The Bioinformatics CRO Podcast

Transcript of Episode 5: Quin Wills

Grant: Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard, and joining me today is Quin Wills. Quin would you like to introduce yourself? 

Quin: Hey, Grant, thanks for having me. I’m Quinn wills. I’m the co-founder and CSO of Ochre Bio. We’re a sort of deep-phenotyping, tissue genomics company, that’s trying to understand liver metabolism and how that maps to liver diseases. For example NASH, which is a type of liver disease that is becoming really big in Western society right now, and liver transplants, which is kind of cool. 

Grant: So what’s the origin story behind Ochre?

Quin: Oh, okay. Well, that goes back quite a bit. You know I started off life on the dark side, so I started off life as a medical doctor and geneticist before I moved into comp bio. And I was always interested in liver metabolism and metabolic stress in those days, more around alcohol metabolism and fetal alcohol syndrome. But when I moved down from South Africa to the UK, I think like a lot of us, I became very intrigued with big genetics and big genomics.

Quin: I could see what was coming on the horizon of the human genome project and wanted to be more directly involved with that. I didn’t like the idea of handing over data for other people to think about and engage with. I really just retrained. Did a few extra degrees in mathematics and comp bio, and then my PhD in systems genomics at Oxford, really focused on technology, but constantly thinking about liver and liver metabolism all the way through. 

Quin: I started my first biotech company before I finished my PhD using, in those days, gene expression arrays. Can you believe it? I’m sort of dating myself now. I was trying to compete with high content imaging to really understand drug toxicities of target effects for the pharma industry. Moved that out East and carried on my academic career, doing single cell genomics and spatial genomics as we do now, these kinds of things. 

Quin: And I pitched the idea to a large pharma company that was coming on to the Oxford campus that we’d like to use these technologies to improve target discovery in NASH or NAFLD rather. I prefer to call it NAFLD, non-alcoholic fatty liver disease. So in other words, too much fat in your liver, which one in four of us have these days with obesity. And they loved it.

Quin: And of course we got going into some big industry-type pipelines and great technologies at a functional genomics level. And I loved it. I genuinely loved it. I think the clinician in me was a little bit frustrated with the struggle to translate this problem. 

Quin: It’s a massive problem. We are realizing it’s so connected to cardiovascular disease, diabetes. Too much fat in the liver now is becoming the main reason for needing a liver transplant in many countries. It’s not alcohol, it’s not viral hepatitis anymore in many places in the world. And it’s also becoming the main reason for the shortage of donor livers. Because fatty livers don’t transplant very well. 

Quin: I just really wanted to solve this and I do really want to solve this still. And I figured that it was one of those sort of moments where we have to be honest with yourself and say, well, “Genomics is great. And all the computational work is great, but we really need more to take this to the next level.”

Quin: And really the idea that came together was when I started engaging the transplant surgeons in Oxford, and we chatted about this problem in the transplant space. And they mentioned to me that they’re about to publish on this incredible liver perfusion machine, effectively a machine that keeps donor livers alive outside the body so you can assess the liver, keep it warm, keep it nourished before you transplant it. And would I want to study these fatty livers, these discarded or donor fatty livers on the machine and do really interesting temporal analysis with gene expression. 

Quin: And I realized very quickly that this was an incredible alternative to a preclinical model. It was so much more satisfying going from sequencing lots of livers or studying liver physiology at a tissue level to then testing out your hypothesis in a living human liver on a machine and thinking about what’s going on rather than going to a high-fat diet mouse, for example.

Quin: But I think for me, there was more to this, and I decided that it deserves to be its own company. And the moral to this is that by really focusing on the transplant space rather than diabetes, which I’ve sort of been for many years, this really allowed us to not only study livers on machines, but it allowed us to find new targets by studying the right spectrum of disease, which is a big issue in the space.

Quin: Right now, people are focused on biopsies of very inflamed, fatty livers, whereas we’re sequencing. We’re building the largest genomic atlas of the human liver, using a thousand livers from one of the biobanks in Oxford, going from healthy level all the way through to the early stages of disease, which we love.

