of related to the first, was much bigger from an undergraduate population, which then meant it also had these things that I really liked about my hometown, which is a real sports team and a major sports league. And you just get all of the more classic Americana college experience that I thought I wanted. So, yeah, ended up moving to Atlanta and going to Georgia Tech.

Jon Chee - 00:15:43: Very cool. Very cool. And it's interesting. Like, I had a similar kind of experience, but I stayed in Berkeley. So I went to Berkeley High, which I think at that time was around 3,500. But I was like, I definitely wanted to just step it up in size. And I think Berkeley at that time was in the 35,000, 40,000 range. And so for me, it was exactly the same thing. It was just like... and it is kind of almost like just bringing the real world to—accelerating it and pulling it forward. But I was in the same mind space. And similarly, when I was choosing a major, I was like, "Yeah, I think being a doctor... exactly. Just like, I think that makes sense. I have no idea what that entails, but, yeah, like, I'll give this a shot." So you're at Georgia Tech. You've now declared your major. How did you start getting involved in the biomedical community? Did you have a lab experience? Were there extracurriculars that you were digging into? Tell me a little bit more about that.

Caleb Appleton - 00:16:36: My first experience actually in doing research was in high school, both because I had this world-class research institution in my backyard and second, because I wanted to make myself more attractive to college admissions counselors.

Jon Chee - 00:16:55: Yeah.

Caleb Appleton - 00:16:55: And so the lab I first worked in was a biology lab. I actually don't remember the specifics of the overall research that the lab was doing.

Jon Chee - 00:16:59: You're probably like washing the dishes. I'm gonna imagine.

Caleb Appleton - 00:17:02: It was maybe slightly better than that. I showed up and the PI is like, "Perfect. We have a high school student. Caleb, your desk is in the basement." Yeah. Truly like a windowless room. "And what your task is doing is taking these hundreds of thousands of histology and pathology slides that we have, and you're gonna put them on the scanner and you're gonna make them digital."

Jon Chee - 00:17:34: Yeah.

Caleb Appleton - 00:17:35: And so I sat there for a couple of weeks just scanning these things. And somehow that didn't break me. Actually, when going into undergraduate, my kind of personal hypothesis and thesis was I was gonna go get a PhD after my undergraduate degree. And so doing undergraduate research was gonna be a way to figure out what it is I wanted to do that PhD in and then to make it more likely that that goal was achievable. And so actually got connected prior to starting at Georgia Tech to a PI who is running a lab that just one of our neighbors from home actually was his grad school roommate. It's just a small world situation. I think this is true, and we can come back to this a couple of times. Like, one of my big beliefs in one's career and just general life path is that you have to learn to embrace serendipity. You can't plan everything out because it will never go to plan. And some of the most exceptional experiences I've had have been from a combination of putting myself in good situations and good places, but then also being willing to embrace serendipity when it presents itself. And I think it's a good example of that. He introduced me to this PI. His name was Gang Bao. Gang's lab was doing a broad array of biology research specifically focused in two areas. One was nanotechnology, and the other was gene therapy. And so he sent me a couple of papers, and he said, "Read these." You know, I have no idea how to read a paper at this point. "And tell me which of them you find most interesting." So I did that, and one of them was about gene therapy. And from what I could understand, it was like, "Oh, this is a really cool way that you can edit the genome and cure disease. That seems like a really cool thing to work on." And so I told him that, and he said, "Okay. Here's this guy, Eli. You're gonna be working with him. He's a graduate student in my lab." And so from day zero on campus, I ended up working in Dr. Bao's lab. And this was 2011 when I started at Georgia Tech. And when I joined that lab, the kind of craze in the gene therapy world for the first six months were these nucleases called Zinc Finger Nucleases, which were highly effective at creating edits, but really difficult to wrangle with. And so then, like six months in, a new technology called TALENs—or Transcription Activator-Like Effector Nucleases—came out, which did that, but slightly better, slightly easier to engineer. And then in 2012, a new technology came into the field, which was called CRISPR. And one of our closest collaborators in the lab was a guy named Feng Zhang at MIT. And so our lab, I think, was one of the first in the world, certainly the first in the Southeast, working with CRISPR. And that wasn't because I sought out to go work in a CRISPR lab. It just happened to me. And all of a sudden, I'm working on this technology that within eighteen months from that moment, maybe twenty-four months, my grandmother in her eighties knew what CRISPR was. It was a pretty surreal experience and a really exceptional undergraduate research experience, I would say.

