Mark Kotter - bit.bio - Part 1

Intro - 00:00:01:

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.

Jon - 00:00:23:

My guest today is Mark Kotter, neurosurgeon, stem cell biologist, and CEO and founder of Bit Bio. Bit Bio is an award-winning human synthetic biology company providing human cells for research, drug discovery, and cell therapy. Bit Bio applies a patented safe harbor gene targeting approach to inducibly express transcription factor combinations that reprogram human-induced pluripotent stem cells into highly defined and mature human cell types. BitBio spun out of the University of Cambridge in 2016 and has since raised approximately $200 million from Arch Ventures, Foresight Capital, Milky Way, Charles River Laboratories, National Resilience, Tencent, and Pulau Capital, among others. In addition to BitBio, Mark is also the co-founder of Meatable, scientific founder and chairman of rejuvenation startup Clock bio, and co-founder and trustee of Myelopathy.org, the first charity dedicated to a common yet often overseen condition causing a slow-motion spinal cord injury. Mark has also been a professor and researcher at Cambridge for more than 15 years. His diverse experience as an academic and serial entrepreneur offers a wealth of insights aspiring scientists' founders can draw from. Over the next four episodes, we cover a wide range of topics, including Mark's early years moving all around the world, his time at Cambridge pursuing a PhD in regenerative medicine, his work in synthetic biology and stem cell research, his transition from clinician-scientist to serial entrepreneur, and the founding and evolution of his latest company, Bit Bio. Today, we'll chat about Mark's upbringing as a curious child in Canada and his exposure to a broad range of cultures and perspectives, as his family moved around for his father's work, we'll also touch on his experiences growing up with dyslexia and how it led him to focus on science and mathematics at an early age. Lastly, we'll talk about his experience as a researcher and PhD student at Cambridge, where he transitioned from medicine to synthetic biology and stem cell research. Without further ado, let's dive into this episode of The Biotech Startups Podcast. We thought it'd be a really fun place to start by you just kind of giving us a little bit of background on your upbringing and how it influenced your business philosophy, your leadership style, and learn how you got inspired to pursue science.

Mark - 00:02:28:

So as you can easily figure out by my accent, English isn't my first language, although I've been born in Canada. So my parents, both Austrian, went to Canada. My father studied there and I was lucky enough to become a Canadian citizen by birth. We then returned back to Europe. My father had a career in industry, so we're hopping around different places, companies and actually countries. And so maybe one thing that differentiates me a little bit is this, you know, from the beginning onwards, locality was one thing, but also moving to new places, getting to know new people, and especially how, you know, the same things can be seen from so many different ways. So. I can remember growing up in this little town in Germany, and they had very set ideas about things. But I knew whenever I went to see my grandparents in Austria, the same things would be seen in a very different light. So that sort of breadth of opportunity to look at the world was something that I experienced just because of the different moves.

Jon - 00:03:38:

That's amazing. And it's funny because when I hear stories of those who've grown up living in different countries, different cultures, I think back about my lived experience. And it's weird because I was born in Berkeley, and I'm now in San Francisco, which is not that far away, maybe like seven miles away. And I joke that I haven't left a seven mile radius. I was born in Berkeley, went to school in Berkeley, and was so adventurous enough to be courageous to go across the bridge and live seven miles away. So it's amazing to hear that experience. And you said your father was in business. Can you talk a little bit about what it was like being in that environment where it seems to be kind of like via osmosis, you might be absorbing the learnings of your parents? Can you talk a little bit about that?

Mark - 00:04:23:

Well, what I knew about my father is that he talks the entire day long in meetings and that he's never at home. So that's how I remember that. But when he was at home, he was good fun, actually. One thing that was clear is that there was a certain focus on a goal and he was quite successful in his career. And I didn't know what success was at that moment in time in a business context. I just saw that there were people running after him and around him. They were discussing things that I didn't know about. And then also I was inspired by the family history, which also has at least on a few occasions entrepreneurs going back, you know, maybe 150 years or so. And so I actively decided not to go into business at a later stage.

Jon - 00:05:08:

That's amazing.

