Mark Kotter - bit.bio - Part 2

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, John Chee. In our last episode, we spoke with Mark Kotter about growing up as a curious child in Canada, his exposure to a broad range of cultures and perspectives moving all around the world, and how his dyslexia led him to focus on science and mathematics at an early age. We also touched on his experience as a researcher and PhD student at Cambridge, where he transitioned from medicine to synthetic biology. If you missed it, be sure to go back and give Part 1 a listen. We continue our conversation in Part 2, discussing Mark's transition from his PhD studies at Cambridge to the Medical University of Vienna, where he became a resident in neurosurgery and ran his own research group. We also touch on his experience at the Max Planck Institute for Experimental Medicine, his return to Cambridge, combining clinical practice with research, and his shift from academia to entrepreneurship, which led to the founding of his first biotech startup.

Mark - 00:01:25:

So I was a little bit homesick and I thought, okay, you know, after my PhD, why don't we try it out? Homesick is weird because my definition of home now is where my wife is, not a locality. But, you know, there was a certain sense of that. There was the effort to create and fund some spinal cord injury research in Vienna. And I just happened to have that interest. So during my PhD, it became clear that I wanted to do neurosurgery and that I wanted to go back to spinal cord injury just at the beginning. My house of the years, I spent really more in ophthalmology and psychiatry and maybe a bit of neurology. So the surgical parts came through rather late, to be honest. So then again, completely serendipitously, there was an opportunity and I was able to set up my lab. I had some core funding provided. And it was amazing because everything came together. I had two PhD students. I kitted out my own lab and I started training. But then relatively in a short period of time, I enjoyed the freedom I had in the lab. No supervisor, being able to run the group. On the medical side, it was incredibly hierarchical. I mean, probably US in the 19th century. And so I just couldn't stand it. It threw me off. And then I decided to see whether there is another way, another place where I could combine research and medical training. So I got this chance to work in the Max Planck Institute in Göttingen, join the medical faculty there. And what I learned is even worse there. The Max Planck Institute was amazing. But by then we published our first paper and people in Cambridge took notice of me again. And then I got invited to apply for a junior faculty position. So that was a really unusual position. It meant that you could start your own lab, but you would still be in medical training. And that is a lot of sort of headache as well. But, you know, a tremendous opportunity. And I jumped at it. And then I moved my little family. My daughter was maybe not quite a year old or so. And we went and relocated to Cambridge and the rest is history. So I only once escaped from Cambridge.

Jon - 00:03:50:

Yeah, for not that long. I'm feeling homesick. I guess I'm back. I have a quick question to just go back to your, the first, you know, research group you ran right after your PhD. Can you talk a little bit about, you said no supervisor and now you have two PhDs. What was that feeling for you to run your own lab? Because like, that's markedly different.

Mark - 00:04:14:

It's exhilarating, but at the same time, I was pretty scared because we had to put everything in place and they were real PhD students. So, you know, I had to teach them everything from how you do the cultures to how you pipette. And we knocked it out of the park. I mean, we published a paper in Brain, which was very, you know, for an unknown person, a very good first pass. And so it was scary at the beginning, but then as things came together, you get drawn in and then things just started to work out. And yeah, it was amazing, actually.

Jon - 00:04:49:

I love the dichotomy as well, where everything you described, I can see the energy. Like I can see the energy of like running a lab. And then we think about the kind of the residency medical part, where it's just like the hierarchy. It's like, oh God, like this is like a night and day experience.

Mark - 00:05:04:

Yeah, it was totally, yes.

Jon - 00:05:06:

And so now you're running your research group. And having this night and day experience. And now you got the invitation to go back to Cambridge. Can you talk a little bit about relocating your family and starting that role while you're still doing your training? And you said there's a lot of headaches. Can you describe what went down?

