The Bioinformatics CRO Podcast

Transcript of Episode 31: Mark Kotter

Disclaimer: Transcripts may contain errors.

Grant Belgard: [00:00:00] Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard. And joining me today is Mark Kotter, founder and CEO of bit.bio.

Mark Kotter: [00:00:07] Hi, Grant. Thank you so much for inviting me to that podcast.

Grant Belgard: [00:00:11] I didn’t want to insert myself into your introduction, but I guess as a matter of conflict of interest disclosure, of course, I’m head of bioinformatics at bit.bio, so I’m not an impartial party here.

Mark Kotter: [00:00:24] I’m so excited about what your team is building and how it’s contributing to the bio. It’s the bit bio. So thank you.

Grant Belgard: [00:00:34] The pleasure is all mine. I just stay out of the way and let them do their work.

Mark Kotter: [00:00:38] That’s a good position.

Grant Belgard: [00:00:41] Can you tell us about bit.bio?

Mark Kotter: [00:00:42] Yeah, of course. So bit.bio is a synthetic biology company and we’re focused on human cells. And what you can do with these cells is you can either use them for your research purposes or to create new drugs, or you can also use this technology for cell therapies.

Grant Belgard: [00:00:59] What’s so special about the technology?

Mark Kotter: [00:01:01] It’s really the approach plus the technology that differentiates us from other companies that also are creating human cells. The way that we differentiate ourselves is that we really look at cells like hardware, like their computers. So for us, the cell has a nucleus that contains the DNA, and the DNA is a bit like the hard drive. So all the information is stored. It’s actually read only memory and then within a cell, only part of that operating system, part of these programs that are stored on the DNA level are actually active. And this is structured in what’s called gene regulatory networks. Then these are the sub programs in the cell. The genes that control these programs are called transcription factors. So what we do is we activate these transcription factors to instruct the cells and obtain certain functions. And what you can do is you can take this approach and you can literally program a stem cell to become the cell type that you’re interested in. And this is ten times faster and we can do it with extreme precision and it’s very, very scalable.

Grant Belgard: [00:02:11] So what’s the big advancement over where the field has been previously?

Mark Kotter: [00:02:16] I mean, stem cell biology and the concept of embryology has really gone and made huge advances over the last 20, 30 years. We’ve identified at the beginning of this field that the stem cell that’s responsible for generating an entire embryo, all the organ systems, all the cells in a growing organism. And the idea was that if we could replicate this somehow, if we could use the tools of biology to recapitulate this development, we could get to every cell type and we would have a source of cells that we could use for research, obviously, but also for regenerative medicine. And there’s been some huge advances in this field and some early applications. But if we’re honest, we really didn’t move this very far. I mean, it got stuck somehow in the process. At this point in time, you don’t have stem cell derived products in the clinic. And the reason why is because it’s very, very difficult to get the stem cells to do what you want them to do. And then another area opened up, which I would call synthetic biology. And that really goes back to the 1980s when Winetraub and Davis, in the heydays of molecular biology, discovered a gene that they named and they called it MyoD. And their observation was, if you activate this gene in a cell, it turns into muscle like magic. And of course, nobody expected that. And that a single gene could turn on a new cell type. But then in 2006 and 2007, something really even bigger happened. Shinya Yamanaka discovered that you can use four transcription factors, and if you activate them, then you can take pretty much any cell of your body back into a stem cell stage. So it gives you essentially everyone a source of stem cells.

[00:04:18] And what that means is access to in principle to all the cells in your body, in the culture dish. And that was the second time around that someone showed that gene combinations dictate the identity of a cell. And then, of course, others like Marius Wernig, took up this idea and they showed that this is probably a generalizable principle. It’s amazing things like taking a skin cell and turning them into brain cells. He also took a liver cell and turned into a brain cell. I’m not sure how useful this is, but it really shook the foundation of what we knew about cell biology, the identity, what makes a cell a cell and stem cell biology. So this is cell reprogramming and this is synthetic biology. And so we’re very excited to bring this into a company setting and an industrial process. But we were able to do is create a technology that allows you to very precisely control these transcription factors. What we can do with that is we can instruct cells so they have no alternative. And of course, if you have that level of control, then you have the foundation of an industrial process that is very scalable and it can open up hopefully all these things that people were dreaming of, better cells to understand biology, cells that allow you to actually study human disease and create better drugs or make it easier for drugs to be developed and actually be successful, which is a big bottleneck, as you know. And of course, the new generation of drugs are cells by themselves, and they’re so powerful because they can react to the environment. And we’re very excited about that.