Mark - 00:05:09:

I always felt, how do people do this? What does it mean to create a company or an enterprise? And it was an abstract thing for the most part.

Jon - 00:05:19:

And was science always a presence in your life? Or was that something that you kind of discovered a passion for later? Or was it something that you were exposed to in your earliest days?

Mark - 00:05:30:

I mean, I kind of was a bit nerdy, I would say. So I would be, you know, looking at mainly animals and bugs and sometimes dissect them. And so in school, it became clear that I would be orientating myself towards maths and science. Also because I was incredibly dyslexic. So much so. That, you know, for a period of time, my grades in German were dismal. I mean, really horrendous. I turned the corner when I turned 17 or 18, but there was definitely a period of time where there was more markings in my essay than words written by myself.

Jon - 00:06:12:

And that's amazing because like sometimes that's just like how it is. Like there are these inflection pointers like, well, I guess I'm doing STEM. This is where my strengths might lie. So I'm going to just pull that thread. You mentioned that you're, you know, 16, 17 and you get an essay back. It's bloodied. You're like, oh, God.

Mark - 00:06:28:

It was more red than blue.

Jon - 00:06:31:

Yeah.

Mark - 00:06:32:

Actually, one of the turning points was around the age of 15, 16, when I decided to go and live away for a year. So I went to Australia, of all places. And that really gave me a lot of freedom and, again, the opportunity to experience something completely different. And coming back, I sort of had a very good idea of what I wanted to do. So I discovered... Probably my main talent in life, which I've totally wasted, is maths. Comparably, I became very good. So I was in a small cadre of national selected pupils who had additional maths at school. So they brought us all together across Germany and hothouses a little bit. And when I then graduated from high school, I decided to do maths and physics. And that's what I did. And then something happened where, and it's probably because I was in a very provincial mindset. But at that moment in time, 1990, I just didn't know what to do with it. So I had this fascination for abstract thoughts. But at the same time, I had this angst that this might lead to nothing. If eventually that I'm going to waste my life doing something that gives me pleasure, but no impact. It was a bit of a hard time then. You know, I had it. Probably what, you know, we call it depression. So it was pretty existential at that moment in time. And when you don't know anything anymore and you think you've lost it, then, you know, I thought, so how do I get out of this? And so I said, okay, first principles. If you don't know what your place in life is or your mission or why you're here and you have no reference, then, you know, what can be seen as good foundationally? And I said, to me, we're helping others. And so after semester two in math, I sort of got stuck with this idea of potentially pivoting to medicine. Which is not something I planned at all. In fact, I decided to no longer study biology around grade 10. So I didn't have biology for two years. And the other thing was that also it was such a strange world. So I said, okay. If this makes sense, and it did make sense, I didn't know whether it was for me, then maybe I should try it out. So I became a nurse assistant for half a year or so. And I ended up in that ward for people with spinal cord injuries. And I've never seen anything like this before. It's very heavy duty. I mean, they need a lot of care. And it really sort of turned my world upside down. And I didn't know whether that was the right thing or not. So it took me a few months. And at the end of that, I decided, yes, I'm going to go for it. So I pivoted away from maths and then jumped and started to do medicine. So by all means, it wasn't a linear path at all.

Jon - 00:09:32:

That's incredible. And it always surprises me when I hear these stories that there's like these kind of serendipitous inflection points in one's business journey, life journey that can totally, because obviously I know now, like looking back, I'm like, that is what you've dedicated a lot of time to is?

Mark - 00:09:48:

My life.

Jon - 00:09:48:

Your life, right? Obviously. And you're just like, it goes all the way back. Like it goes all the way back to this experience as like a nurse assistant. And I guess before we talk a little bit about that experience, going back one moment to Australia, what was it about Australia? Like that flipped the switch for you when it's like math is what I want to focus on, at least at that point in time.