Mark - 00:05:23:

So, I'm super lucky with my wife. She just said, yes, let's go. And that was it. So there wasn't any palaver around that. And the lab that I joined, so the institute was set up by Roger Peterson, one of the sort of founders, I would say, of human stem cell biology. And it was a very special place. It only existed for maybe seven, eight years. And then the university shut it down. It was an incredibly special place because we were like an outpost, a handful of PIs with their groups and everyone was interacting and working together. When everything at that point in time was really difficult to do with human stem cells, we didn't have media yet. So, you know, we had to mix our own media. And for months, the media wasn't quite right. And you lost all your cultures or many of the techniques that we now use were just introduced. CRISPR, for example. So it was quite an extraordinary time. And Roger, again, was very thoughtful how he combined different labs. And we had some mathematicians there as well. So it was quite a special environment, very open. So information flew very easily across the groups. And that lifted us all up. When I look at my fellow PIs, all of them were extremely successful. Whether they took on very senior academic positions in Cambridge or elsewhere, but have a ton of respect for them. Amazing, actually.

Jon - 00:06:58:

Absolutely. And it sounds like you're taking a leap of faith, but it was just like a slam dunk more than anything. And also, one thing I love hearing, and it's something that I always like highlighting too, is how important having the support of your significant other and your family is in all of this. Like, no one could do it alone. I talk with my wife and I think all the time about, you know, for Excedr. In the earliest days, it's just like when it really did feel like a leap of faith that she didn't stop believing and said, yes, let's go for it. And I can imagine relocating the whole family is no, that's not trivial. It's a big move. And so I think that's critically important in anyone's career and journey is this having the support.

Mark - 00:07:38:

It's absolutely critical. Yes, I'm very lucky in that regard. But back to Cambridge, there also were two worlds. So you have the research world. And I probably was one of the best environments I can dream of. And then I had the clinical world and it was very different. So the good news was it was very meritocratic. But still, there was a huge reluctance of some of the old-fashioned neurosurgeons that their trainees should spend time away from the bedside on the bench. It was nearly an insult to them. Because at that point in time, you were still a glorified slave. And so that was also, I think, a very tough environment. And one of the character traits I have is I just walk through walls if I want something without hopefully breaking too much. So I would say I was broken in by the system to become the neurosurgeons that they wanted to see. But I also broke the system. And actually, now Cambridge is one of the premier places probably in Europe, where clinician scientists in neurosurgery can pursue their research interests.

Jon - 00:08:54:

That's amazing. I didn't realize how much of a juxtaposition the clinical side and the research side. I've never been in the clinical side. So this is the first time I'm actually hearing about it. But I love that now it's an embrace of rather than just like these things that are at odds.

Mark - 00:09:09:

Now it is much more sort of come together. But at that moment in time when I trained, it was just like absurd that you would even combine those or seek to combine those two aspects. And in theory, it actually makes a lot of sense. You know, I mean, why wouldn't you is my question now. But one of the things that happened, of course, is that, and this could have only happened in that context. On the basic science side, I was exposed to the newest technology around pluripotent stem cell research. And then on the clinical side, I had access to patient samples. And that combination was pretty amazing because what I learned, and that was another big learning opportunity, was that the cell that I'm most interested in at that moment in time are ligandocyte precursor cells. And we were using mainly rat and mouse models. And we didn't care so much about human cells because we thought they're similar anyways. And there was a protocol that was published to turn pluripotent stem cells into OPCs. And it took something like 170 days. So imagine me telling a PhD student, you've got half a year to differentiate your cells. And at the end, you're not sure whether you have some or not. But at that point in time, you can do an experiment. So that wasn't very enticing. But then what happened was we got some brain samples and we extracted some of these OPCs. And they looked in culture very similar to the rat and the mouse OPCs. But they behaved completely different. They didn't differentiate the way that the rat OPCs did. In fact, some of the growth factors had the opposite effects. And I remember realizing this and thinking the floor beneath my feet has just evaporated. I'm in free fall. Because I said, okay, I'm doing all this research on rats and mice. And all that I could ever dream of is become a rat doctor or a mouse doctor. And then the complexity around the differentiation protocols, which were untenable. And that really was what drove me to look into different or alternative scenarios. And this is when I learned about cell programming, essentially. So Yamanaka, of course, the foundational program that everyone uses. But actually, you can trace it back to the 1980s. There's a chap called Harold Weintraub, who showed that a transcription factor can convert fibroblasts into muscle cells. And of course, around 2010, when I started in Cambridge, Marius Wernig, Tom Sudhof, they published their direct reprogramming protocols, turning fibroblasts into neurons. And then they did another one where they turned liver cells into neurons. And then they applied the same paradigm on pluripotent stem cells. And that paradigm questions everything that you think you know about biology. So the dogma at that moment in time, of course, influenced by development biology, was that cells are defined by the history. And it's an epigenetic state. And, you know, we talk about Waddington's landscape. But actually, that data is in total contradiction to that. And that was noted by Weintraub, who said, well, maybe cell identity isn't that fixed. Maybe we should call it metastable. And then he said, and these cells don't undergo any of the developmental steps, as far as I can see. It looks like this transcription factor that I've identified kickstarts a feedforward loop, and somehow that becomes self-maintaining. Of course, now we call these gene regulatory networks. And then the third question he asked was, can we combine cell identities? Can we create hybrid cell types? So he showed that that's possible as well in certain circumstances. And then he died from glioblastoma, and all this knowledge gets lost. So essentially having to rethink biology because of the constraints that the current thinking or paradigm puts in place, and finding ways of rethinking it, moving to a different place. That's a bit my history, moving to a different place.