Quin: And I can tell you a little bit about exactly how we’re building up this atlas of what’s going on in the liver. And then finally–and this is more clinical twist rather than a comp bio twist–we wanted to get around the biomarkers problem. You and I both know this is a massive problem in our field and a massive problem in clinical trials.

Quin: And fatty liver disease, NAFLD, is like a lot of chronic diseases: silent for many, many years before it presents. And they are just no good biomarkers, so there are no ways to do good clinical trials, particularly for the early stages of disease. So everybody’s very focused at the moment on very late stage disease endpoints, crude endpoints, and molecules and experimental drugs that frankly do fall too little too late. And this is why we still don’t have a therapy on the market. Not to over simplify: there are many reasons. But it’s a difficulty in clinical trials that is frustrating the space right now.

Quin: Of course we love biomarkers, like any good computational biologists, and we were thinking about it, but we don’t want to bank on it. And so rather than trying to do these very difficult clinical trials in the fatty liver space, in terms of NASH and NAFLD, we rather want to think about this in the transplant space. So treat fatty donor livers with the same kind of therapy we would use for patients living with the disease and improve outcomes in the transplant space. And those trials are much simpler. I mean, they, like all clinical trials, are a big gamble, but compared to the biomarker perspective, have much clearer endpoints.

Quin: And then what we will do as part of that, is look for improved long-term outcomes in these livers, and we’re doing this using these new GalNAc siRNAs. So they are liver-specific siRNAs that can last, with effects for many, many months. And so we can treat these livers entirely ex vivo on these machines before they’re transplanted. And so it never really goes into the patient. It’s entirely a liver specific treatment, but we can see the effects play out over the first six months of the transplant life. And, that’s where we’re at. And that’s what we’re doing as a company. 

Grant: That’s amazing. So tell us a bit more about the lasing efforts.

Quin: Our first big target discovery project is this human liver atlas, which takes a thousand livers from the QUOD biobank in Oxford. So this is a collaboration with transplant surgeons and the QUOD scientist at Oxford, where we are genotyping these livers. We are bulk RNA sequencing these livers. We are spatially sequencing these livers. So in fact, all of these livers get sequenced up to 4 times. So there’s really a lot of data at an RNA sequencing point of view generated on these. 

Quin: We also do imaging AI. And that is really to standardize the histopath. So we have about seven images taken from each liver so we can understand what’s going on. The imaging AI also identifies the key regions that are interesting to us. For example, there’s this cell phenotype called ballooning degeneration that happens into the cells that we think is really important, and we’re trying to understand as something that connects too much fat and then inflammation and fibrosis cirrhosis in the liver.

Quin: And then we have all the bloods from the donors so we can understand cardio-metabolic parameters. And we have about 150 clinical variables from the donors and the recipients. Because most of these livers that we’re working on ultimately exist in somebody out there somewhere. And so we can really start asking questions both around disease progression and particularly the early stages of disease, which we’re quite keen on and then how that maps to transplant outcomes. So can we think of targets that are applicable to both?

Grant: So what would be your ideal outcome in say five years, if everything goes perfectly?

Quin: Yeah. I think like all biotechs, we have what we’re doing now, but there’s a grander vision and unlike a lot of computational biologists, I believe that this type of work is what we call deep phenotyping or cellular genomics is going to be such a big part of tying this together in our space. You know, GWAS and associating SNPs with clinical disease is a great first step, and pharma is beginning to embrace this in many ways. But in particular, I would argue for chronic diseases where there’s so many factors and so many steps in the progression, this has to come into play.

Quin: And so we’re using this to understand liver metabolism and particularly fat metabolism and how that plays out in the liver and also how that plays out systemically. But I think we consider ourselves a cardio-metabolic company, and we’re really looking at more fundamental health span drivers that we think we can be targeting in the liver to improve outcomes and really improve human health span.

Grant: Great. So you guys went through YC. Can you tell us a bit about your experience there?

Quin: Loved it. My co-founder and I, Jack O’Meara, had an unusual meeting. I left my job with this pharma company. I decided to go build my dream treehouse in Costa Rica and rethink how I want to do this and where I want to be based. Do I want to be European in terms of biotech or do I want to be on the US side. And of course, they are very different cultures. Even in the US, West coast biotech is very different from East coast biotech which is very different from UK/ Europe biotech. Very different funding, cultures, VC styles, trajectories in terms of how the companies grow.