Grant Belgard: [00:06:07] So it’s amazing to be able to differentiate cells that are very much like what we ordinarily have in the body. How excited are you about cells that may have characteristics from different types, cells that may have synthetic circuits engineered in them and so on. How far do you think that that thing can take us?

Mark Kotter: [00:06:28] So this brings us back to the question what is actually how is the cell defined? And there’s maybe two theoretical concepts. You could say, okay, within our DNA, a cell is defined as the whole package and you can’t do anything about it. It’s what it is. It’s like a blueprint. This is one cell type, a neuron, and the other cell type has a completely different information content. Or the alternative hypothesis is that a cell is really not much more than the parts. The individual sub programs that are active in any given time. Actually Weintraub and Lassar already in the 1980s looked at this a bit and said, can we combine traits of different cells? So they showed that they can create cells that have a bit of a muscle phenotype that behave like muscles. They also bit like neurons, like brain cells. And they also did that in melanocytes and combined these are the pigment cells of your skin and also create some hybrid cells there. And I also had a very talented PhD student in my lab who did some experiments combining macrophages with brain cells. And she showed that that’s also possible. You can create cells that have this dual identity.

[00:07:44] And so what we’ve learned from that is really, again, we have to refine the concept of what makes a cell. And we really think I’m at the point where I’m really thinking it’s just the information program that’s active and you can puzzle it together and you can combine it and certain combinations aren’t possible or not. And then of course, you can think about cells that have combination of functions that you may want for a therapeutic application that don’t really exist in the human body. And I think that’s very exciting. It’s very science fiction, but it’s very exciting. You could go even further. As you said, you could create logic gates. You can gate their function in constraints. And I think that might be very interesting and helpful. And potentially you can even import functions that don’t exist in human cells. So I think there’s a lot we can discover. It’s just like endless opportunities of engineering. But let’s be realistic. Right now, I think we have huge amount to do to actually recreate some of the cells that actually exist in our human body, and that’s really the focus right now.

Grant Belgard: [00:08:51] What areas do you think will be impacted first by this technology?

Mark Kotter: [00:08:55] So speaking from our own experience in bit.bio, there’s always this huge ambition of creating software and we’re working on it. But it’s also think about the regulatory hurdles, the quality of the cells that you have to have for clinical and preclinical studies, etcetera. That’s of course a huge endeavor. In bit.bio, we decided to look at another alternative application initially, which is really providing these cells for drug discovery. If you think about Alzheimer drugs, they have been very successful, let’s say, in the past. So drug companies are extremely good at creating a drug to a specific biological problem. But really the biology is the thing that they need to get right so that the process actually is running and providing the output, the drug that you desire. And here’s the meta, mice don’t get Alzheimer’s. So what people do is they create something in the mouse that looks a bit like Alzheimer’s, which it isn’t. It’s a different thing. It’s something that humans created. It has certain features, and then they use this model and then create drugs to treat this model. But because the thing that they’ve created in mouse isn’t real Alzheimer, the drug then fails in the clinical trial. And there’s other reasons as well. Sometimes it’s just toxic. Mice can tolerate other things than humans do.

Grant Belgard: [00:10:21] This is a bit of a recurring theme on this podcast. There’s an industry wide reluctance to move forward without rodent data, even when it’s so widely recognized that the translate ability is nil.

Mark Kotter: [00:10:35] There are some papers that make very strong statements about the correlation of animal models, but I don’t want to at all argue against the animal models. At some point, you probably need to understand how biology works in the context of an entire organism. But in order to fix that translation gap, I think you need to start with the actual condition, in the actual cell that is actually sort of human. And I think that’s what we’re really excited about, being able to create these cells for big pharma companies that have ambitious programs to develop a next generation of medicines and enable them to do this in a real human cell in the right, real human cells. I think it’s extremely exciting.

