The Bioinformatics CRO Podcast

Transcript of Episode 96: Tom Weaver

Disclaimer: Transcripts are automated and may contain errors.

Grant Belgard: Welcome to the Bioinformatics CRO Podcast. I’m Grant Belgard, and today I’m joined by Dr. Tom Weaver, a Cambridge-based scientist and entrepreneur whose career spans genomics, diagnostics, and therapeutics. His company building experience includes Hexagen, GeneService, Congenica, and PetMedix, and he is co-founder and chairman of CellCodex. Full disclosure, I’m also a co-founder and CTO of CellCodex. We’ll explore what Tom is working on now, how he found his way from research to building companies, and what he would tell scientists considering that path. Tom, welcome.

Tom Weaver: Hey, how you doing, Grant? Thanks for having me on.

Grant Belgard: Yeah, it’s great to have you here. What’s taking most of your attention at the moment, and what are you trying to move forward?

Tom Weaver: Oh that’s i’m 64, so I’m sort of at the end of my career, and my wife always says, ” when are you gonna retire?” And I should be retiring, but that’s not the case. I’m doing lots of things. So as you it was a kind introduction. I’ve actually been involved in seven startups four of which have exited and three of which are still private. I’m also an angel investor, which means I’m quite active in meeting young startup companies young CEOs. I really enjoy working with them, learning about what they’re doing and maybe mentoring them a bit and potentially investing. But basically I’m doing early stage board work. I’m on three three different boards including CellCodex, which we can talk about as, along with yourself, helped co-found and am the chairman. But I’m involved in some other early stage companies in both human health and animal health, which is quite interesting.

Tom Weaver: We might touch on that ’cause there’s so much overlap. Science doesn’t really care, right? And what we’re learning in human health we can translate very effectively to animal health, which I think is really important. But my current interest in this sort of portfolio of activities ranges from drug discovery, early stages, preclinical drug discovery and early development and vaccine discovery to novel medical devices and wound care. So it’s… I’m quite a generalist, I suppose.

Grant Belgard: Let’s spend some time on CellCodex and explain it from the beginning for listeners encountering it for the first time. What is CellCodex to make possible, and who would benefit first if it succeeds?

Tom Weaver: Yeah it’s quite interesting. CellCodex, for me, and this is true for any of the ventures that I’ve been involved in, this won’t sound like rocket science. I’m sure it’s true for many entrepreneurs. What attracts me to a company really is a world-class team. And that’s absolutely essential. You have to have fun and enjoy the people you’re working with. But then it’s really having cutting edge science that’s protected and cannot easily be replicated. And the third really is an opportunity to make a difference in patients’ lives. And the reason for that intro is ’cause I think CellCodex has all of those in spades, and it’s what I believe in the company. I think it’s gonna make a real difference. ‘Cause I remember 30 years ago at the new millennium, and I was thinking, a conversation like this, what’s the future gonna hold?

Tom Weaver: And I really thought neuroscience R&D was gonna lead to really, transformative new therapies for conditions like neurodegenerative diseases and Alzheimer’s, ALS, and Parkinson’s. But here we are today, 30 years later, nearly 30 years later, and there really aren’t really any transformative new therapeutics for these diseases. They’re just starting to emerge. And I know two people personally who have had Parkinson’s disease, and they have suffered what is an incredibly debilitating disease for which really there are no effective drugs that modify the disease, but really only treat the symptoms of the disease. And whereas cancer, and I’ve been involved in, in, in different cancer programs, there have been many new therapeutics that have come out, which are really putting patients into long-term remissions, and this just isn’t the case for neurological diseases like Parkinson’s.

Tom Weaver: And so CellCodex is really trying to address this and change this. In my opinion it’s a drug company using an AI driven approach, and we hear a lot today about, oh, the, an AI drug company or whatever. CellCodex is a drug company, but it’s using the advantages of the tools that, that can help us to really lead to really what are gonna be first in class therapeutics to transform the lives of patients with this disease.

Grant Belgard: Can you take one question CellCodex is working on and walk us from the choice of cells through the experiment to the decision you hope the result will inform?

Tom Weaver: So I’m not the scientist, so I can’t probably go into too much detail. What I can tell you what I think at a really high level the USPs are and the approach, why I think the approach is going to be successful. So the first is really what what we’re calling the MaxDiff platform. And like all good companies, you need a platform to start with, and there are really two unique aspects of the MaxDiff platform that really separates uh, CellCodex apart from other drug discovery protein companies. And the first is that we’re able to age cells reflecting disease pathogenesis.

Tom Weaver: Often people are working with cells in culture that are naive immature cells, and they’re not going through the whole disease pathway, and I think that’s something that the founders bring to the table using a variety of different cell engineering technologies to that to get this reflection of the disease pathogenesis over time. And the second really unique aspect is putting on top of that a perturbome analysis, which is dear to my heart as a geneticist. Perturbome is a fancy new word to basically mean, changing the conditions that a cell or a tissue is exposed to, either through genetically using like CRISPR-Cas9, so you’re perturbing genes up, to full complement of genes in a genome, but also, through the treatment of drugs or environmental changes. And this is now doable with the emerging technologies to allow this to be done on a genome scale.

