The Future Of Drug Discovery Is 4 Billion Years Old (Viswa Colluru, Founder & CEO at Enveda)

24:45Viswa Colluru:You know, I actually flipped it in my head and I said, most often we tend to conflate innovation and novelty. But if I look around, most things that have changed the fabric of our lived experience were actually not new when they did so. You know, steam engine, yes, initially toys and then to power water wells and then ultimately locomotion in water, actually, before the railroad. I love that you know this so much better than I do. I brought it up, but you've gone deeper. And that same thing is true for electric cars, neural networks, alternating current, the internet, transistor, rockets, flight.

25:27Viswa Colluru:And I was like, wait a minute, that's also true for statins, morphine, rapamycin, transplant medicine. And this for me was interesting because if you made the bet that most often, even LLMs, you know, when they changed the world were like by AI terms, fairly old, nearly a decade. Totally. And so if you make the calculation that most ideas that change the trajectory of human life are actually old, then you're increasing your odds that you are on the inflection if you just pick an idea that's old enough, where you also feel like both the constraints that restricted its potential are clear, and that the world in ancillary technologies has developed enough that the idea could be revisited.

26:16Viswa Colluru:So those are the two things you have to evaluate. So one of the big leaps I'd make from my time in graduate school is to actually leave immunotherapy, which had then been rechristened to immuno-oncology, which held a lot more sway and budgetary power than immunotherapy, was to actually go to the intersection of computer science and biology because I thought that the story was far from done. The idea had gone through many troughs of disillusionment, but computers and processing power and our ability to store and move data had been increasing exponentially. And so I said, wait, you know, this is an unfinished idea that I think deserves attention.

27:00Viswa Colluru:And so I found myself in AI drug discovery, what, like nearly a decade before it became cool and half a decade before the term even was coined. Yes. Before we get to that, you know, and looking at the work you did at University of Wisconsin, you know, it's full of all of these terms that I can't pretend to understand. You have, you know, working on new vaccination methods, new DNA, novel DNA vectors. And, you know, looking at your LinkedIn, you have all of this. And then you also have that you are part of the University of Wisconsin Table Tennis Club. It made me wonder why that is in there and what that meant to you.

27:34Like, was that the way that you blew off steam during this period?

27:37Viswa Colluru:Was that where you made your friends? So what's funny is I always grew up really wanting to play tennis. And I still remember watching Roger Federer beat Pete Sampras on a 16-inch CRT TV that we all used to have back in the day that you needed to give a solid whack once in a while because the antenna wasn't perfect. And I went up to my dad and I said, dad, I really want to play tennis. He's like, great, let's go check some places out. And we go check them out. And effectively, they're about in that time in the mid 90s, about$100 a month. Oh, wow. US. And my dad was like, yeah, no, we're not doing this.

28:20Viswa Colluru:And instead, he's like, let me go do this for you. Let me go buy you a table tennis paddle racket and find you a good coach. And so we found an academy that was subsidized by the government for$1 a month. And so I went to play table tennis every day instead of tennis and fell in love with how fast the sport was, how it demanded flexibility. And that became my thing. So I would go on to actually choke in every tournament in high school. Oh, wow. No way. I learned a lot about myself and how I dealt with pressure to perform because I didn't feel that in any other domain. But I felt that because I felt like I had to win because I was only one of the few kids that had coaching and overcame that partly and would go on to be on the table tennis team at the University of Wisconsin, which is really Indian and Chinese kids.

29:17Viswa Colluru:And it was also overwhelmingly undergraduate, so college students, not graduate students. And so it was this really insane, beautiful window into American life through the lens of an immigrant in a competitive sport that was viewed as a drinking game. and I fell in love with the intercultural mix, you know, competitive play. I would go on to be, even though not the best player, captain the team and even coach the team as a retired player for a year or two and made some of my best friends that way. I don't think we ever did spectacularly when I was on the team. We were like in the top 20 in the country, but we did beat Harvard at the Nationals.

30:03Viswa Colluru:And I was like, that's good. I'm going to keep that in my back pocket. I bet that, you know, that would have made your family very proud, right? Absolutely. It was great. You know, there are plenty of, I think of someone like David Foster Wallace who talks so much about and writes so interestingly about the parallels between tennis and life and writing and creativity and all these sort of things and math. Are there any sort of observations that you have about the way that table tennis or those lessons feed into your daily life? I think this is true of any sport. But the biggest observation I made that I perhaps drew parallels and lessons from is that competitive sport is really about winning one match at a time.

30:48Viswa Colluru:And each match is its own journey and is one equally, I would say, in mind and strategy as opposed to skill and practice, which is why I think I got picked to be captain and coach. is because I would see these extremely talented kids that could beat me left-handed, blindfolded, not kidding. And I had a teammate who was so good, she could hear the spin. So she could receive a serve from just the sound. And all they really needed was a dispassionate but interested observer that taught them in the matter of a few points, you know, I wouldn't say teach, maybe guided them towards the particular dynamics of that matchup.