Grant Belgard: [00:11:21] So bit.bio didn’t start out as bit.bio. Can you tell us about the origins and what prompted you to start? What was to become bit?

Mark Kotter: [00:11:29] So that brings me back to a personal experience. I’m a lost mathematician. Let’s start at the beginning. I did a year of Maths and then had crisis units that had to do something that’s somehow contributes to something in this world. And I was not aware how great mathematics can contribute. So I decided to go into medicine and then of course, drawn to the how and research in medicine. This led to some very early encounters. So before I decided to go to medicine, I tried it out. I became a healthcare assistant for six month period and I worked with people with spinal cord injuries. And I just saw how that condition changed their lives. And I just thought something has to be done. One needs to push this forward. This is really something that needs to change. It turns out this is extremely difficult problem. And I think we’re not very close to a cure. We are much easier problems to solve. But that set me up and really defined my career, not consciously. So I didn’t have this picture in my mind, but I ended up as a neurosurgeon that looks after spinal cord injury patients who went to research and discover regenerative processes in the brain and the spinal cord hit those limitations of stem cell biology that we discussed before, try to find another way, follow the footsteps of giants. And that had this extreme luck to identify a technology that allows you to really exert, I would say, supreme control over cells. It’s like a control system or an antibody to the operating system of a cell. And that then sparked and it became first a hopeful project. So we called the company after the Greek goddess of Hope, Elpis. And then when it got legs, when we saw that actually it’s not only fanciful, but actually real, we decided to call it what it is, really the merger of data science and biology, and this is how it came about.

Grant Belgard: [00:13:40] What are you long term ambitions with bit.bio?

Mark Kotter: [00:13:42] So if you think what human cells can do fundamentally change medicine in the form of cell therapies, and we already saw this, I always say that the right flight in cell therapy were CAR T’s. So they were really products that were extremely expensive, not very scalable, very I would say crude at the beginning, often with a lot of side effects. But what they taught us is that cancers that had no hope of surviving suddenly were cured. Nobody expected this. This is a real revolution. Why is this the case? Because cells are not drugs like small molecules or biologics, and they interact with the environment and then they instruct other cells to do certain things and they can mount an immune response and they wipe out the cancer. And if you think a bit further, think about Parkinson’s, think about other conditions, diabetes, where cells are lost. And the only way to really fix this is to really somehow replace these cells. Then you can see how powerful this is. And as a medic, seeing that hope, seeing that glimpse, seeing actually this progress is just a huge driver of ambition. And then that hopefully has translated into bit.bio. Everyone in bit.bio is really excited about the opportunity ahead, enabling something that hasn’t been there before, but not only our own progress in cell therapies, but also as we discussed the application of cells to enable better research and better drug discovery.

Grant Belgard: [00:15:24] What do you think are the biggest challenges that the field has to overcome?

Mark Kotter: [00:15:28] The biggest challenges in cell therapy is really manufacturing scale with precision and high product definition. And this is really what was the biggest bottleneck for the application of stem cell biology. And it’s a huge task. I do think that the approach that we have provides a real unique opportunity to overcome some of these challenges, and we were able to demonstrate this. So, for example, our two products that we have released into the market, one of them is a human brain cell glutamatergic neuron, and the other one is the human muscle cell. And then of course, more to come. But these are the first products that are consistent and scalable enough for high throughput screening, which is the process that drug companies use to create new drugs. And that’s a major step. So we’re very excited and hope that we can translate this into a clinical product as well.

Grant Belgard: [00:16:22] Going way back maybe to childhood, what do you think influenced you and shaped you, what made you Mark Kotter?