Quin: And I figured I possibly want to be on the US side, even though I have such strong roots in Oxford and the transplant scene and the liver scene and the metabolism genomic scene. But then I was introduced to Jack. I called Jack. And at the time I called Jack, he was building huts in Tanzania.

Quin: We immediately realized we were kindred spirits and equally crazy. Jack is an individual who also comes up through biology, more tissue engineering and is really focused on clinical progression. So getting therapies into markets. He really was my natural counterpart and shared a lot of my philosophies. We both share a lot of philosophies on how to really innovate in biotech and what that really requires. So we started off in London. I came back, Jack was in London, but it was a strange one. We went out to California for a conference, met the YC folks on the day that particular cohort was beginning, chatted with them. Within two, three hours I said, “We like you guys, stick around.”

Quin: And we canceled our tickets back and never went back to London until COVID forced us to come back, take our money and get set up. We’re very much a Californian company, but with a sort of subsidiary in the UK and very, very international operational. Oxford lab is what handles a lot of the target validation and screening work after we’d done with the target discovery and before we put it into profused livers, which we do with transplant centers here in the UK, particularly Birmingham.

Grant: So, what is your philosophy of innovation?

Quin: Well, now you’re going to get me to step onto my podium. Yeah, I’ve learnt a lot. I’ve been humbled a lot over the last 15 years of doing comp bio. I’m seeing a lot of different cultures all over the world on how to do things. For me, there are three things that seemed to be common to a lot of very successful genomics companies.

Quin: So maybe we call ourselves a genomics company rather than a biotech company. One is speed. I mention this because this is something that I think a lot of academic computational biologists struggle with. It’s such a culture shock to them particularly if you come from big academic centers. There’s this whole culture of “Oh, it’s okay. Get it a hundred percent right six weeks from now, Eighty percent now is probably not fine.” Whereas in our world it’s very different. 

Quin: The centers in academia are very different. There’s this “publish or perish” sort of notion, whereas in our world it’s “deliver or die”. There’s just no substitute for speed. A biotech company with half as good an idea and twice the amount of money will probably get there faster, unless you are super quick. And there really just is no getting around that. Building that culture in a comp bio company is extremely tough. I am far from perfecting it, but we try our best every time and hopefully get there with the teams.

Quin: I think the other important thing is value based innovation. I can’t think of a better way to describe it. Again, in academia there’s very often this idea of blue sky, go be a brilliant computationist and come up with new algorithms. It doesn’t matter if they’re relevant or not. Just over-engineer, go wild. For us, innovation by definition has to be better, cheaper or faster than what somebody else is doing, because if it’s not, don’t waste your time. Get on, do it the way other people are doing and focus your intelligence and creative mind on other problems where we can be better, cheaper, faster, and it really must be valuable. As a biotech, you have so many priorities and you’re moving so fast that even if something does seem like it could be better, cheaper or faster, right now, it’s just not a priority for you. And being able to balance that, especially if you’re naturally a creative person as so many computational biologists are, it is a difficult balancing trick.

Quin: And I think companies that get that right tend to be more successful. And I think one final one, and this is where I do believe US companies are winning hands-down, is a general can do positive attitude with a positive risk-based culture. We in Europe struggle with us. We are still very risk averse. We still always find ten reasons for why something won’t work. And it amazes me how much of general positivity, which you see both on the East coast and the West coast, can really transform innovation within a company. And those are the three things. 

Grant: What do you think American biotechs can learn from European biotechs culturally?

Quin: That’s a toughie because I’m always raising it the other way around. Let me rephrase that question a certain way. There are certain attitudes in American biotech that won’t play out in European biotech simply because the funding structures are very different. A lot of what I’ve just discussed works extremely well when you’re also chucking a lot of money at the problem.