Mark - 00:10:09:

So if you go to another place, you have to reorientate and find new bearings. And of course, here there was a void. You know, it was just me. There was no inference from outside. I chose maths there because I knew it was relatively easy for me. But I sort of got the chance also on the language side. English is my second language. And interestingly, that meant I didn't experience any dyslexia. So in German, I was heavily dyslexic. But my English wasn't affected by it. So it sort of reset everything. And then I learned actually, you know, I can solve this dyslexia thing by treating maybe German as a foreign language in some ways. And when I came back, it was really just that, you know, I don't want to sort of come across in the wrong way. But I just felt maths was super easy. And I just was always at the top. And then there was this national competition. So every school was allowed to send. One or two of their best pupils. And then there was, I remember, a six-hour test or something like that. And from the hundreds that were there, you know, 20 or 15 were picked. So it kind of tells you that that is something that you're good at. And I loved it. I really like ordering the world.

Jon - 00:11:25:

Yeah, yeah, yeah. And now I'm like, maybe I should get out of San Francisco and get out of the Bay Area. Because I'm like, maybe the problems I'm experiencing right now, I'm like, I've been in the same area for too long. Maybe I just need that shock to the system. And just like, maybe that's exactly what I needed, rather than just trying to like, hammer away this problem that I've been focusing on for so long. And, you know, kind of fast forwarding a little bit here, it seems that you went from maths, and then you decided to like try your hand at medicine. And I guess my first question for you is like, how did this nurse assistant opportunity even come about? Was it just a simple thing where you're like knocking on doors? Or was it like something where someone made an introduction? How did the opportunity arise?

Mark - 00:12:06:

So I knew someone who was doing that. And so I tapped his shoulder and asked him whether he could help. It was an experiment on my side, on myself. Just coming back to what we discussed earlier on, going abroad, actually, you learn more about yourself than location. And I think that is sort of the important thing there. When I then entered the hospital, again, it was a completely strange world. And medicine is a completely different set of rules and ways of going about. So I was catapulted into some unknown territory, being exposed to patients. You know, you come to them very close. I remember a young vet that just graduated. And to celebrate their graduation, his group went to Odessa. And he came from Russia. And he jumped into the water and he broke his neck. And he was paralyzed from the neck downward. So that person was maybe six years older than myself, maybe seven. And seeing this and seeing what happened to him, that made a very deep impression on me. And so it's strange. But, you know, 25 years later, I end up as a neurosurgeon with a specialist interest in spinal cord injury. And it's not something that I chose knowingly, at that moment in time, it's something I was drawn back into this over time.

Jon - 00:13:36:

That's incredible. And like, it's those memories that really get seared into you. And I can very much think about like experiences that are continued, it's like seared into me. And a lot of my friends are like, they say they have the blinders on, but I just call it focus. But now that you've had this eyes open, awakened moment while you're in school, how did that translate into? So now you're like, okay, we're now pursuing medicine. When you come back from your stint at the hospital, how did your kind of academic career change from there?

Mark - 00:14:04:

I basically changed to medicine, also changed from Germany to Austria, wanted to come back to Germany, but serendipitously got stuck in Austria. It was a very nice time that I had there. But what was very clear, you know, I was asked the question, how does it work and why? And so relatively early on studying medicine, I knew that I wanted to be exposed in research. And so I looked for those opportunities as well. Well, it wasn't clear, however, yet the choice wasn't fully baked because I also had the chance to study music at the same time. And so there was a little bit of, you know, a period of two or three years where I did both. So I got up six o'clock in the morning, played the piano for two, three hours, and then I would go and see some lectures and come back and do my composition and homework, etc. So medicine won.

Jon - 00:14:57:

Yeah, yeah, yeah. But that's amazing. Like, you know, and I, in a similar vein, while I was at Berkeley studying basically biochemistry, I also was studying philosophy. Had a moment where I was like, I might do the philosophy route, but biology one in this case, but I still very much find that I'm tapping into the lessons learned via the philosophy training. It's things like that. I love taking inspiration from various industries, various disciplines, because I always think that you can incorporate it into whatever you're focusing in.

Mark - 00:15:30:

I mean, nobody can say that you've got blinders on. These are so disparate subjects. You're right. You can draw things. Often it's a structure in your thought process or so that you can transfer. And, you know, I think it does, I believe, potentially gives a little bit of an advantage.

