Patrick Short  0:01  
Hi, everybody, and welcome to the genetics Podcast. I'm really excited to be here today with Dr. Mark Kotter, the CEO and founder of bit bio, a company that's developed what I think is an amazing and novel method for cell reprogramming. Mark has a very compelling vision for building a platform and a company that can programme ultimately, every human cell type. We're not there yet today. But we're going to talk about what it might take to get there. And this, of course, has applications in fundamental research into basic biology and the building blocks of life as well as medical applications like cell therapies. So we're gonna dig into each of these hopefully, today. And Mark, first of all, thank you so much, and welcome to the podcast.

Mark Kotter  0:38  
Patrick, thank you for having me here. Really good to be on the podcast.

Patrick Short  0:41  
I'd love to start if you could take us back to when you were actually first introduced to the concept of stem cells and cellular reprogramming you were not a scientist, initially, you're actually a surgeon. And I'm really interested to hear what got you so interested in this topic and cause you to maybe change career trajectories from what you might have imagined when you started medical school.

Mark Kotter  0:59  
It's been quite a journey, quite frankly, I started off actually studying maths and physics. But halfway through the course, I felt that this was not taking me into future that I'd say it. So I sort of had a deep crisis really thought I was what I what I needed to do and what my purpose was in life and make the choice to switch tack and go into medical school and in medical school that very quickly realised it was pretty drawn into the why questions. So the research in addition to the application. And so I was very lucky that during that time, I met my later PhD supervisor at University of Cambridge. And the idea that I had was to somehow combine something to do with the brain and the spinal cord with my future career. And so after I finished medical school, I joined Robin Franklin's Lab at the University of Cambridge, and we were investigating regenerative processes in the brain and spinal cord. And we weren't, we didn't actually know that we were studying stem cells, essentially, that wasn't a particular topic at that point in time. But very rapidly, of course, it became a topic. And through a lot of luck, and hard work. I ended up a few, a few years later, a decade nearly later, as a pie at the University of Cambridge. And I was part of what were the early beginnings of the Stem Cell Institute, under the umbrella of Roger Peterson was one of the founders of embryonic stem cell research. So that put me in a very, very, very important spot where I was able to work as a surgeon, already sort of going, undergoing my training. But at the same time, I was able to do some research and continue my own research. And one of the things that I noticed was that there's a big difference between human and animal biology, just by studying the same cell in animals models, but also then from surgical samples. But the whole reason why I went into surgery into neurosurgery was because I had this idea of using cells to promote repair.

Patrick Short  3:16  
And where was the field at when you started your PhD? And where is it at today? What have been the major changes? And then what are the things that maybe stubbornly haven't changed as much as we might like,

Mark Kotter  3:28  
there was some really radical changes. Probably the biggest was initially that wave of realisation that human stem cells could potentially provide a source of any cell type, if we could somehow harness them turns out is much more difficult. And although we've been working with human stem cells for nearly 30 years now, there's still no product in the clinic, there's no treatment at the moment. And that just tells you how difficult it is to control these. That was sort of that was a wave of interest that came together. And that was the reason why the Stem Cell Institute in Cambridge was formed. But in terms of scientific breakthroughs, there was one particular one that I think has really shaped our understanding of stem cells, but also of cell identity as such. And that was the discovery of Shinya Yamanaka, who showed that you can turn probably any cell back into a stem cell by activating a code of transcription factors for different transcription factors. If you activate them together in a cell, they can turn the cell back into a stem cell state. And of course, that's mind blowing, because it allows you now to create stem cells from any individual. It took away all the ethical constraints of working with human stem cells, and it also means that every one of us has their own prepare kit in theory Now, this inspired a colleague of mine called Marius vernick, in Stanford, who thought maybe that concept of using transcription factors to programme cell identity could be generalised. And what he did was he was he developed the protocol that allows you to turn a skin cell directly into brain cell. And then another programme that allows you to turn a stem cell directly into a brain cell, and ultimately, even a liver cell directly into the, into his a neuron. Not quite sure what this is useful for. But it serves to show the point that we have to rethink the concepts of cell identity, what makes a cell a cell, and it suggests that it's radically different from what we used to think that cells are defined by the history, it's more likely that cells are actually the the identity of cell is contained in the cellular state, at the moment, that is driven by transcription factors engineering and gene regulatory networks. So programmes.

Patrick Short  6:15  
That's a pretty, I guess, profound distinction. I'd love to hear more about that. What sort of if that's true, where cellular identity is about transcriptional state, and there isn't a path dependence, or maybe not as much of a path dependence as we might think, what does that allow us to do that, that maybe wouldn't be possible in a in the previous paradigm where path dependence and the past history of a cell had some fundamental impact on its future?