31:37Viswa Colluru:And so it was really about winning one match at a time, which is a metaphor that I really like. And each match, as you might imagine, is not about rankings or numbers. It's really about what happens on that day and your ability to win in the mind as much as it is winning with your body. And that for me is, I think, a lesson I still take to this day. David versus Goliath is not as lopsided as it seems ever. And so you bring those lessons from the table to Life at Recursion Bio, which sort of had these two sort of this tech and this bio component coming together and riding this new exponential wave that you sort of mentioned.

32:23How did that specifically become the place where you decided to spend your time? I imagine there weren't maybe that many companies even that fit that bill.

32:32Viswa Colluru:Not at all. And it was actually a wavered LinkedIn ad that caught my attention. And of course, as highly skilled immigrants that enjoyed taxpayer subsidies for advanced degree, you only have 60 days to find a job or else you have to leave the United States. So like everything else I'd been doing since my time becoming someone obsessed with trying to be successful in this domain. I spent a lot of time researching companies and jobs. And I think somewhat ironically, this one fell in my lap. It had the most interesting story. And I would go on to Marvel, continue to hold my fascination for technology during this time, which had taken the form of smartphones, which were half a decade ahead of my life in India at that time.

33:22Viswa Colluru:That's no longer true, but it was back in the day. And my Samsung Galaxy, whatever, S13, had a facial recognition program that was actually not bad for that time. And with no pre-training on my face, you know, and just a couple of photos, half the times it unlocked my phone. And I recognize that that belie a deep improvement in processing and algorithms, specifically of visual data and pixels. And what recursion was doing was effectively facial recognition for cells. And I could grasp that very early on in even, you know, their job ad and the videos that Chris and others had on YouTube. And I said, wait a minute, this sounds really cool because the way that the industry was at that time obsessed with treating disease and to some extent still is, is by mapping out molecular underpinnings and figuring out what genes may be causing a particular disease.

34:22Viswa Colluru:But no one was asking, hey, what does that do to a cell? And can we somehow generate very interesting, believable, underwritable patterns and correlations in biology that were not driven by a priori theoretical explanation? And that, for me, was very interesting. And the way that recursion in its original form wanted to use that technology was also very, very elegant, which is normally you have this massive body of literature that develops over decades that reaches a tipping point about how you think a disease works. And then you create a drug for it by trying to manipulate one node or another.

35:06Viswa Colluru:But rare disease patients and rare diseases, which are in the thousands, so there's about 5 ,000 to 7 ,000 diseases that are caused by mutations in a single gene. And they're rare, like teleologically, they're rare because most genes are conserved for a reason. And if you lose their function entirely, or if you gain too much of it, then it becomes toxic in utero, right? But there are small, like about a fourth of the genome where you can have some loss of function or gain of function where you can still be born and you can be, you know, usually somewhere between sick and very sick. And these diseases, while the genetic cause is known, there's not enough of a body of literature that's been built up because the interest and the funding isn't there for you to take an approach and say, you know, I'm actually going to study this one pathway that I think is dysregulated because of this gene.

36:01Viswa Colluru:And so this ability to shortcut But through facial recognition of cells, the study of rare diseases in a way that can be directly applied to drug discovery felt, you know, deeply intellectually satisfying and impactful to me. Because those patients most, you know, go through a very long journey to even be diagnosed, only to be told there aren't medicine. And so it was a very easy bet. And I would be the first hire that I think Chris claimed at that time that he didn't personally interview. And so I'm very glad that, you know, he found me up to the mark after he came and saw me. He was away traveling at that time.

36:41Not just up to the mark, because he writes such a phenomenal parting post when you left a few years later.

36:48Viswa Colluru:I think that says more about him than me. Well, I don't know if I've really ever seen that happen before. So it says something about both of you, probably, that, you know, a CEO goes to the trouble to write about what it was, a departing outstanding employee or something like that. I think I'm happy. I'm happy that I was on the ride at that time. But, you know, he's an incredible, incredible founder CEO. What did you learn from him? Like what, you know, are there things that you take from the recursion time into your operating today? Absolutely. And I wrote a unpublished letter in response to that and shared that with my colleagues at that time.

37:24Viswa Colluru:And, you know, I think I made a few salient points then, but two that stick out to me today here on this couch. One is I saw the way that Chris operated with a sense of urgency. You know, for example, we had, I think, a partner visiting a tiny office, which was about twice the size of the studio at that time. Or we had a bunch of new employees joining the next day and all the desk needed to be rearranged. So he just, you know, came after he came back to the office after five o 'clock and he was like, hey, whoever's here, we're just going to move the furniture ourselves. And we just rearranged all of it.

38:05Viswa Colluru:And I was like a week into my job. Yes. And I didn't know what corporate life was, you know, how a CEO was supposed to behave. And thanks to Chris, I never picked up any bad habits. You know, I'm still happy doing everything from the now famous Jensen quote of cleaning toilets to like moving, you know, furniture, which I actually saw Chris do. So that was maybe one thing is this bias towards action and the action being urgent by default. The second is, I think we was very clear that not only the application of AI, but this unbiased discovery of new hypotheses that may not be treading well-erected goalposts was very different from how the industry thought.