Tom Weaver: And what’s unique at CellCodex is the ability to do that in these aging cells. So for example, using CRISPR-Cas9, anyone who’s used it, it’s very difficult to get that to work on aged matured neurons, for example. And so we’ve got a trick special sauce to do that. So really bringing together that ability to age cells in a controlled way and to reflect the disease pathogenesis and to perturb many different environmental factors. You can start looking at very… Generate really large causative data sets, which we can do under very controlled situations, and we can use that now with with this AI or this really machine learning to look at models based on these dataset and make predictions from these models, which we wouldn’t have necessarily had before. And then test those models using a variety of different functional tests in vitro, ex vivo, or even in vivo models.

Tom Weaver: And of course, learning from those experiments, we can generate more data and evolve the models and make our predictions better. But the whole point is to capture the intellectual property around what really will be novel targets and pathways defining really new disease mechanisms. And that’s what’s really exciting for me. Other companies are trying to do the same thing. I think CellCodex is doing it really in a unique way. But ultimately, what we’re trying to do is, with these validated targets, to undergo our own internal discovery program so that we can discover really first-in-class therapeutics.

Grant Belgard: What evidence would persuade a skeptical scientist that CellCodex could improve a real drug discovery decision? And what remains to be demonstrated?

Tom Weaver: Yeah, that’s a fantastic question. And you could look at this from an investor, so for those of yous, you listeners that are setting their own companies up and they’re going, trying to raise money, this is the question that the investors will be asking. But also as a scientist, ’cause I consider myself, even though I am a investor, first and foremost a scientist, and these are the questions you should be really challenging yourself for any, whether it’s a company or you’re just doing your PhD or your postdoc or working in a government lab or whatever. And from this, you’re taking a more skeptical or, prove it to me that this is gonna work, the ultimate aim for CellCodex and everything I was just talking about, doing novel discovery, in Parkinson’s disease, what you would need to do is to find really what are validated targets before you start your discovery programs.

Tom Weaver: And to do that you need to be convinced really that the drug target is really involved in the disease mechanism, and it’s been validated in two ways. You have to convince yourself. The first, again, showing my background , it really should be strong genetic evidence that the target is associated with the disease. So for example, using, comparisons with other model organisms many of which are often much further advanced than what we have in human medicine neuroscience. But also GWAS studies that are performed in humans in large population studies, or familial inheritance that we can take advantage of in rare conditions. But of course, with the idea of then expanding that to more common conditions which we know works. And the second point you have to really be convinced about is really the clinical evidence that the target is causing the disease.

Tom Weaver: And there’s a bit of a challenge there if you’re looking for new targets and new mechanisms that haven’t been there before, how do you get that clinical evidence? But you can do that really you identifying targets that are already in the clinic for other indications. I’m not saying we’re repurposing drugs necessarily, but you’re really learning from, biology has a lot of redundancy and we can learn a lot from other cell systems and the way they work. But failing that if there are some sort of proof of concept data, certainly in multiple in vivo disease models, that, that’s really important. And I’ve, that’s certainly what has been my experience in other companies. So having that genetic evidence and the clinical evidence before you start is, it should be really important in your, thinking before taking a project forward

Grant Belgard: What do you want CellCodex to build a business around its science through data, predictive models, therapeutic targets, or some combination?

Tom Weaver: So I’ve been around for a while, and I’ve been involved in quite a few companies. But to be honest, they all share the same themes. And really there are two key elements, I think to build a robust company. It’s certainly true for CellCodex, but I’m sure for your listeners for their companies. And the first is really to build and validate your platform this is super important. So I was just describing the MaxDiff. Your MaxDiff kind of exists in individual parts, and what you really need to do for many platforms is put those parts together, glue them together, be really smart in how you put those together, and make them really hum and optimize all the different parts. That’s really important, and I enjoy that. That’s my background. Sometimes we call it technology development, high throughput screening, all that sort of stuff.

Tom Weaver: It’s really fun, building that, that platform, but you need to validate it. So that’s good. But the second key point is, and I often say this it’s a bit of my soapbox, is product is king. Nobody really cares about a platform, certainly in, in biotech. Everyone’s got a platform. Everyone says it’s the best platform. But it’s meaningless unless that platform comes up with something that works. And the value of your company, certainly when you’re raising money from investors but also when you’re selling your company or, trying to exit in some way, you really have to look at those value inflections of your company, and those are really based on your products that you’re developing. And for me, it’s the minimum usually of three. I often hear this when people are talking, if they’re on the radio, they’ll say, “Oh, I always have three examples.” It’s the same in, in your company.