Mark Kotter  6:43  
Well, I think it changes everything. And if the identity this the sub identity, the state of a cell is defined by the act of genetic programmes, and not by the history, where where the cell accumulates epigenetic changes in order to then form a particular cell type, we can completely rethink how we generate cells, how we manufacture cells, and what might be possible. So one of the interesting origins of all of this research is really a string of scientific investigations and papers that were conducted in the 1980s, when veinte hope and Lazar essentially demonstrated that you can turn a skin cell into a muscle cell. And that was the very first transcriptional reprogramming and protocol. And he started the speculations. And one of the questions that he asked is, whether it might be possible to create hybrid cell types cells that have traits of two completely distinct cells, like pigment cell and melanocyte, and a muscle cell. And any show this is possible, which essentially means that in this paradigm, you can not only create cells that exist in the body, but you might be also able to create cells that actually don't exist within the body, but that are possible from the genetics network point of view,

Patrick Short  8:22  
as fascinating. So from a rejuvenation therapy standpoint, or in a medical application, I'd love if you could paint the picture of what this opens up from here. And where do we go from here. And I'm also really interested in digging into whether you see a future where individual persons, my cells are taken out of my body reprogrammed and then put back in me to treat my kidney disease or brain injury or whatever it may be in the future. Or is or is there a world where it's more of a to use a more technical term allogeneic stem cell therapy, where there's a bank of universal donor type cells or, or large subset of cells that could be transplanted off the shelf, so to speak into people? What Where do you see the future going? And what are the hurdles that we've got to face?

Mark Kotter  9:11  
Well, a lot of questions. So the first one was, is the way of rejuvenating people. And, and I think yes, there is also something like the ageing programme. And it's it's also probably driven by a transcription of state. But I think that sort of leads us down a completely different aspect. What can we do with cells that we can produce from pluripotent stem cells? We can use them as as intelligent medicines. So what makes them what makes that medicine intelligent, the cells can replace cells that are lost, that's of course unique. You can't have that with small molecules of biologics. And the other thing that's unique, the cells can adapt and respond to their environment. And that's probably the reason why we've seen this incredible breakthrough with the first cell therapies that To enter our clinical setting qualities of, I would say the blood of the brother right flights of cell therapies, these are T cells that have been engineered to, to identify tumour cells and wipe them out. And they've shown to be incredibly powerful in the context of blood cancers. So patients at the end of treatment, can now receive a cell therapy that essentially eradicate the tumour. And that's incredible. This particular early stage, very expensive treatment is autologous at these are cells derived from the patient and engineered, to me, that is more an experimental medicine paradigm. Why? Because at the moment, the cost of this is incredible. In in the UK, I think the NHS pays more than 350,000 pounds per treatment. So this is certainly not a treatment that can be rolled out to everyone, and certainly not in in lower income countries. And for me, the definition of the medicine is that it needs to be available to everyone. So we need to push beyond this personalised approach at this point in time. And there are really two opportunities here as you as you mentioned, and I'm not quite sure which one is going to win, probably, they're going to sit next side next to each other side by side. One is the autologous approach, where you take a cell from from an individual, turn it back into a stem cell, and then create the cell type that you require for your treatment. For example, a dopaminergic neuron if you if you suffer from Parkinson, if you suffer from diabetes, a pancreatic islets cell, and by the way, these have been shown to be a ficus in a clinical setting. But in order to, for this to become a medicine, by definition, available, we need to really commoditize the process by which cells are turned back into stem cells, and then turned into the cell type that you want. And that's going to be extremely difficult, it's going to happen over maybe a decade or so. But at this point in time, this approach is extremely costly. So the alternative approach, then, is to somehow try and match a bank of cells to the patient that requires the cells do do the allogeneic approach. And here, there's really three options, there's a number of cells that it turns out, you don't have to match. So for example, if you want to treat an individual with an NK cell, that you again programme, so they recognise a cancer, it has been demonstrated that the NK cell does need to be matched. So you can take anyone's NK cell and transplant it into, into into the patient. And that, of course, makes for a huge reduction in cost for this approach. Not Not many cells can be transplanted, without having to match. But we actually know how to match cells. If you think about it, we've been doing organ transplant now for decades. So we're very versed with the paradigm that allows us to match organs with patients. And we can do the same with cell therapies. And the great thing about cell therapies is that you can actually tap into what what I would call super donors. So these are individuals that have the same HLA alleles on both chromosomes. And and with a very few of those you can match a wide a wide population of individuals give you a number, about three of these super donors, if you pick the right ones can be matched to 50 60% of the population in Europe, or 12 of them can match 99% of the population in Japan. So that means you can build a relatively small bank and still provide cells off the shelf. So the cost reduction here, I imagine is about a factor of 100 to two patients. And then of course, the third approach that you mentioned is maybe there's a way to make cells universal, maybe we can create strategies for them to evade the immune system. And that is, has been achieved by by quite a few labs so far. Obviously, you'd have to edit surface molecules etc in order to achieve that. But if that turns out to be successful in human beings, and if it turns out To be safe, then that will that will give you another option of really reducing the cost rapidly. But also making sure that the cells that that are produced have a much higher quality, and much more specific than if you'd say, it takes time to toggle the cells which which you which are always a mix, and you never know what really what you get to you at