Mark Kotter: [00:16:32] I think one thing that you already glanced from my accent is that I don’t think I have a locality. I was born in Canada and I was raised in Austria and Germany. I had the pleasure to live in Australia and my parents tried to make me comfortable with speaking foreign languages. And I think that’s one aspect I would say that has shaped my thinking. And the necessity to move around places and adapt, I think was the other thing that really influenced me. So new cultures, new locations mean people act differently, they think differently, and I had to reinvent myself a few times. And another reason I think is because I have a certain handicap. I think you would now call it dyslexia. And this is like someone throws a huge spanner to your brain and it means that you have to deal with things that others don’t even encounter. And it’s hard and you have to iterate around it. You have to figure out how you think around this problem. So I started to, I think, program my mind away from languages, more into Maths. Music and Maths, I think these are probably my biggest talents or were my biggest talents, they’re not now. So I was then entered national selection of Maths special programs in Germany and I really really enjoyed this. But then came the stage where I felt, what am I doing with this? And I didn’t really realize at that point in time how powerful Maths can be. And I had this idea of I love what I’m doing, I love all these problems, but I don’t see a reason why I should pursue this.

[00:18:21] And that made me go into the thing that really would be the last on my list, which was medicine. But it made sense to me because I thought this is something all goes to pot. That’s something that makes sense, helping others, serving others. I can live with that. But what it also meant was I had to learn a complete new language. So medicine to a large extent is a language. It’s words that you use to describe biology and disease. And it was fabulously difficult for me to memorize stuff because I inherently was programmed to think in causal relationships and cause effect relationships and not natural to synthesize information. And I managed over time, got better there. And then I had this battle between medicine and music. I sort of end up doing music. So I studied music medicine in parallel. And I guess looking back at this just means that I probably had to keep my head plastic, I had to reinvent myself. And I think that’s really given me a slightly eccentric perspective on problems, which then allowed us to do things that other people might have not done, being very persistent to generate this object of knowledge. That was a real huge risk for me. I nearly lost my credibility in my academic lab, my funding because people said [it was] crazy. I’ve had people saying this is not stem cell biology. You shouldn’t be part of the Stem Cell Institute, but you get a bit feisty over time and then you start pushing through walls. Even just combining neurosurgical training with academic work was extremely rare. And I still got accepted in Cambridge and I had the opportunity to push through these walls.

Grant Belgard: [00:20:15] How do you manage it all?

Mark Kotter: [00:20:18] Now I think my life’s become a lot simpler. I have this incredible opportunity to help facilitate other people to work on an interesting problem. I think scientifically it’s super fundamental. What makes a cell? A cell identity. And the moment you crack it, we have a system that allows you to actually use it for research or other applications. And so my job now is really much more to give other people the opportunity to do what they enjoy doing and what aligns with that purpose. And it means, of course, I’m a bit busy. But at the same time, it’s really amazing to see how things come together. So I really enjoy that and the creativity.

Grant Belgard: [00:21:01] What preparation would you say you found useful in that transition, going from doing yourself to creating an environment in a structure where others execute on this vision in an orchestrated way?

Mark Kotter: [00:21:16] A certain amount of self-awareness is really helpful. Knowing yourself, I think, and getting to grips with the good things and not so good things, and then the impact that you have on others I think is really, really critical for any person that assumes any kind of leadership. And I don’t mean management or I don’t mean power. It’s more about leading and enticing others, stimulating others to join the path that you’re on. And the other thing is having experience in different environments. So I know I had a lot of things that I saw different hospitals, different universities, even different companies. And you experience the culture and you experience how people interact, and then you have a vision of how you don’t want to have what you don’t want to happen and then what you would like to happen. But the reality in a startup is that things are moving so rapid, so that you create a culture that’s right for one moment in time and then you transition to a bigger stage. And then you have to recreate the culture because it what happened and what worked in a 30, 40 person company is no longer applicable in a company that is 100 people because information doesn’t just flow easily, people don’t see each other and they’re not in sync. So suddenly you have to think about structures and responsibilities and roles and responsibilities. And that’s a transition that’s been talked about before. And it’s hard because people have to give up things that they like to do at the beginning, and some people don’t like it and others thrive on this.

Grant Belgard: [00:23:02] And in COVID probably hasn’t helped.