Tom Weaver: I’m not a real believer in single asset companies. I think having a portfolio approach is really important, so having multiple programs on the go. The first should be, I often call it falling off the log, so it’s the least amount of risk to really push your platform to show that it can work, but you’re gonna get a decent drug out the other end. It’s unlikely to fail. Hopefully, there’s no guarantee. So your second program is really your backup, another shot on goal so in case the first asset fails, you have the second asset. But then you always have to have that, that third asset, which I call the, you know, knock the ball out of the park. And this is really in terms of, maybe a higher risk but really a higher reward program. So if you really hit that, boy, you’re in business.

Tom Weaver: Now, what’s interesting is it’s very rare that a company will be able to take all three of those programs through if you’re successful, and I’ve been in the, some would say, enviable position of these drugs aren’t failing, but it’s also unenviable as to which one do you really take forward, ’cause you can’t afford to do that. So you have to make some choices. But one thing you can do is partner. This is a really great way. Again, a portfolio approach allows you to work with other partners larger companies, hopefully, that are much more sophisticated in taking a drug through to commercialization and so you can use that, these other programs to establish those kind of relationships.

Grant Belgard: Let’s rewind. I’d like to understand how you found your way into this. So what kind of kid were you and what first made science interesting to you?

Tom Weaver: Oh, that’s a that’s a embarrassing question. I’ve got two daughters that are grown up now, and they’re very different, and we talk about this all the time because they do the humanities and for me, that’s really foreign. And it’s hard for me to understand. I was the kid who was terrible at history and English and writing and all that sort of stuff, but I was always good at math. I liked to read, but I, I wasn’t really good at writing, being creative. But what I was always really interested in, other than baseball, was math and science. And I remember again, I’m an old guy. I remember the first mall that came into… I’m from Madison, Wisconsin in the Midwest, and I lived in a, in an area that was fairly close to our first mall. It was called West Town. And I remember riding my bike out and just sitting in one of the bookstores, ’cause the first time I’d really been in a bookstore.

Tom Weaver: And sitting around and I’d find myself in the science section. I’d just sit, ’cause I couldn’t afford to buy any of the books. But I sat and read the books. It was fantastic. And I had a paper route, and I’d make money on my paper route mainly to buy, a new mitt or baseball bat or whatever. But I remember buying, or I think I- I did a, in America you got the PBS, public broadcasting, and that’s supported by listener sponsored. So here I was, I think I was about 14. I had some money from my paper route. I actually donated to our channel 21, which is our public broadcasting in Madison, and I did it because I got a book for it. They sent me a book called The Ascent of Man by Jacob Bronowski, which was like a, a treatise of science presented on the television, and it was actually from England.

Tom Weaver: And Jacob Bronowski was actually quite a famous scientist who immigrated from Poland to England during World War II, and he came to America, ended up settling in America and working in La Jolla. But he was just inspiring. I read this book and I was like, “Oh my God, I have to be a scientist.” And then that finally, drove my parents nuts. When I was in high school, I didn’t know what kind of science I wanted to do, but I did a a kind of a an essay, again, on a book. I read The Double Helix, which people will know that was James Watson, his version of the discovery of the structure of DNA, which happened in Cambridge in the 1950s, the early 1950s. He was an American being in England. And I just loved it. I wrote it and I think I got an A on it. It was like the only, one of the only As I got in that class. And I love it. That, I graduated that year. That was my senior year in high school.

Tom Weaver: It was 1980, and it was the same year that Fred Sanger received the Nobel, second Nobel for the method of sequencing DNA using enzymes. And here I am now 40 years or whatever it is later living in Cambridge. I just feel so privileged working here where so much of this groundbreaking work is done. And funnily enough, last night I was at a conference dinner at a place called St. John’s College. It’s one of the colleges here in Cambridge. And we were sitting… You have these dinners, right? Like networking dinners. And above us where we were sitting was just this beautiful portrait of Sir Fred Sanger. He was a member, he was a fellow of St. John’s College. And he’s passed now, but it’s amazing to be just part of that. It really is inspiring. And so it was inspiring when I was, a kid. It’s inspiring now even. That’s why I probably never will retire, ’cause it’s so much fun.

Tom Weaver: So message for all your bioinformatics guys, gosh, it’s exciting. You’re in such a, a wonderful time to be in science now with all this AI stuff. And don’t think of it as, “Oh, the AI’s gonna replace me.” No way. It’s just gonna be able to do more cool stuff. Old guys like me wish we would’ve had it back then.

Grant Belgard: How did Cambridge become part of your story?

Tom Weaver: Actually I actually moved, it was for, like a lot of things in life, it was totally opportunistic. And, fate, had it. I, I was studying tumor virology in Wisconsin in a medical school pathology department. It’s called McArdle Lab for Cancer Research. And yeah, it was at the time the big epidemic. It wasn’t COVID, it was HIV. I was working on turkey AIDS. It was a, kind of a cousin of HIV, and we were using it as a model to study the pathogenesis and the life cycle. And I wanted to go to NIH. This guy Robert Gallo, was a really famous scientist working on it, and, I wanted to go there and work on a vaccine or whatever. But what happened is I actually met another geneticist. Her name was Rachel. She was doing a PhD in the department next to me, and we fell in love, got married in Wisconsin, and she’s English and she had done her undergraduate at Cambridge, and she’d already…