Patrick Short  15:25  
bit by you and the team have attracted a lot of interest from a lot of very smart scientists, very, very smart venture capitalists and funders to help you to build this vision, I'm, I'd love to hear more about what it is that you all are doing really differently and how you're tackling some of these challenges that you've outlined.

Mark Kotter  15:44  
So it's a bit bio is really built on this paradigm of cell reprogramming, which basically means we can now without technology, turn a stem cell into probably any cell type within days, and we can get pure consciousness. That is something that everyone dreamed, but nobody thought possible. And this is, and the reason why we can do this is because we have understood the biology behind so reprogramming a process called gene silencing, Excel essentially recognises if you try and switch on a different programme, and tries to shut it down. So we had to trick them into accepting the new programme. And we did this using an approach that targets the genetic safe harbours, we call it OPTIO, x, and it optimises, the inducible expression of transcription factors or other genes. And so this creates a platform by which we can turn the fuzzy logic of biology into something that is deterministic, and it's extremely scalable as well, by the way. So we have a sister company mytable, that just announced the first product, a sausage made of porcelain IPCs with fat and muscle cells. And they're now in the Chilean cell range on a weekly basis pushing beyond now that the kilogramme range, obviously they have to go into the tongue, and then kiloton range, but it is possible this biology scales incredibly and so. So that's one pillar, I would say. That's our manufacturing platform. The other pillar that we have to build is what I call the discovery platform. So because nearly all stem cell research focuses on directed differentiation, which is essentially using chemical cues, in order to recapitulate what happens during development, the space of transcription factor reprogramming the knowledge space is very, it's very patchy, so very little is known. So there not many cell programmes out there. And what we wanted to do is we wanted to be in a position where the company can create any cell type from scratch. So let's say tomorrow morning, I wake up and I said, Oh, I'd like to have a pancreatic islet cell, we can do that. We have built the systems that allow us to screen transcription factor combinations in very high throughput and scale. And and we've systematised the discovery process, and then the translation into product. So the product isation process so that we can that we can actually produce this, I think this is totally unique. I don't think there's another company or in lab that can do that, essentially create cell types, Dyno for the competitors that we have there, mainly based on in licencing, of existing IP. So so we can create, in theory, every human cell type, and then we can manufacture it, as well. And, and so this is a very, I mean, this is huge. If you think about the the opportunities, and that's a blessing but also occurs. Why is it huge, every cell in the body is a potential cure is it is a therapy. So that's the potential. It's also a thing that you can use to do research and drug discovery. So these are the applications, again, very sort of important, impactful opportunity. But as a startup, of course, you have to, although we were late stage startup, so we've raised about 200 million so far, we have to be careful with with our focus. And so we have to show the depth of our platform, in this case, how clinically relevant the platform is, in addition to the breadth of the platform, demonstrating that we can actually do what we say we can actually add cell types at our ad libitum. And so and so that's where we are at this point in time, this transition from a sort of a late stage I would say startup scale up stage to accompany that Hopefully in the not too distant future, is in the clinic demonstrating what this technology can actually do.