Quin: As I hinted at early on, there is no substitute for just chucking a lot of money at the problem. That is part of the high risk game that we play when we take venture capital, and we try to move quickly. A lot of biotech in Europe tends to follow a trajectory of incubating within a university center, which perhaps is not so different from other biotechs, but then taking on grant structures, which have a longer timelines. These are all great. There’s no right or wrong way. People will argue whether it’s right or wrong, and there are lots of opinions around those. I do believe fundamentally there’s no right or wrong way to do that, but that is a much longer trajectory, and so certain attitudes won’t play out to that.

Grant: Great. What about the other way around? What can European biotechs learn from American biotechs under the constraints of differences in availability funding?

Quin: Stop overthinking everything is the one simple way of explaining what I see when I look at a lot of European biotechs. Again, it’s really about focus on speed, focus on value-based innovation and focus on creating a can-do culture. Really those three things for me are so, so important. I’m South African, even though sort of the UK is my home now. Even after all these years after making the UK my home, it still amazes me at how difficult it is to get a high five kind of culture going. It just doesn’t always work. It just doesn’t work with the culture. It doesn’t work with people, but finding ways to implement a more positive can-do culture needs to happen in a lot of biotechs to emulate what’s happening in the US. But maybe reappropriated the way we do things on this side of the pond.

Grant: So changing tack here, if you weren’t a scientist or a physician, what would you be doing?

Quin: It would be building tree houses in Costa Rica nonstop.

Grant: Talk a bit more about that. I’m curious about this. What’s the story here?

Quin: It’s easy to make up stories to defend things you’ve said when you were young. I want you to be careful about causality, but I remember in my first year of school when your teacher asks you what you want to be and what do you want to do? I suppose I was a bit of a precocious kid. Probably still a precocious kid now, even though I’m in my forties. I said to my teacher, “I want to be a medical doctor that does research.” So that was my career choice then and there and that one played out.

Quin: Maybe I was creating a self-fulfilling prophecy. I always said I wanted to live in a wooden house. So growing up in South Africa, that had a very particular idea attached to it. But as I learned to love traveling all over the world as a scientist, as so many of us do, I just fell in love with Central America. I really fell in love with Costa Rica and the life out there. And so together with a really good friend of mine, who’s in many ways the Jane Goodall of Central America, put some money down for some jungle and started building my dream treehouse out there next to a beautiful river with gorgeous waterfalls. And I will keep doing this as long as the money is available and I can do it. Build my little community and friends and retire out there one day. 

Grant: When is the other South African internet enabled satellite service coming available? 

Quin: Yes. Soon, please. 

Grant: You can just work from your tree house, right?

Quin: Yes, absolutely. You joke, but right now I’m trying to solve this problem from a distance because one of the first things I had to do out there was set up some solar powered WiFi. Well, 4G to WiFi routers. The solar panels are still working and the repeaters still seem to be working, but the main router is sitting on a hill somewhere. It seems to be giving in. With my poor Spanish and others’ poor English, it’s difficult trying to fix this. So yes, please. Somebody needs to sort out internet to the jungle very soon.

Grant: Pretty cool. Tell us a bit more about when you were a kid. Why did you say you wanted to be a medical doctor who did research? Did you have a family background in this or read some book? Came to you in a dream?

Quin: Honestly, I still don’t know where that came from. Something must’ve sparked that. I come from a long line of engineers and tinkerers and inventors, so that there is the invention streak in my family. That’s for sure. But it was bizarre. I said I wanted to be a doctor. My brother said he wanted to be a lawyer. He did the next best thing and became a banker. 

Grant: I knew it. Where are they living? 

Quin: My brother lives out in the UK, too now. Enjoying the London highlife as a banker.

Grant: Fancy schmancy, huh?

Quin: I hope to make as much money as he does one day.

Grant: So tell us about the COVID situation. I think you two had maybe even a more interesting than average experience with the timing.

Quin: I did a quick trip out to Costa Rica. A few days into the trip I just realized that the world was shutting down with this epidemic which became pandemic and very quickly flew back to California to watch California shut down and everyone panic. I was there when everyone’s doing the panic purchases and toilet paper was disappearing and all the rest. We have to make a call. Do we hang around in the US and try to continue our fundraising out there? Or do we assume that the whole world is going to go virtual and we need to be right back in the UK so once the money is in, we can set up and continue in the UK. It was again one of those things where Jack and I just looked at each other and said, “Right, tonight we’re going home.” and we did and got there.