Tom Weaver: She’s a bit older than me and was a bit further advanced in her PhD. She’s like, “I got a post-doc sorted out, and you wanna get married we’re gonna move to England. We’re going to Cambridge. I already have a job.” Yeah, so I had to come over and find a job and I was, again, I was quite lucky. I I didn’t know it, I knew it from reading The Double Helix. MRC, the UK Medical Research Council, is just this awesome organization, government science, not the university. It’s, just it’s like NIH, a smaller version. And I went to the same lab where those guys were Watson, Crick, and all the famous Nobels and stuff. And I basically pleaded for a, a job. And I got really lucky. I actually got to meet Sir Aaron Klug, a Nobel Prize winner structural virologist, actually. South African guy, was super intelligent.

Tom Weaver: Grilled me for an hour over tea, introducing to the English culture of having tea and talking science. And yeah he’s like, “What do you want?” And I’m like “my wife’s here. I need a job.” And he’s like, “Oh, we’ll find something for you.” And it was great. Whether that’s true today, maybe 40 years ago, whatever, they were more desperate for scientists. But it was just by chance. And I loved it. I ended up staying here. I’m still, we’re still here, obviously. So it’s fantastic.

Grant Belgard: What point did starting a company become a real option for you, and what other paths were you considering?

Tom Weaver: Yeah. Again anybody that tells you they have this grand plan of what they’re gonna do with their life and, write it out, I wouldn’t believe them. At least in my experience, my journey. So I needed a job. So my wife Rachel was very successful and had an academic position. She went from bench top genetics into data science, and was involved in a really cool database, one of the first genomic databases called FlyBase, which was really cool. So she had a job, a permanent job at the university, and I was a post-doc. And I love post-docs. Post-docs are really important, I think, but I didn’t want to be a post-doc forever. And I had an opportunity, so I needed a job, but I knew I wouldn’t I was never good enough to get to be a, a l- a professor at Cambridge University. So basically I was I knew some guys in the genetics department.

Tom Weaver: Peter Goodfellow, who’s just an awesome scientist, he was the head of department a really famous geneticist, and he was leaving. He was going off to be CSO of a major pharmaceutical company i- in the UK. And so he’s shutting his lab down, and so he was setting up a new company. So I got lucky and got in. It was the first genetics company really in in the UK and it was, oh, just fantastic. But I basically fell into it and got to work with some really excellent scientists. And what was really ironic is a lot of my friends who were all going down the academic route, many of them incredibly successful, they thought I was a loser because, I couldn’t make it as a professor. And it just couldn’t be further from the truth. I loved it.

Tom Weaver: I had a lot more freedom and opportunity to do what I wanted to and also to work more in a team rather than just, and often in academia, you’re in a kind of little … You’re supposed to do it all on your own and be a genius and all that. I’m sure science has changed a lot since then, but in, in startups you have to work effectively as a team, and I’ve, I was good at that and I loved it. So I’ve never looked back. It was I was lucky, but it was, purely by chance. I just needed a job and there was a new company setting up in my network. So that was really great.

Grant Belgard: Is there an early company building task that made you think my PhD didn’t prepare me for this?

Tom Weaver: Actually I think PhDs and actually more so postdocs. PhDs I’ve given this view to many young people, whether they believe it or buy it or not, I’m not sure. But when you’re a PhD, certainly the ones I’ve seen, they’re often, there’s a great English word called mollycoddled, they’re really looked after. Their principal investigator sees them as their children almost, like they, “I’m really gonna look after this PhD student and I’m gonna make sure they’re successful.” Mainly ’cause if they’re not successful, they look bad, right? The professor. And so these, these guys get get really treated well and a lot of help for what they’re doing. Postdoc’s not like that.

Tom Weaver: Postdoc you go out there and you’re essentially in competition with a lab, ’cause if you’re successful at what you’re doing, you’re gonna go out and write probably grants in the same space and, there’s horror stories which I know about which are, people are put on the same project and set up who’s gonna get there first and, it’s a thankless job. But, and you’ll probably start with an idea that’s completely wrong, and it’ll fail like a lot of science does, but then you have to fix it. And because it’s only, you pushing this for your career, you have to fix it. You’re responsible, so you really have to mature and have faith and belief in what you’re doing, and find the solutions. Develop your network. So my network really started when I was a postdoc, is same people I know today.

Tom Weaver: And this is really important that postdoctoral time to learn that, so then when you’re going off and starting your company or joining a company, you’ve already got that network and people that you can work with. So it, that kind of training does help I think. And a lot of kids I think now are, they don’t wanna do postdocs. God help they don’t even wanna do PhDs. I’m like, “Oh my gosh, you gotta… if you really wanna get anywhere you need a PhD, and I would, give it a try. Give it at least two to three years to earn your stripes and fail a bit and then go and do it.” Rather than, “I’m 26 years old and I wanna be a CEO of a startup company.” I think that’s a bit naive. So go and work with people who have done it, and yeah.