Jon - 00:13:27:

Also, what I'm seeing too, in addition to a new environment, is you have the clinical side, or if we're thinking about back in the day when there used to be church and state separate, but combining two disparate fields, you wouldn't have had the floor underneath you disappearing moment unless you tried to force these. The cells that we're looking at in mice is vastly different than what we're seeing on the other side. But if you hadn't run through that wall to try and combine the worlds, perhaps you would have still been in this, you know.

Mark - 00:14:00:

I'm sure. I would have thought about it. Of course.

Jon - 00:14:03:

Yeah, you would have just been focused on that.

Mark - 00:14:05:

And then you see everyone is struggling with this. And actually, that's probably one of the main causes for what we call the translation gap. You know, what works in a mouse doesn't work in a human being. Yeah, it's a different species. And most of the conditions that we try to treat are purely human. So just thinking about how we approach drug development, you know, okay, let's find a cure for Alzheimer's. So let's start with mice. Oh, mice don't get Alzheimer's. In fact, there's not a single mouse on this planet with Alzheimer's. So what do we do? We engineer something into the mouse, a mutation that then creates a disease that looks a bit like Alzheimer's. Now we have a model. Now we find a mechanism and we can treat it. But if we then translate what we have found into the clinic, more often than not, we learn that it's a different disease. So how do you fix that? It's only by actually really using human cells from the onset onwards. And that's really one of the big motivations. The other big motivation for me was always to go back and find a way of improving spinal cord injuries. And I really thought cell therapies were the way to go because it's so broken that you need to somehow replace things. You know, things are lost. Cells get lost and damaged. You need to put them back in because the body can't treat them. This was the combined interest in stem cell biology. And the barriers then pivoted me into what I would call synthetic biology.

Jon - 00:15:39:

Amazing. And it's, again, just like the timing. The timing of it all. And just your ability to put together. It reminds me of your early PhD experience where you said, we had mathematicians in the lab and we had various disciplines. And it's very collaborative. And I can definitely see this through line where it's like, we're only going to get better by people from different disciplines coming together and really working together on a joint problem. And first, you come in into Cambridge, still trying to wrap up your clinical side. Obviously, you're running a lab. I'm going to imagine you also had to teach. Can you talk a little bit about that kind of progression at Cambridge up till now? What has that experience been for you?

Mark - 00:16:17:

A little steep.

Jon - 00:16:18:

I can imagine.