Jon - 00:15:49:

Absolutely. And so while you're studying music, and obviously you ended up getting your medical degree at the University of Grasse, I guess my first question is, what inspired you or kind of sparked the interest in research? Because usually they're kind of like separated. You're either practicing medicine as like a practitioner or you're in the lab. And, you know, obviously MD, PhDs obviously are a thing, but like, was there a moment in time where you're like, this is really cool. I want to do research as well. Or was it something that you were just like. And just like figure it out on your own?

Mark - 00:16:19:

Well, I think firstly, when you learn how the body works, and it's across different scales from the molecular scale to the body that we see, it's fascinating. Everything's intertwined. And then if you look a bit closer, you know so little. So there's gaps everywhere. So the question always, the next why or how, there's always a point in time where that fails. You don't get an answer. And I'm quite curious. So I think that's sort of what drove me into wanting to find out more, even wanting to understand how people found out what we now seem to know. And then, of course, also realizing that what people know might change over time. And so even science, there are ways of looking at things and they come and go, or they just are replaced. So most of the truths that we believe are potentially not as robust as we'd like them to be.

Jon - 00:17:16:

Absolutely. And that is definitely something I have encountered time and time again. You always have to, exactly what you're saying, checking the why. You peel back the layer of the onion and you just ask yourself why. And so you get, sometimes you just get to a point and you're like, ah, I get it. I now understand. But sometimes you pull back the layer and you're just like, huh? And then you're like, maybe we can reevaluate why we have this world lens or understanding of this mechanism of action. And while you're completing your medical degree, were you doing research simultaneously?

Mark - 00:17:48:

Yeah, it was sort of intercalated. So I was able to join a lab in Cambridge and did a year or so during my medical degrees. And that's another reason, maybe, why I was so drawn to research now that we talked about my sort of earlier past. So when you have dyslexia, you actually have memory issues, short-term memory issues. So how do you bang the amount of knowledge into your head that you need to accumulate for a medical degree? And for me, it's always understanding cause-effect relationship as far as you can. And so I never learned anything just by sort of memorizing it. What we call pharmacological names were probably the worst thing I had to memorize. And it was just like repeating them a thousand times, drumming them into my head. But most of the other times, I realized if I try and ask why and go to the bottom, as far as we know, actually, you know, I can store it. And maybe the sort of curiosity, was a self-help mechanism to overcome.

Jon - 00:18:50:

Yeah.

Mark - 00:18:50:

It's extra.

Jon - 00:18:52:

Yeah.

Mark - 00:18:52:

I still ask why all the time. Or how.

Jon - 00:18:55:

Or how. Yeah, absolutely. We can't ignore that. And I think that was like, for me, is what got me so fired up about this wet lab research was exactly that. That's the name of the game. It's like just trying to peel back the layers as far as you can and just deepen the understanding. And so you have a year of research. And I guess maybe my first question is, how did you land that position? And like, can you tell me a little bit about, was it an instance where you're knocking on doors, asking friends? Because obviously, they're not that close to each other. And also, can you talk a little about your first lab experience at Cambridge?

Mark - 00:19:28:

So it's a mix of all the things that you said. So I was somehow lucky. I applied for an elective. And this is of clinical placement. And I got to be sort of given that opportunity. So I was doing the wards and ward rounds with the neurologists here. And then I was quite impressed. Very different atmosphere to where I studied. And I was trying to see, you know, how can I get into this? Not only in terms of technologies that you had here, sequencing was a big thing at that moment in time, but also the culture seemed to be different. So I made friends with a PhD student here. And he said, hey, if you're interested, I can introduce you to my prof. So basically knocked at the door. And I said, look, you know, I'd like to work with you and do some research. And he said, okay. I mean, I don't have any. I don't have any stipends or anything that I can give you. But why don't we try it out? So I just pitched up. He gave me a project. We looked at mutations in a metabolic gene. And I liked it. And he became extremely supportive of me. And so that was the entry to the lab. So it was the most old fashioned lab that you can think of. It was in the mid 90s. So it looked a bit more like a lab from the 1930s. Bottles everywhere, things everywhere. It was filthy. It would fit into one of these movies. But we managed to look at and identify some unique mutations in this gene. And then my year was up. And then he asked me if I would like to come back for a PhD. And I said, I'd love to, but not with you. I want to go and work in a neurology lab.