Grant Belgard: Take us to the beginning of Hexagen. What was the opportunity as you saw it, and what needed to be proved first?

Tom Weaver: Yeah like I mentioned before, and it’ll sound like a warped record, it was a platform technology that we did. And this is… You gotta remember, this is like 1996. So DNA sequencing was expensive. It wasn’t very efficient. You couldn’t do a lot of sequencing. So what we were trying to do, the platform technology, believe it or not, it was to generate mouse models of human disease, and then to license those models to the pharmaceutical industry. And so I got some real interesting lessons to learn. So the technology platform was basically a non-sequence first approach to identify polymorphisms in candidate genes that we thought were involved in in human disease. And so what was really cool about it, my role was R&D we would work with expert key opinion leaders, which is super important in any company you’re doing. Early on find the best, expert.

Tom Weaver: In our case, we were working with type 2 diabetes, chronic chronic diseases like, diabetes and osteoarthritis. And there are experts in places like Cambridge. Not surprising there’s great startups in Boston and Cambridge. So these KOLs are there. So we talked to them, and they were like, “Oh, yeah, here’s a gene list of I don’t know, 120 genes.” Problem is, we didn’t know the gene structure of these, and what we were going to do is have to, And these are often human genes. We had to find the mouse equivalent, figure out the gene structure, then go and then sequence these I think there was 10,000 mutagenized mice that we would identify allelic series in these candidate genes and then breed the mice and make models for, say, diabetes. So we, molecularly, we were able to do that. It was amazing. We put together this platform technology to do that extremely efficiently.

Tom Weaver: And I’ll just bore you with some numbers. So what we would do is, I think we ran, like this is before capillary electrophoresis. We were running 96 well plate like gels on ABI 373s, I think they were called, 377s. And we would run three gels a day, and we would multiplex all the PCR products. We had four sizes on each well, and they had four different colors. And then we would capture all that data, and we… It was a huge data challenge then. We had to capture all that information and annotate it, and so we put together one of the first sort of gene annotation programs based on something called [hDB?], which eventually morphed into Ensembl. But we got access to that way before Ensembl existed, and we created our own internal database as a viewing tool and annotation tool for all these really cool potentially disease-causing genes. So we were doing it in mice, and, ah, this is nuts.

Tom Weaver: So after a year we pivoted, and this is again another, another lesson. So the technology platform we built, but then the business model didn’t really make sense ’cause, again, product is king. The, the drug companies we were talking to were like, “We don’t really give a shit about a mouse model. What we really want is a drug, so you need to show me human data.” And what we were doing was very applicable to human data, so we did that. We changed completely. We didn’t work on mice anymore. We worked on human, and that worked really well, and we started partnering with a US company called Insight in California who were doing massive amounts of sequencing, and they loved what we were doing. And they acquired us. So within two years, we were now a fully fledged sort of human genetics company looking for disease models and backed up by a publicly traded US company.

Tom Weaver: It was really quite exciting. But the interesting thing is, another, then I’ll shut up anecdote was at that time genomics was huge. It was before the genome project. The genome project was just building up and Solera was out there. They were the competing company with us. And at the time all this genomics was really to identify targets. Sound familiar? Really great targets. We’re gonna use genomics to find all these targets. And so targets were king at the time, and we were doing that. But then what happened is everyone’s realizing, oh wow, these targets are great, but are they any good? Just because you found this mutation, what further validation do you need? And the drug companies were like, “We actually want products. We don’t want the targets.” So suddenly the targets and all these, genomic elucidated targets became unfashionable.

Tom Weaver: And it suddenly that was really not in, and so that sort of whole business model really didn’t really work. You had to focus on the actual assets. But now 30 years later, we’re, just talked about cell code. That’s back in vogue. Using, of course new tools, and AI and, virtual models and, a lot more tools for high throughput real chemistry and biology. But it’s back in vogue. And and we were… Just to say, we were doing machine learning 30 years ago, so using the data that I was just describing, we were using that to prioritize mutations and genes. So it’s not necessarily that new, it’s just, of course, we’re using AlphaFold now and maybe more powerful tools.

Grant Belgard: What problem were you trying to solve with Congenica, and how did you work out what clinicians actually needed?

Tom Weaver: Yeah. So that’s a it’s a good segue, actually. So what we’d certainly learned at Hexagen was really the power of like genomics and genetic analysis, and what has now been called precision medicine. But, at Hexagen we were doing precision medicine before it was really a thing. And obviously I picked up on that and the ability to use high throughput sequencing, ’cause that had obviously come out with the Illumina technology to stratify patients both in terms of I suppose drug discovery, but in, in Congenica’s case it was really in medical genetics and diagnostics. So using the entirety of a patient’s genome and understanding that in the context of the disease the patient had, we used that as a way to get a definitive diagnosis for the patient. And this was really focused on rare diseases, which is a misnomer. Everyone’s like, “Oh, it’s a rare disease,” like cystic fibrosis or whatever.