Quin: Thankfully, everybody adjusted to the new normal very quickly. Thankfully, biotech funding only improved. Not that I would wish for COVID, but I think it focused individuals on healthcare and investing in companies with longer term goals rather than immediate profits. And so that played out very well for us. And thankfully again, we’re able to get set up in an academic center so that the lab can continue on rota. Because a lot of this initial target discovery was in collaboration with QUOD and the transplant scientists as being processing tissues, that could continue. Not without its problems. It’s cost a lot more money to keep the show on the road. I think a lot of international couriers have made a lot of money out of us getting samples sent all over the world, But again, count our blessings and thankfully, so far, so good.

Grant: Great. So what advice would you have for biotech entrepreneurs? 

Quin: So the common question you get asked is, do you need to have a brilliant idea? You do need to recognize your unfair advantage as an individual. What is it that you’re not only particularly passionate about, but that you’re probably better than average with, and that you could really trade on?

Quin: I think in many ways that’s more important, but of course, a fantastic idea doesn’t hurt. Most important, and I’ve learned this painfully over the years and growing up in the space, is that your co-founder is everything. I was really adamant that I didn’t want to have another very academic scientific co-founder. It’s kind of like finding a life partner and getting married. Somebody who just naturally compliments you. You match each other, when you’re both down, you can fill in for each other, it’s you two against the world, that kind of thing. I found that in my co-founder, and I know that no matter what, we will keep assisting together and we’ll find a way to make this successful. And that is just so important to do. 

Grant: So other than serendipity, how can people maximize their chances of finding a good co-founder? How can you increase the likelihood of a serendipitous event?

Quin: That honestly, I think the rise of these accelerator programs internationally has been a fantastic way to do this. Yeah, I could have done things up through the Oxford ecosystem, but one of the reasons why I went for these accelerators is because of this. Something perhaps that we are better at, says he controversially, in the UK versus the US is how accelerator programs are done here. There’s a truly excellent accelerator program here in London that we started off with called Entrepreneur First. They have many philosophies on how one could be competitive as a UK company. 

Quin: And right at the top of that is getting the right co-founder. Versus a YC where it’s “come with an idea and your co-founder, and we’ll give you a good chunk of money just to move very quickly with it”. EF’s approach is “find the right partner”, and they give you money and time to play with the right individual and really test out if this fits together. Both are great models. Both worked for us, but really first and foremost, it began with Entrepreneur First, here in London. 

Grant: Cool. So long-term, looking out when you retire whenever that is, what would you like to be known for? What would you want to have done?

Quin: I think really fundamentally, I am driven by this concept of improving human health span as somebody who started off life with a condition. When I look at health care, it doesn’t matter which health care model you believe in on either side of the pond. When you look at how as a species we’ve doubled our lifespan and are progressing to tripling it, and what that means in terms of crippling healthcare in the later stages of life. I think one of the best ways to flatten that curve, no matter which side of the funding equation you are on in healthcare, is that we need to start moving away just from disease endpoints and to start focusing on fundamental health span endpoints. Some people would call this aging myths and anti-ageing myths.

Quin: I’m careful of using those terms because it does come with a lot of traditional baggage around that, but really focused on the fundamentals of health span and how we tackle that as add-ons to other therapies or even fundamentally just to improve your health span. And when you’re in the cardiometabolic space like this- diabetes, liver metabolism, NAFLD, it’s a really juicy problem to be thinking about. I hope one day I can, I can just make a little bit of a dent in that problem and improve health care for humanity.

Grant: And what do you think are the most sensitive levers there that we can pull?

Quin: That’s a very, very big question. I think perhaps I will answer this in an overly simplistic way. I love to listen to this debate, the healthcare debate. And for me, the obvious debate is always the side of the pond, the US verses universal healthcare. And how does that pay out? It’s interesting because if you look at big data and how it’s driving health care, a lot of trends are non-obvious. For example, a lot of preventative health, which overlaps a lot with how I think about health span, has been driven by private medicine. Insurance companies are rewarding you for your apps and staying healthy and taking so many steps, which is light years ahead of perhaps how we do it in the NHS here in the UK.