Jon Chee - 00:20:35: That's a pretty badass undergrad experience. And I totally agree with you on embracing serendipity. And it really is exactly what you said: putting yourself in the right places and then just seeing what happens. For me, it always is sometimes a thing where I'm like, "But I don't wanna go do this thing," or, "I won't know anyone there." And then my wife usually just nudges me. She's like, "Go freaking do it." I'm just like, it's like a night. Just go do it. And I'm always pleasantly surprised at how it shapes up because you just meet really interesting people. Getting out of your comfort zone—don't let that hold you back, I guess, is what I'm trying to say. Is that it may not be comfortable or might not come intuitively to you, but it's always really fascinating what type of connections you can make when you just put yourself out there. And that also is digital too. Like, obviously, physical spaces, for sure go. But digitally too. The Internet just has this ability to connect. You would think that you're the only person into this thing, but if you put yourself in a digital space, you're probably gonna find like-minded individuals no matter how niche your passion or interest is. You'll ultimately find that connection.

Caleb Appleton - 00:21:47: Yeah. And I'll also say, particularly for young people in school or directly out of school, maybe early in their career: never underestimate how willing to help people who have already had kind of success might be, especially if there's some kind of shared background or history. I think I'm certainly very lucky to have had a number of mentors, and people helped me out that I had very loose connections to. But just putting my hand up or reaching out or sending a LinkedIn message or an email or whatever resulted in a conversation that resulted in a friendship that resulted in something, maybe five or ten years in the future. But it all started with just like, yeah, putting myself slightly out of my comfort zone of being willing to ask. And I think there's a lot of power in that, and people underestimate how often people will say yes to the thing you're asking.

Jon Chee - 00:22:36: Yeah. Yeah. Yeah. And I think, at least for me, it was always a fear of just getting rejected, which has held me back. But just don't let that... for anyone who's had something in draft mode just sitting there. Just hit send. Just hit the send. It'll be okay. Try your best. Try to add value if you can or show genuine interest, and you'll be okay. And so you're now in the lab. Talk about the actual lab experience. Sounds like you had a postdoc or grad student that was kinda taking you under their wing. What was that like?

Caleb Appleton - 00:23:07: I mean, it was super exciting. I think a lot of the engineering curriculum at any school feels very academic in nature, right? Like you're doing these problem sets, you're learning about concepts, but it feels very distant from the actual application of it. And the lab was kind of the opposite. It started with, "Hey, you need to learn how to grow E. coli and purify protein. And I'll tell you about why that matters as you're doing it," versus the opposite way around. So it was a little bit of just like, learn really quickly. There was a little bit of grunt work. It was like, "Hey, these cells need to be passaged. That needs to happen at 3:00 PM on the weekend. I don't wanna come in, Caleb. Can you do it? You live closer."

Jon Chee - 00:23:51: Yeah. Yeah. Like, cell culture maintenance, it was a big thing. Just like, "Oh, goddamn it. Really? We gotta get it done."

Caleb Appleton - 00:23:58: Yeah. And someone has to do it. And maybe that's slightly better today with robotics, but I think it's still a lot of RAs coming in on the weekends or undergraduate students doing the same. And so that was a lot of how it started. It's just like I was basically scaling the PhD student I was working with from a manual labor perspective. Right? Like, it was an extra set of hands to drive pipettes. He was very computationally focused. He was building some early tools for how do you predict off-target effects of CRISPR and similar nucleases. How do you actually design them to be more effective? And so at that point, in order to confirm those predictions, we had to go in the lab. We had to make them, and we had to test them. Right? And so I was to go in the lab, do it, make it, test it.

Jon Chee - 00:24:41: Yeah. Yeah.