Tom Weaver: If you actually look, there’s like 7,000 rare diseases, and if you look at them cumulatively, they’re common. It’s about 1 in 17 people. You’ll know people, there might be people in your family, you might have a rare genetic disease. There’s so many of them. So it’s really important, and often certainly when we started, and this was, 15, 20 years ago there was something called a patient odyssey where patients who had a rare genetic disease, it would take them years, maybe 10 years before they actually got to the bottom of what was wrong. And that, it’s obviously not a that’s not a great place to start, and even if you make a diagnosis and there’s no treatment, it’s still not knowing what’s wrong, especially 70% of this is pediatric, not knowing what’s wrong with your child is horrible.

Tom Weaver: So the use and the whole point of Congenica was to use genomic analysis as a way to really shorten that odyssey, and it works. It works really well, and more so than just at looking at exomes or gene sets gene panels. You do the whole genome. You look for, regulatory changes, et cetera. And it works. So we can, shorten this disease sorry, diagnostic odyssey and of course also help with family planning and getting on the right treatment course. It’s super exciting. And now with all the AI and getting larger data sets, we’re getting better at predicting mutations that are out there that haven’t been seen before that we believe are truly disease causing. So that was that was really a point, and I’m proud of that. It’s gone really well.

Tom Weaver: It’s been adopted by the the NHS, and literally hundreds of thousands of patients have been diagnosed using this, this approach, and it’s now going around the world. A lot of, and a lot of companies are doing this. It’s really quite exciting

Grant Belgard: How did the idea for PetMedix come together and what made animal health worth pursuing?

Tom Weaver: The segue isn’t to do some grand plan of the technology. It’s more I’m a starter, so I’ve never worked anywhere more than five years. Five years into Congenica, I was looking for a new challenge that was really at a stage where it was gonna scale and go commercial and all that sort of stuff. I’m more into there’s a real challenge, a scientific challenge. Let’s get it to work from the back of an envelope to make a difference and get the platform up and running and start the programs. And so what I did was looked at what were opportunities that would be quite exciting, and actually looked at three different opportunities. The first was genetic counseling, sort of online counseling, ’cause something from Congenica was like we’re getting all this data, and the patients and the clinicians the consultants are really gonna struggle with this. So mainstreaming that genomic information.

Tom Weaver: It still needs to happen, I think, but so that was an idea, but it was how to do that was… And it was more of an ed tech thing, and it was beyond me. I’m really not a software person. So- I still think it’s a good idea. But we looked into that but also looking at genome analysis, like I just described for human patients in diagnosing rare disease, you could do the same thing for sequencing pathogenic bugs, bacteria, in a hospital setting to look for and detect the presence of antimicrobial resistance in those genomes, and maybe even predict when they’re gonna happen and where they’re gonna happen. And so it’s sort of Congenica for bugs, I called it. And the third idea was about the idea of developing monoclonal antibody therapeutics for pets translating what we know worked so well in, in human medicine in, in, into animals.

Tom Weaver: And behind all three of those things I just talked about were people I knew who I was talking with about, oh, wouldn’t it be cool if we did this? Wouldn’t it be cool to do that?” And I ended up going down the PetMedix route because this really stellar individual scientist who I’d known for a while, his name’s Alan Bradley, who’s a genome engineer, immunologist just, great scientist, super motivated scientist, and I’d worked with him previously at different projects. And he’s a very successful entrepreneur, and he had a company called Chimab, which was… I won’t go into the details, but it was a, just a, Herculean genome engineering feat. He put basically five megabases of human genomic DNA into a mouse and to the base pair, precise replacement of the immunoglobin containing genes for I- IgG genes that make antibodies for humans.

Tom Weaver: We put them in a mouse, so it basically made it a transgenic mouse, incredibly complicated transgenic mouse, which could recapitulate a exquisite immune response to an immunization. And if you were to immunize those mice with a drug target, they would make antibodies against that drug target, but they’d be human antibodies rather than mouse antibodies, and it worked. Worked really well. That was what Chimab’s business model was. Very successful. They were a- acquired by Sanofi for $1.5 billion dollars a few years ago. But I met halfway through that, that Chimab journey, I met with Alan, and he’s “Why don’t we do Chimab for dogs?” And I thought it was nuts. I was like, “What?” I know nothing about dogs or, animal health really other than, using mouse models and stuff like that.

Tom Weaver: And but then because Alan’s such a smart guy, and I have so much respect for him it took me about 30 seconds to think, “Oh, maybe there’s something in this.” And then, you look into it, and it’s massive. So there’s so much in so many diseases that our pets suffer from that are common with a human condition. And it’s not exactly the same. Dogs aren’t little humans with tails, but there’s a lot of commonalities. So for example, lymphoma, which is a leading cause of death in dogs is cancer, and the leading A, a type of cancer is lymphoma, which we know from human health has been transformed by drugs like rituximab and in combination with chemo R-CHOP is incredibly successful. And we’re now in second and third generation antibodies in human health that can treat lymphoma, often with bispecifics using engagement with T cells to to target the tumor. So we did that in dogs, and it worked.