Jon - 00:21:19:

Yeah, yeah.

Mark - 00:21:20:

So I made some intros and I was lucky enough to be accepted.

Jon - 00:21:24:

That's so cool. Whenever I have conversations with folks who are deciding to dip their toes into wet lab research, sometimes the impression is that it's very procedural and very like, you know, you fill out this form, you do this, you do that. Step one, step two, step three. But I love hearing when it's frankly, it's just like you speak to the PI and say, can I do some work? And sometimes it's as simple as that. I think in this day and age, you know, now that we're at work, hooked to our computers, it can always feel like, okay, I got to fill out the application and do all these things. But people are people still. And you can still just say hello and see if there's an opportunity.

Mark - 00:21:57:

I mean, it might have changed by now. But quite frankly, I also, when I look at the people that I recruited, mainly, you know, knowing them, meeting them, being introduced to them. So, yeah, I think it's people's game.

Jon - 00:22:10:

Yeah. It's funny that you're talking about how the lab look, because I remember like stories just like when you had to mouth pipe that.

Mark - 00:22:17:

Yeah.

Jon - 00:22:17:

You're like, clearly now we're like, don't do that. Don't do that. But it was just so commonplace. And you're just like, oh, God, well, damage has been done. Like, I can't. That's in the past now. So.

Mark - 00:22:28:

I remember that, you know, we had a little sink with lithium bromide. It was glowing in UV lights. It was crazy.

Jon - 00:22:34:

Yeah, it's so crazy. And so how far we've come in wet lab research today. And something that I'm curious about, you mentioned that the culture was really different when you eventually went to Cambridge and did the year. What was the cultural difference that you noticed like and surprised you the most?

Mark - 00:22:49:

So I connected with a sense of curiosity. And Austria at that point in time was much more procedural. I think it's massively changed, by the way, but at that point in time. And also the PI that I had in Austria was very formal. So if I wanted to have a conversation, I had to find a secretary and then I would be given a slot. And sometimes it would be in the far distant future. And in Cambridge, I basically called Professor Cox. I just knocked on his door. And most of the time he would welcome me in and we'd have a chat about things. So that immediacy of having access to people that know and receiving input and directly and immediately being able to change tack in the lab versus having to wait. So what actually made me decide to quit my lab job? So in Austria, I went to the secretary and she said, yes, yes, you can see Professor so-and-so in three weeks. And I asked, is there any earlier opportunity? And she said, no. So I just yanked out the keys and said, thank you. And resigned. That was it.

Jon - 00:24:03:

Sometimes it's like, I got to do what I got to do. It's like my hand is forestier.

Mark - 00:24:09:

I was full of myself at that moment in time. I mean, you appreciate that. But this is not the way it works. Dynamic questions pop up all the time. You can't just leave people without answers for weeks. That's not how it works. I mean, if you're a postdoc level and you drive your own project, that's fine. I mean, I didn't want to see my PhD supervisor after my second year more often than maybe once every three months or so. But at the beginning, you want to have connectivity because you have no confidence. You don't know what you're doing yet. So, yeah.

Jon - 00:24:41:

Absolutely. And that's not really a feedback loop either. I guess it's like a three-week feedback. You lob the question and you're just like.

Mark - 00:24:52:

Okay, what can you do? And you know, at that moment in time, three weeks, like endless. It's just like-

Jon - 00:24:56:

Yeah, you're like, your samples are going bad. You're like, by the time I get my answer, my samples are non-existent. So I don't know.

Mark - 00:25:06:

I'm moldy by that moment.

Jon - 00:25:09:

Yeah, he's like, all right, well, I guess let's just scrap the whole project. So you're now at Cambridge, there's a more dynamic kind of, you know, it seems to be the more rapidly iterating feedback loop. And you've told your PI, you're like, hey, I actually would like to spend my time on my PhD in a different department. Can you talk a little bit about the run up to the lab that you ultimately spent your PhD in and the story and how that unfolded?