Mark Kotter: [00:23:05] Oh yeah, I think COVID has been, everyone was locked up in the Zoom box. We started out with this idea, we have this technology, what can we do? So how do we use it? It was one research question. The second question was, okay, is this really transferable to other cell types? And then how can we create new cell types? And and we figured out components in bioinformatics, how important it is screening. But the areas that little bit remained, let’s say artisanal for a longer time period. It’s only recently, only this year that we have identified structures and patterns that allow you to really create a cell with high efficiency. And I never thought that we could really process this part because I think that’s the bit of biology that can’t be structured. But I was taught wrong. We’ve got this incredibly talented scientists who essentially showed us a way of actually how to do this efficiently and allowed us to design processes.

Grant Belgard: [00:24:15] What advice would you have for other biotech entrepreneurs?

Mark Kotter: [00:24:19] So the first thing that you need to do is come to a clear visualization, I would say, of what it is that you want to create, and that’s extremely hard and then find a way to communicate. And I still struggle with that. It’s extremely difficult. So how can I make people understand that having a human cell is really impactful, creates opportunities that you haven’t had before. Often it’s a bit like sculpture and you start with a stone and changing create structure and you basically discover structure. The second thing that you acquire, I think is really that self-consciousness. And I was the least self-conscious person when I was in my space. I thought I was extremely clever and everyone else wasn’t and turned out to be wrong. Of course, if you have this distorted view of life, learn more about who you are or how others perceive you. I really do think that having a strong moral compass is also very helpful. I think it’s very fundamental. And then once you know what you want to do, you will have so many people telling you that you can’t do it and you just connect with what you think is right. More often than not you’ll be right, but you still make some massive mistakes. And then you have to be not shy to acknowledge that you’ve made a mistake and change and pivot. I think that’s the other thing. You don’t learn when things go right. You learn when things go wrong. It’s painful if things go wrong. I mean, it feels awful. And then you just have to pick yourself up and say, hey, I did this, I own this, This was wrong. What can I learn from it? And more often than not, you’ll end up at a higher level of understanding. You become better at what you do, the ability to rethink yourself, rethink your approach, rethink your context is really important as well.

Grant Belgard: [00:26:24] One thing I’ve noticed is I think you do a really good job of bringing in a team players. How do you do that? How do you attract really good people to your vision?

Mark Kotter: [00:26:35] I think it starts a bit with a vision. I think it’s easier to attract someone to a problem like, Hey, it’s great new medicines and more efficient trading platform. And the other thing that I do is I try and just be myself and honest. I’m going to be very frank with things that I didn’t do well, and I try to just be naming the things as they are and then give other people the opportunity to contribute and shape and change the trajectory of the journey that you go on. And I think if people sense that you are well meaning honest and trustworthy and that you connect them or enable them to pursue something that’s close at their heart and you don’t shy away from saying, hey, I’ve done something stupid here, let’s get together and correct it. I think most of the time they forgive your mistakes and will follow you. And I think that’s what we’ve been able to do in bit.bio, incredibly smart people. The scientists are much better scientists than I was. And my job now is really just to try and connect things, getting people to work together.

Grant Belgard: [00:27:48] What’s something about which you’ve changed your mind over the last few years?

Mark Kotter: [00:27:53] There’s so many things that I don’t even know where to start. I can tell you one thing that I haven’t changed my mind about, although I have been pushed to change my mind about very often, is this idea of either doing only a therapeutic play, only self therapy, or having cells for tools. And for me it always seemed a bit weird because the only difference is the market and the data package that we wrap around the cell. But the process fundamentally is very similar. Of course, clinical manufacturing is dimensions more difficult than others, and so that’s something I held. But in the science, one thing that really changed where I was wrong was this concept. There’s errors that can’t be captured where you just need scientific intuition and you’re going from a known transcription factor to a combination or unknown to [actual] cell that you can grow and produce. I always thought that’s probably the heart, that’s where you need intuition. It’s more like exploration. And again, I think I’ve learned that you can actually process this. This is something where the approach and the mentality is more important than the skill set, which is extraordinary. And for me, I’ve never expected this. A very young scientist was able to teach us how to take a cell from a concept to a tool for yourself.