Tom Weaver: So we went through another Herculean genome engineering. We put five megabases of dog DNA and cat DNA into mice and did the same thing. And so it’s a unique platform. First time, fully canine antibodies were being made. They weren’t canonized. We weren’t taking a human antibody and messing around with it to get it to work in a dog. They were fully dog antibodies. And yeah, it works. It works really well. It was a, a really great time

Grant Belgard: Can you tell us about a time when the evidence made you change your mind about a company or a scientific program?

Tom Weaver: Yeah. Too many. If you’re an entrepreneur out there, they’ll… that’s what’ll make or break your company. So the first thing is there’s a need, obviously, to focus 100% on your plan, and certainly don’t treat your business plan as a academic project, and I hear this all the time. I see so many, academics… And to be honest, the Hexagen model was an academic model, and we had to change straight away in a to do that, and I’ve already described that. But another example, actually, was in PetMedix and what we were doing, we were the first company certainly in Cambridge, probably in the UK, to use B-cell sequencing first. So DNA first discovery of antibodies rather than if anyone’s made monoclonals before. It’s different approaches that work. And what we were doing is what Chimaerb had pioneered, was using dilution PCR.

Tom Weaver: So you’d do this sort of infinite dilution and find a plate where there was a single B cell from an immunized mouse, and then you would do PCR to amplify up all the variable genes and then rederive your, the molecular structure of your antibody from that single B cell. And that requires some really green-fingered scientists or automation to do that effectively, and we tried that at PetMedix, and it basically was one person in the lab that could get it to work, and that’s never a good look in any company. You need a robust, resilient technology. So we made the change quite early. We were the first to use 10x Genomics.

Tom Weaver: It was a new technology that came out, and we were basically purifying our B cells doing FACS sorting, so we had enriched B cells that had really functional B cell receptors, and then we would make libraries, 10x libraries, and sequence those, and then bioinformatically using a variety of tools, select what we thought were the the most likely candidates that were good. So that was really important. It worked, and it was super fast and cheap, and actually Chimaerb moved over as well to using the same method. I’m sure a lot of people are using that methodology. But the other was also at, at PetMedix is a classic. So again, being a startup company, you wanna be capital efficient, certainly in this country, maybe less so in America where there’s more money. But here, you’ve got that hard-earned VC funding. You don’t wanna waste it. And so we were part of our…

Tom Weaver: I just mentioned about having to do FACS sorting of B cells before we did the the library prep and sequencing. We were planning on doing all that through CROs working at either the institute, the, the kind of science park we’re on, or even through the NHS or the university. Cambridge, there was, multiple CROs that we could do that. Problem is that COVID hit, and as soon as COVID hit, they all shut down. They were, number one priority was the NHS, not a startup company, not one working on dog health. So- Within a week, we had a quick call with the board, maybe even just email saying, “Listen, got a solution here.” We found a FACS machine that was available in Italy we could acquire and have it sent to us. They were willing to it was like one of the last shipments in from the continent before everything shut down ’cause Italy went down quite early with COVID.

Tom Weaver: But we were able to convince the board, “I’m gonna spend 500,000 pounds.” That’s a huge amount of capital that we weren’t expecting to do, but such an important element of what we were doing as a company. We were able to a-agree to that as a board, and then immediately get that shipped. So in a couple of weeks, we had an instrument which then we went through, and we didn’t have any techs to know how to run it, so we had to train our techs by Zoom, which Zoom at the ti- we’re using Zoom right now. In 2020, that wasn’t, hardly anyone was using Zoom. It was a new thing. We trained our scientists, and also we took advantage because the core labs that were running FACS machines weren’t operational.

Tom Weaver: We recruited one of the best FACS technicians scientists in Cambridge to come and work for us, and they came and within six months, we had probably four people that could really do FACS well, and we had one of the best, you know, B cell sequencing companies FACS companies certainly in the city. So yeah, that kind of pivot really was important how to change the program, and we really benefit in hindsight now. It’s oh my gosh, if I was to do it again, I would make sure that core technology was embedded within the company.

Grant Belgard: What would you tell a bioinformatician who has a promising idea but is unsure whether they should start a company, join a company, or stay in research?

Tom Weaver: Okay, so you’re going to hear my opinion, which of course take with a grain of salt. Everybody’s going to have their own personal journey. The this is just my very strong opinion, and that you’ve already heard it: let’s hear it for the postdocs. So don’t be in a hurry to get your company out. And for all the reasons, I won’t go over them again. The other is often, if you’re going to take… I suppose it depends on what kind of company and where you’re coming from. Everything I’ve ever done usually has intellectual property that was developed in a research lab owned by a university, a hospital system or a government lab or another company. You’re inheriting some intellectual property that you’re giving away part of your company for, you’re paying for quite expensively, maybe through a license or IP, equity for IP swap kind of thing.