Caleb Appleton - 00:24:41: But with time, that shifted, and it was more of a kind of collaboration. And I was able to bring ideas to the table. You know, I was still much more narrow in scope and structure than what any of the PhD students were doing, but still was able to cross that chasm and begin to say, "Hey. We've been trying this one thing. What if we tried this other thing that's kind of related?" And some of that ended up working. One of the papers we published from that work was from an idea that kind of came in one of those whiteboarding sessions. One of the kind of canonical—still today, I get pitches from companies working on this specific challenge—which is one of the big issues with CRISPR: how do you deliver it in the body? And it's a pretty large chunk of genetic material. And so getting it into the body and into cells is challenging. And what most people use for in vivo editing are viral vectors to deliver it, and viral vectors have a maximum capacity in terms of number of DNA base pairs that they can handle. And so we were trying to come up with a clever solution to that. This was back in 2013 or something. And we had this incredibly complex solution, which is: "Hey, you deliver it in multiple pieces and then they come together in the cell and it works and fuses itself into a single functional unit." For a number of reasons, that's a really bad idea for some regulation at all. It's just like the more things that can break, the more things will break, but it resulted in an interesting paper. And still, that problem is something that people are wrestling with for in vivo editing today. How do you deliver enough CRISPR to cells or base editors or whatever it may be? And it was a fun and exciting learning experience until we ran a single Western blot like 15 times trying to get the image for the publication.

Jon Chee - 00:26:28: I know the band. Yeah. Yeah. Yeah. And was your PI like a very hands-on PI or just like, "Spread your wings, y'all. Just do your thing"?

Caleb Appleton - 00:26:38: Just the honest answer, I spoke maybe 100 words to him over four years.

Jon Chee - 00:26:42: Okay. There we go. There we go. It's just sometimes, people don't realize. Sometimes, it's stylistically, some folks are super hands-on or some folks are just like...

Caleb Appleton - 00:26:50: I think if you look at his publication record and you look at his lab, they've continued to put out really high-quality, high-impact publications. Most recently, he moved his lab to Rice and was leading bioengineering there. He was spending more time, obviously, with the PhD students than myself. Then there's lab leading and all these things. But I think, yeah, an effective leadership technique can be hiring really great people to work for you, giving them enough guidance, but not too much guidance to be overly prescriptive and prevent them from reaching their full potential. And I think that's kind of how he managed that specific lab. And by all quantitative accounts—citations—like, it seems to be working.

Jon Chee - 00:27:31: I love that because I think I always try to... whenever I talk to folks about leadership styles, it's like there is no one way to do it. Like, really, there are some folks who are very much the opposite of that, and they also just rip.

Caleb Appleton - 00:27:45: Yeah. For sure.

Jon Chee - 00:27:46: Oftentimes too, it's like a personal decision. It's like, what style works best for you and resonates with you? So, like, I could not work well in an environment where I felt like I'm micromanaged, but some folks just thrive with structure like that. And I guess I know to go back a little bit, like, pretty rad to also just... even though it was a good paper, but things will inevitably go wrong the more complexity you add into it, but pretty rad to get published as an undergrad.

Caleb Appleton - 00:28:12: Yeah. It was super cool, and I don't think it was ever my expectation going into it.

Jon Chee - 00:28:18: A happy little side effect of it. Yeah.

Caleb Appleton - 00:28:20: Yeah. For sure.

Jon Chee - 00:28:21: Yeah. That's rad.

Outro - 00:28:24: That's all for this episode of the Biotech Startups Podcast featuring Caleb Appleton. Join us next time for Part 2 where Caleb recounts choosing Bain despite having no idea what consulting was, mastering case interviews in seven days, and why working seventy to eighty hours a week with exceptional people felt like being in a group project where every teammate was yourself. He also shares why he turned down Stanford Business School when the pandemic made it a February Zoom cast and how leaving Bain felt liberating while staying felt constraining. If you enjoy the show, subscribe, leave a review, or share it with a friend. Thanks for listening, and see you next time. The Biotech Startups Podcast is produced by Excedr. Don't want to miss an episode? Search for the Biotech Startups Podcast wherever you get your podcasts and click subscribe. Excedr provides research labs with equipment leases on founder-friendly terms to support paths to exceptional outcomes. To learn more, visit our website, www.excedr.com. On behalf of the team here at Excedr, thanks for listening. The Biotech Startups Podcast provides general insights into the life science sector through the experiences of its guests. The use of information on this podcast or materials linked from the podcast is at the user's own risk. The views expressed by the participants are their own and are not the views of Excedr or sponsors. No reference to any product, service, or company in the podcast is an endorsement by Excedr or its guests.