[00:29:21] There’s another young scientist and she was working on a particular cell type and it looked fine. But after 18 months, she said, I haven’t made any progress and I just want to step up and say, Hey, this project has failed. And she did this in town hall and she said, I’ve done this and this and that. And I went down the rabbit hole and I just want to show you and I want to tell you guys that this has happened to me. It wasn’t good. It was painful. And then the credibility and being honest and stepping up and saying, hey, this project didn’t go well. And then she started to talk about the learnings and it’s like a miracle this year as a side project, she just cracked it. She changed her approach and within a few weeks, a few months, something that was stuck suddenly turned into something that worked. And of course, it has to do with technical innovation, etcetera. But it is that resilience not giving up, knowing when you go wrong, acknowledging that you go wrong, that something has to change fundamentally and resetting and being open and honest about it. I really think that’s incredibly important and powerful at all levels.

Grant Belgard: [00:30:38] What do you think is the worst piece of advice you’ve received since starting bit.bio?

Mark Kotter: [00:30:45] And the advice that was totally wrong at the beginning turns out to be extremely valuable at the stage of the company that you are now. So the advice that I’m referring to, if someone said you need to create role profiles, but at the beginning, when you have a four people band, you don’t have any roles and you have no idea what you’re doing and how you get to where you need to be and you think, Oh, this person could be this role. And it turns out that’s absolutely not their skill set. But first of all, you can’t recruit anyone else that has that specific because you’re not in a position to make an offer to a person who has. And because you don’t know what you need. And so at that point in time, that piece of advice wasn’t a good piece of advice. But a couple of years later, now it’s an incredibly important piece of advice because it helps people to understand their role within a larger organization. And now like any company, we’re working on definition of these roles. I guess what I’m saying I don’t think I received any bad advice.

Grant Belgard: [00:31:52] It’s all a matter of timing.

Mark Kotter: [00:31:53] Yeah, exactly. It doesn’t match the circumstances, but I often think about this advice.

Grant Belgard: [00:32:00] It’s interesting. Yeah. I guess as an insider, you’ll always have more information on the company and the stage things are at and so on than outside advisors who may have a much larger breadth of experience, but may not have as much insight into the applicability of that advice in terms of the stage the company is at.

Mark Kotter: [00:32:21] Yeah. And the amazing thing about bit.bio, we’re recreating something completely new, something that hasn’t been there. I mean, the team that we’ve got is incredible. The people are incredibly skilled. The personalities that we have in bit.bio, really handpicked individuals that are fundamentally collaborative, kind, purposeful, ambitious in the right sense and empirical. And I think it’s the biggest and strongest team that I’ve ever seen. And what they were able to do is really to do something that’s never been there before. I mean, we have more cells in our company than any other company. I know of more different cell types, more cell types than the entire Stem cell Institute in Cambridge, which have been working on this for 20 years, plus the speed at which we can innovate the complexity of biology and approaches is second to no other institution I know. I think the commercial capabilities, the interest that we were able to spark at that very early point in time is extraordinary. So I think when things come together in the right way, you can create such a powerful team and such an incredible force that I think that’s the most exciting thing at the moment for me, to be honest, seeing how this thing is crystallizing and it’s actually creating cells that are really valuable. We know, for example, that the first screens are going to take place very soon with our cells, and I can’t wait to hear some of the results. So this would be very large. Billions of cells going into screening systems, etcetera. So these are major feats. And knowing that we’re probably maybe the only company that can deliver this, this is incredibly exciting and also exciting to see the investors that we have, the backing that we have received to facilitate our growth, etcetera. It’s thrilling.

Grant Belgard: [00:34:17] It’s really interesting because in a way it feels like we’re looping back to music because you change a few words in there and you could be talking about improvisation.

Mark Kotter: [00:34:25] I guess an orchestra is very similar, isn’t it? It has to listen to what other people do and be synchronized. It’s better if they have the same score sheet. It’s better when they play the same tune. I mean, when human beings come together and come together in the right way with the right purpose, I think magic can happen. I certainly see a lot of magic in.

Grant Belgard: [00:34:49] Well, thank you so much. It was a lot of fun.

Mark Kotter: [00:34:51] Thanks, Grant.