Quin: And I say that very carefully so that I don’t get myself into too much trouble. So there are a lot of non-obvious things happening in the space, but I think what is universal to all of us is that we spend an extortionate amount of money in the later years of life to stay healthy. You know, we’ve all now in the COVID era, become familiar with this concept of flatten the curve. Flattening the curve in healthcare I think needs to come from therapies that are fundamentally focused on health span and health span modifiers, whether that’s more preventative medicine or that’s attached to other therapies.

Quin: Even more simply put, one way I like to say this to people who think a lot about obesity, because of course, obesity is a very big area that I think about too, in the space. We really need to stop preaching to people and telling them to move more and eat less. It doesn’t work. It really doesn’t work. And if we could solve obesity as an issue, we would make massive strides towards flattening that curve in healthcare. 

Grant: Well, it’s impressive how strongly heritable obesity is in the context of environment. But in terms of comparing across different phenotypes, it’s very heritable.

Quin: It’s incredible. And it’s just incredible seeing what we know about obesity and body fat distributions and how that affects different diseases. Why are we still so moralistic about this in general health care? I can only hope that future generations will look back at and shake their heads at how silly we were at really just forcing this. Body shaming people and making them feel bad about how much they eat and the sedentary lifestyle. Of course, these things are important.

Quin: Of course, we should do our best to exercise as much as we can and not consume too many calories. but we need to start thinking more smartly about how we modify these phenotypes like obesity and fat distribution. There are the three distributions, and in many ways as a company we focus on one, there’s fats around on the outside of a body. And many of us in research know there’s fat around your internal organs, but now we know various organs also build up fat inside of the organs and inside the cells of the organs as you age, and the liver is one of them. We just need to think about how we treat this problem.

Grant: So on a completely unrelated topic, what surprised you the most about the COVID pandemic? 

Quin: I love non-obvious things playing out, and especially when they come out in your favor. And I think the thing that has amazed me is how well biotech, investment is happening right now. And again, like a lot of complex systems, you should be very careful of coming up with overly simplistic explanations. But it seems to me with COVID that it has really highlighted to people how fragile we are as a species in terms of healthcare. We can fly to the moon. And yet, a simple virus can wipe out an economy very quickly.

Quin: It seems to have really made venture capitalists more eager to focus on companies like biotech, where you’re not expecting to turn out a massive profit in three years’ time. And that’s fantastic and power to all of us, because that is where I believe the future is in good innovation, and venture capitalists need to be taking bigger risks.

Grant: Many people who maybe weren’t in the infectious disease space weren’t seriously anticipating something like this. What things do you think are underestimated? What things do you think in the next decade or so could really come out and change things in a way that most people aren’t at all prepared for. 

Quin: Quite honestly, I think it’s worth pointing again to infectious disease. You know, it’s really incredible. If you’re interested in aging medicine and aging drivers and nutrient sensing and how these things play out as we age, you look at some of the great, popular books that have been written recently. Particularly coming out of East coast, West coast, US, and I think almost all of these books, by various academic authors, except for one or two, perhaps have all said that. Of course the future of humanity is so dependent on understanding the fundamentals of aging metabolism, et cetera, et cetera, with a one exception. That there could be a massive viral or disease pandemic that can wipe us out. And there you go. This is what we live in right now. We are a very fragile species.

Grant: This is the little league version here, right? If it’s at the fatality rate of SARS or MERS or something, we’d be in a deep shit.

Quin: No, absolutely. Let’s hope we learn from this, but history dictates that humans need a few things to go. You need it to go wrong a few times before we learn. Fingers crossed, it is not the case this time round, for sure.

Grant: Great. Well, thank you so much for joining us today. I really, really appreciate it. And also, is there anything else you want to say before we go? Anything else about the company, a shameless plug, some hobby of yours, whatever. 

Quin: No shameless plugs, only to just thank my co-founder and thank my team. It’s such an honor and a privilege as a modern human being to be able to chase your passions, to be financed to chase your passions and have, even if it’s just a small chance of being able to make a real difference to human health. And I’m very lucky to have the people I have around me. So thank you. And, thank you for having me on, man.

Grant: Well, thanks for joining us. It was great.