Mark - 00:16:20:

So look, you undergo neurosurgery training and that's very time consuming and it's full on. You know, it's probably the worst thing you want to do if you want to do a research career. It needs to be bloody hard-nosed or driven, but it is what I felt was right for me. And so I took all these things and I hit through a number of glass ceilings. Over time, of course, you get used to it others used to what you're doing and things become a little bit easier. And at some point in time, they actually recognize that maybe there's something in it. Maybe it's actually quite good for a department to facilitate this. So then at the end of my training, I go and again, go away for a year to Toronto, which is the premier, I would say, place for neurosurgeon, clinician scientists. And that really, again, transforms my thinking and I'm learning completely new aspects that I didn't know much about. So very much I had a basic science lab and that was very disconnected from my clinical practice. And in Toronto, I learned translation and clinical trials. So I came back. Before I went to Toronto, we discovered this Opti Ox technology. This is now the basis of my startups. Coming back as a consultant, your life changes again. Suddenly you're self-determined. You can control your schedule. And if you can do that, you have much more flexibility to do other things. And this is then also the period when I started these companies. So in some ways, I was filling a void. It was so full on. And suddenly life became quite quiet in comparison. So it filled up very rapidly again.

Jon - 00:18:08:

Interesting. And so it was, again, kind of like Australia. But now you're in Toronto and you had this shock to the system. But just like fresh perspective in Toronto. Can we double click on like you mentioned consultancy?

Mark - 00:18:19:

Consultancy is staff, if you are fully trained. Attendee would be, I think, the US expression.

Jon - 00:18:25:

Got it. Got it. And so you're starting to think about the startup world and the entrepreneurship world. I can imagine very different than academia and clinical work.

Mark - 00:18:35:

Oh, yeah. So I can spool back a few years, actually. When I joined Cambridge, I said I'd be incredibly happy to run a lab and be a clinician. And I knew that there's some certain constraints around, you know, salary in Cambridge. It's not as attractive, let's say, as it is in the US. And so I said, how can we fix that? Because I quite like it here. So my wife was an architect and I started a little business and that became quite successful. And after a few years, we felt it's fine. It'll help us get by. I don't have to be worried about pension and things like that. That's covered. But it exposed me a lot to dealing with banks, doing things that I never did before. And I quite like learning the new stuff and the rules of that game. But I didn't want, once we found this Opti Ox technology, maybe something we also need to discuss. I didn't feel the need of spinning out companies. It wasn't the primary aim, quite frankly. It was a result of nobody seeing what this technology could do that made me say, okay, I'll do it myself.

Jon - 00:19:47:

I'm very fascinated here. So it seems like these are realities. We have bills we need to pay and school we need to pay for. And correct me if I'm wrong, was this like a family business before all the startups, a family business that you and your wife started?

Mark - 00:19:59:

Yeah, it's completely different. She's an architect. So it's real estate. But, it was a really good training ground to understand financial models, how banks think about things, how you need to think about things. Cash flow plays an important role. I mean, all the basics are applicable. So I learned a lot doing that.

Jon - 00:20:22:

And honestly, I love that because I think now, just quickly doing a fast forward to 2024, in startup land, particularly in venture-backed, startup land, we tend to forget exactly what you're describing about the fundamentals. There was a world before venture capital existed where, it was only the banks that were going to fund you or you're doing this out of pocket, like a family business. You almost had like a crash course MBA, but probably more intense because it's your family business.

Mark - 00:20:52:

I mean, you're on the hook for sure. Some aspects, of course. I mean, the other aspects, which are probably the main thing now in my state, our company stages, dealing with people. Bit bio is now 200 people. So you can imagine that it's quite a complex environment that is very deep in science, but you need to make sure that everyone is in sync. And it has ups and downs, like any sort of structure or organism. So I guess what I'm trying to say is I learned certain things, but other things I had to learn on the way.

Intro/Outro - 00:21:31:

That's all for this episode of the Biotech Startups podcast. We hope you enjoyed our conversation with Mark Kotter. Be sure to tune in for part three of our conversation to learn more about his journey. 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 on the Biotech Startups podcast for Part 3 of Mark's story. 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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