Patrick Short  20:09  
Yeah, I think that's perfect. And you, you talked about this breadth versus depth challenge, I'd love to hear more about where you all are going deep and where the field is going deep, what are the types of diseases or cell types that are going to have the biggest impact first,

Mark Kotter  20:23  
so I can't announce what we're doing right now. But if you think about it, theoretically, you want to find a application of human cells, that is the risk as much as possible, you where there has been efficacy, or there has been a very strong clinical signal in a previous clinical trial. So that's one criteria, I would say. The second criteria is you want to have a condition where you don't have to think about too much about the matching question for the first person at the clinic, you just want to make sure that the cells do what they need to do in order to help a particular indication. So we were obviously talking about an Italo this approach there. And there's ways of making cells autologous encapsulation is another thing that I haven't actually discussed yet. That's the route that vertex has taken, for example, with their pancreas, pancreatic islet cells. And another paradigm, perhaps, is think about cells that have large impact independently, you need to put them administering cells into the brain is a much higher barrier than say, infusing them into the bloodstream. So those are the criteria by which I would say, you can decide what is a good first path into the clinic,

Patrick Short  21:49  
that it's really helpful, and in many ways more helpful than naming any specific diseases, because I was going to follow up and ask about the framework. And actually how you think about these is, is it fair to say that delivery is one of the big challenges across the board? How do you get cells or cell therapies to the right tissue, because he mentioned the challenges of the brain compared to bloodred, liver and others, that seems to be a challenge that almost everybody in the cell and gene therapy space that we talked to comes up against, in one way or another, it varies, as

Mark Kotter  22:19  
I said, you know, it, you know, infusing something into someone's blood is, is typically pretty easy. Getting the cells to the patient might be tricky. So that's sort of the logistics of it, especially if you take autologous cells. The ideal version here, of course, is if you've got an off the shelf product that is frozen, you know, that you could just take out of the fridge essentially, and administer. And that's really the holy grail in obviously, that's something that we'd like to deliver. But there are organs that are very delicate, very, very, very difficult to reach, where cells have to be administered in a very particular location, or location, or where they have to integrate in a very particular way. So let's think about the brain again, in most cases, even if you've got the most beautiful neurons, so it won't suffice to put them into the brain because they will then have to create connections with other neurons. And they have to sort of some some of those connections were very distant, so they'd have to navigate their processes across a very complex organ. And I think that is going to be a challenge all the way. other cell types in the brain might be easier. So if you think about the glial compartment, for example, but the good news is that in in some instances, you can actually choose the location for the cells that isn't the original location. So let's go back to this wonderful example of the pancreatic islet cells. It was like, for me, that was like an earthquake, when they announced the data, the first patient that was treated with a pancreatic islet cell, was cured from his diabetes did not no longer require insulin, and they did not put the cells into the pancreas. They were injected somewhere entirely different than somewhere where you can with much easy access. So there's that option as well.

Patrick Short  24:21  
Have you off and I'm sure you have thought about this. It's a comes down to the focus question, but it seems like your platform could also help to answer a set of really interesting questions around exceptional people. And what I mean by that are the people who have ApoE e4 But don't get Alzheimer's for the people who have C nine or seven, two, but don't go on to develop FTD or ALS and there there may be something in their genome or or otherwise, that is protective. How do you think about some of those types of applications where you maybe create a bank of cells or or, or a single cell I'll line from people like that that might be exceptional. We could think about all sorts of interesting exceptionally sounds. So I'm sure your team comes up with new ones every week.

Mark Kotter  25:07  
What? Now we're talking, obviously, about the use case of the cells as a research tool as a research tool. Yeah. And, I mean, yes, you can do incredible, incredible things with with with this approach. So just to summarise what we can do. And what we've shown we can do is create pure cultures of individual cell types that are highly specified. So not only cell type, or cell identity, but also sub cell identity. So we can, for example, created dendritic type one versus two cell, or a particular form of a sensory neuron versus another sensory neuron. And what you can then do is you can combine very precisely these cells with each other to create more complex model systems. So your question is, why are certain mutations not penetrating into disease phenotype? And that's a huge question. It could be, of course, that that mutation requires a particular genetic background that has certain risk genes, that that enables that. It could also be epigenetic, of course. And it's an incredible question is something that we have seen when we induced and created disease models, cells that have exactly the same genetic edit, but don't display phenotype. I have in my academic lab had a had a family, that we were able to study using stem cells, where the parent had the same mutation, as the Son, and the parent, there was no phenotype, and then the son was was heavily autistic. So so you can see exactly that question. And the tools now are here to pick these apart. I think that's, that's, it's extremely interesting. And the other thing that I find extremely interesting is you can unpick the disease pathology in the context of a more complex tissue. So what you can do is, for example, you can mix, let's say, brain cells that have a disease mutation neurons, let's say, with microglia, that don't have the disease mutation, and see whether having the mutation only in one cell population is sufficient to drive the phenotype. And vice versa, you can of course, then, you know, create disease and wild type neurons, just as an example. So it's an incredible way of unpicking human disease, which is very different from, you know, in a way from the animal models, because they're, they're always in a different species. And that has massive limitations.