Mark - 00:25:33:

So that was pretty simple. Prof Cox introduced me to Professor Blakemore at the vet school. And I went there, it was really a vet school in the middle of the green, you know, cows and horses and a shed where they were doing regenerative medicine research in the brain. I kind of found that very cool. And so he had a chat with me and he said, well, there's this upcoming PI, youngster, you know, I'm not sure whether I have space, but why don't you talk to him? And that was Robin Franklin, who then became my PhD supervisor. So we connected, he said, yes, let's organize that. And actually, after a lot of paperwork and finishing my studies, I joined his lab. It sounds simple. And it was simple at that moment in time.

Jon - 00:26:18:

That's amazing. And can you talk a little bit about that lab? What was the lab culture like? And what was it like to have him take you under his wing and mentor you?

Mark - 00:26:27:

So he again, was early stage, he just started out his lab. And so I think he didn't quite know what to do with PhD students. So, you know, that was one of the first computer networks that we had access to. So what I remember is we were trying to, you know, always see whether he leaves the lab, and we would just hijack the computers and play some video game.

Jon - 00:26:51:

Yeah.

Mark - 00:26:52:

So that was great. Of course, he knew, but he was fine with it. I got a direct feedback loop from Robin immediately. And he's very thoughtful. He was very critical, but very thoughtful. And I think I had fantastic, very conventional training. So hypothesis driven research, really going all the way to the core. Very rigorous. And I think that's what I learned from him. It was mainly in vivo work at that moment in time, some in vitro. And that combination again provides, you know, opportunity that not often people have. And we were... Playing around with a precursor cell population or a resident stem cell population in the brain, oligodendrocyte precursor cells. And that was also an opportunity that one didn't have so often. Stem cells weren't the thing yet. And so that together provided some unique opportunities for me. And I continued to be working in this field after I set up my own lab, years later, of course, until then I pivoted into more of the synthetic biology world that I'm sort of inhabiting at the moment.

Jon - 00:28:02:

That's amazing. Again, I just can't emphasize enough how much I love how it just sometimes these things aren't planned. You just happen to be in an environment that afforded these kind of like rare opportunities.

Mark - 00:28:13:

There would have been other opportunities because every choice you make closes other doors. So how do you navigate? And all you have is a sense, what might be right or not. And often you don't really know. But if you have the sense of your purpose, what you're trying to achieve, then you have a better chance of getting there. And even though, for example, at that point in time, I didn't know whether I wanted to become a neurologist or whether I wanted to become a neurosurgeon. That was the least of my choices, by the way. Or an ophthalmologist. I knew something around neuro. And I knew that it had to do with serving other people and somehow making them better. And not only at the bedside, but also in the lab. So that was sort of clear at that moment in time. But the details weren't.

Jon - 00:29:04:

Yeah, absolutely. And it just reminds me of what you touched on when you were deciding to move from math into medicine. And it was that North Star, that guiding North Star. It's like, I want to help people. And then you let the kind of details fill in themselves. But you use that as the navigation system. And it's interesting. Also, I love that you were hijacking the computers because I was talking to David Baker at UW and he had the exact same experience when he was doing his PhD. They were just the campus had the computers and they would just like go at night and just go hijack the computers.

Mark - 00:29:38:

So we were playing. It wasn't a very nice game. It was a shooter game called Doom or so.

Jon - 00:29:43:

Yeah. Yeah, that's exactly it. It's the earliest days. And I think David Baker was saying the administration was like, you guys have to stop. We know we know what's going on, but you're going to have to stop.

Mark - 00:29:58:

Yeah. Yeah. Yeah. I mean, the good news is we're at the vet school that it was pretty far from everywhere else.

Jon - 00:30:03:

Yeah. He's like, you can just go under the radar as long as possible. Yeah.

Intro/Outro - 00:30:11:

That's all for this episode of The Biotech Startups podcast. We hope you enjoyed our conversation with Mark Kotter. If you enjoyed this episode, please subscribe, leave us a review and share it with your friends. Thanks for listening. And we look forward to having you join us again for part two of our conversation with Mark. 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.

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