Tom Weaver: So I would rather wait until that technology has really proven itself, because tech transfer departments love to have these ridiculous valuations on technology that hasn’t even been proven yet, saying, “Oh, yeah, this is the most important thing since sliced bread, and you got to give me, a big chunk of your company.” Eh, has it worked? Keep it embedded within that institute until it’s actually done something. A trend I’ve seen certainly in the United States with therapeutics is actually getting all the way into the clinic, getting to phase one funded through grant funding or institutional funding at, the Mayo Clinic, Mount Sinai, whatever, that you get into the patient before you then spin your company out. And I think that’s really an interesting trend because I think investors now are being very risk adverse.

Tom Weaver: So the longer you can hold onto it in a nice environment that’s got some funding, and then take it out when it’s mature enough. But I know that’s not the case for everybody. But often the CEOs I’ve met, the young, entrepreneur founders, they’re just chomping at the bit to set up their company. They want to go out and do it, and my advice always is don’t be in such a rush.” And also earn your stripes, like I said, with a postdoc. And also you need to build your network. So everything I’ve ever done I’ve been lucky enough to work with people who I know, like Alan. I knew Alan for at least six, seven years before we set a company up together, and, he’s done it before. And now, I’m working with people like Manos Metzakopian and yourself. You’ve done it before. Manos hasn’t. He’s worked in biotech, but, whereas I’ve done it. And so having that relationship I think is quite good.

Tom Weaver: And also a thing I really believe in is if you’re working with people, pick the ones who are smarter than you are. We’re always learning and can improve. Even at my age, 64, that’s why I get up. I want to learn new stuff. When I get up, I want to learn new stuff and, try and be better than what I am. And that’s on- really only comes through having a good network. And so I’d say with that personal journey, stay in research long enough that you feel comfortable that you can do that.

Grant Belgard: How do you work out whether someone will be a good co-founder before you’re under pressure together?

Tom Weaver: That’s funny you should say, ’cause we’re, we work together. But this is absolutely true what I- I’m gonna say, and that’s you have some sort of shared history in your network. So Manos Metzakopian who’s our CEO I knew Manos. He was actually working in Alan’s lab. He did the first CRISPR-Cas9 screen genome wide at the Sanger Institute’s big genome campus here in in, in Cambridge. And he, Alan loved doing big science a- as I do and high throughput and all that and Manos did it, and he’s fantastic. And I used to have a desk next to him when I was writing the business plan for PetMedix. I actually camped out in Alan’s lab, and I was literally sitting cheek to jowl with Manos. It was great, and I think we even played basketball together. It was fantastic. And we even have a shared history going back to Oxford. Your PI I knew, from previous collaborations and stuff.

Tom Weaver: And for me then that was fantastic, the ability to work with someone who… And then build that trust that, it’s gotta be there when you’re partners. And also somebody who has complimentary skills. So I’m a data guy. I know how important data is. Every company I’ve been involved in, the real value, it’s the product, but, often it’s the data underpinning that product. The composition of matter for an antibody, for example. It’s actually the data which is the real value, not your platform of how you got that, that thing. And also if you enjoy working together, socializing and having fun, ’cause, this is a fun time, when you’re setting your company up and doing stuff. If you’re not enjoying it, you gotta really evaluate why you’re not enjoying it, and is it the right thing to do? Maybe this is ’cause I’m old now and can say this, but I really have believed that.

Tom Weaver: I remember at Congenica my CTO, his name’s Eugene, one of the coolest guys. He’s so smart. He’s a lot like, like you, Grant, actually. The, the super brain informatics guy. He’s a computer scientist from Moscow. He’s just brilliant. I love the guy. And we would sit together at the end of the day, ’cause again, you’re founder, CTO you’re gonna be there all day, right? So it’d be like 6:00, 6:30. He’s like, “I gotta go home. My wife’s gonna kill me,” whatever. “Oh, we got this issue. Let’s sit around and talk about it.” We had a bottle of vodka that we had hidden away in the in the filing cabinet. Now I’m not suggesting or condoning drinking at work, it was so cool. We would sit back and say, I’m not saying we actually opened the bottle, but at least we had it there, and we could talk about stuff and, and we really enjoyed working together, and we had fun.

Tom Weaver: Even though, man, it, it was intense and all that stuff, but, having fun with your co-founders I think is super, super important.

Grant Belgard: What question in biology would you most like to see answered in your lifetime?

Tom Weaver: Yeah, that’s a, that’s an easy one for me at least. I already mentioned, I thought this millennium would be the millennium of neuroscience, and frankly it let us down. I know we’ve making some significant advances, but not compared to other areas of science. So to me, we absolutely need to have much better ways to diagnose and treat mental illness. On top of neurodegeneration, I think the mechanisms that are more defined, I think it’s more tractable for that’s why we’re doing it at CellCodex. But I think in general for mental illness, for example, anxiety and depression, it’s, it is really adversely affecting so many of our young people today regardless of what country you’re from. So I think we really need, we need more efforts i-into that, and whether we can do, these fancy genetics, fancy AI, whatever we should be cracking on that, get cracking on it.

Grant Belgard: Absolutely. Tom, thank you so much for joining us. It was great.

Tom Weaver: Yeah. Thanks, Grant.