Patrick Short  28:03  
We're coming close to the end of time here. And I wanted to just ask you, maybe on a more personal level, how you found the shift from practising medicine to I think you were hybrid, practising medicine and doing research at the same time to Now I suspect, you're not seeing patients anymore, you're spending most of the time building the team and running the company. How has that been? How's it been? For you? What's what's better than you expected? What's harder than what you expected?

Mark Kotter  28:29  
I'm still actually seeing patients. Yeah, but so what have I learned? So one of the strong one of the big lessons right at the beginning, that got awfully wrong, and then fixed with, with with huge focus and intensity was in a company, the team is everything. In fact, the company is the team. And if you if you make compromises here, you are damaging the company. So you got to make sure that the people are motivated, aligned, and that you can work with them, and they can work with each other. So that is something I learned the hard way. And it's been the reason why we then implemented a very, very intense, let's say, screening or recruitment process. And we defined a core set of values that people that were very open about communicating with anyone so that people can make their own choice as to whether they fit into intubate bio or not. And, and we also try and live these values. Nothing is perfect, obviously. But we're really trying to embed them in into the organisation. And this has allowed us to create something that I think is very special. So bitbuy has a very, very strong culture that I think anybody The two will will will sense the moment they come to us.

Patrick Short  30:04  
What do you think is the most unique aspect of the culture one, one or two.

Mark Kotter  30:09  
So, if you think about is, this is a very deep scientific problem that we have to crack. So it requires a lot of incredibly talented scientists. But not only that, it requires incredible engineering, incredible manufacturing people that are interested in doing something that's never been done before. So the act of creation is really important. But often you see that the more brainy someone is, the less good is that communication. And so, so we had to find a way of picking individuals that still that make the effort to connect and and to come together. So what are the four values very briefly, the first one is purpose bid buyers purpose is to programme cells to enable a new paradigm in medicine, novel cures, and novel cell therapies. So be very open with that. Now, people that are thinking of coming into the company can see whether their own purpose matches with this purpose. And it doesn't have to be the same by the way. But you could be a chap who likes finance, but wants to do something good, rather than impactful rather than, you know, perhaps, you know, running a hedge fund or something like that. It could be a scientist that is deeply curious about self identity, or it could be someone who's really, really passionate about translating something into the clinic. So it provides an umbrella. And of course, when your purpose matches the company's purpose, you immediately are motivated, what we try not to stay away from his people that don't know, I don't know what my purpose is in life, those will not feel very, very home in big pile. The second is ambition there is of course, to two sets of ambition, ambition, towards the purpose, that's what we're looking for, or self optimization, that's something that we're very, very negative against. This is part of the screening process. The third would be then collaboration and trust. Collaboration only requires trust. Again, there's two ways of trust, there's, I would say, the lazy trust, we've known each other for the last 10 years, you've always been on my side, I trust you. And there's this other Trust, which is leaning forward. I don't know you, but I trust you. And that's an effort. So we're looking for people that that can make that effort, and finally, do a science company. So we need to be empirical facts above opinions. So that's the call for I would say, that we formulated. And that has allowed us to really create a very unique team, very strong, very community, very communicative. But if but at the same time, you know, very deep scientifically, I mean, I'm a nerd. I think we're a company of nerds, but I would say this is a badge of honour.

Patrick Short  33:10  
Yeah. And I've interacted with a number of members of your team, and I think a they live all of those values that you just described. And I think what you've described as well about having not just smart scientists, but smart scientists and great communicators is is absolutely true and and critical. It makes it makes it harder to find people, but you've got to be be patient and rigorous. Right.

Mark Kotter  33:32  
Yeah. And that you say that? Yeah, no, absolutely. It should be difficult to join it by an easy to leave it.

Patrick Short  33:38  
Well, Mark, I know we're up against time. Thank you so much. I think this was a great, I appreciate you, entertaining all my left field questions about what what made where this may be going and where it is today is there. If people want to find you, they can visit you and your website that bio.com I assume you're you're always hiring the rate at which you're growing. And for you personally, you're on. They can find your your team's contact info on the website. Are you on social media?

Mark Kotter  34:06  
Not enough I'd say I need to get up my game here. But thank you for the conversation. Really enjoyed it.

Patrick Short  34:15  
Great. And thanks everyone for listening. And as always, please share with a friend if you liked the episode and we'd love if you could leave us a review on your favourite podcast player to help other people find us. Thanks for listening and see you next time.

Transcribed by https://otter.ai