38:55Viswa Colluru:And it required a lot of courage. And I would spend my first part of my career there really trying to sell the recursion approach as the first platform product manager, probably first product manager in tech bio at that time, which I dubbed as connecting the creators to the customers, right? Selling that to Pharma and being essentially the victim of many blank stares. And I think this idea that, you know, if you believe in something from first principles, it is completely okay being misunderstood was maybe something, another dimension of courage relative to what my mother showed me that I picked up at that time.

39:41This episode is brought to you by Persona, the B2B identity platform helping businesses verify users, fight fraud, and build trust. Fraudsters are already using AI to spoof faces, voices, and documents. So your defenses need to adapt just as fast. Persona helps secure some of the internet's largest and most trusted platforms with identity verification. If you're building a product where trust matters, identity should be a priority. You've probably already experienced Persona without realizing it, verifying your LinkedIn profile, signing up for Etsy, or renting a scooter with Lime. Trusted by leading companies like Square, Brex, and Twilio, Persona gives you the building blocks to create identity flows that adapt to your customers, risk tolerance, and locales you operate in, whether you're verifying age, onboarding businesses, or automating KYC.

40:30It's fully configurable, so you can launch in days, not quarters. Want to see for yourself? Generalist listeners get a free year of the starter plan. Head to withpersona.com slash generalist and check it out.

40:44Viswa Colluru:How did you know it was the right time to leave? Had the idea for your own company visited you at that point? Yeah, I mean, I was having the time of my life at recursion. I would go on to make incredible friends, many of whom are now at Enveda, luckily. And I did not want to leave at all. But I realized during my time at Recursion that there's really only one problem in biotech. It's drugs that work in the lab don't work in people. And because my job was to create landscapes of where the industry was evolving and where recursion technology platforms sat within that view, I made a striking observation that 100 % of our collective human effort to solve that gap lie in the biology bucket.

41:37Viswa Colluru:And this was interesting to me because we had medicines before we had biology labs and before we even had molecular biology as a formal scientific field. And that was simply by focusing on interesting chemistry. Our ancestors walked the Silk Road, drank the milk of the poppy, realized that that soothed their ankles and their feet, and that they could sleep a good night's rest after drinking that. That allowed us to discover opioid biology, gave us morphine, understand how pain works, and till today, have really the only solution for breakaway pain. And for me, that was interesting going back to my roots, where as a South Indian boy, I had my friends, family, mother, grandmother give me herbs whenever I was ill, you know, like that ginger I had this morning.

42:33Viswa Colluru:And it struck me that there were many other morphines, aspirins, artemisans to be found, Nobel Prize winning, disease busting, you know, billion people treating medicines. that where a large section of society somewhere on this planet would be unsurprised by that discovery. And so I started asking the simple question, if things that work in the lab don't work in people, and hundreds of millions of people believe in something working in people, doesn't that warrant a second look? I didn't know it at that time fully, but I would go on to recognize that that was how the industry started. And this was an unfinished idea.

43:17Viswa Colluru:Like immunotherapy, like AI drug discovery, it was an unfinished idea. And I just didn't quite know at that time how unfinished, but I knew enough to know that, you know, I knew of several plants just off the top of my head where I've experienced, you know, their effects. And I know that millions of people would be unsurprised if there was a modern medicine found, but we weren't paying any attention to it. So that became the precipitating, I would say, realization and maybe the observation that no one was doing it. Not only was no one doing it, when I tried to find out why no one was doing it, I uncovered a tremendous amount of stigma.

43:59Viswa Colluru:And that stigma was rooted in past failure, which I was actually leaning towards, not away from. And that stigma was essentially misconstruing absence of evidence as evidence of absence. And, you know, it would have perhaps discouraged me if not for the fact that around that time, as I was thinking through this idea, there was a company called GW Pharmaceuticals that had gotten the first novel anti-seizure medication approved in a very long time. And it was nothing but a purified form of the cannabis extract with essentially one compound called cannabidiol. It was non-psychoactive, but it was tremendously neuroactive.

44:42Viswa Colluru:And if you trace the origins of the cannabis plant, I think there's a 2 ,000-year history of treating symptoms of what we now recognize to be seizures. And so there was this massive section of the world that was like, of course. And that company would go on to get bought for$7 billion. and they didn't even change anything. All they did was they generated the evidence. And so I said, given my background, given my training and naivete, given my roots and my desires, that I was perhaps the best champion for this idea because I couldn't find another one. Yes. And I said, if I don't do this, I'm going to regret it for the rest of my life.

45:28Viswa Colluru:and I didn't quite frame it as elegantly as Jeff Bezos, but I knew that if I let that moment pass, I may never do it again. I never have the opportunity to do it again, and that may end up being one of my biggest regrets. You mentioned that all of this energy is focused on the biology and that maybe the industry didn't start that way, but that's where it was when you found it. For folks that aren't familiar, why did it evolve in that direction and why has it been so hard to move it away from that? You know, I think the scientific method in general biases towards breaking things down and simultaneously calling them fundamental.

46:09Viswa Colluru:For example, I think if you go visit CERN, the word fundamental is thrown around almost on every billboard inside the museum and even formal writing explaining science to you because they think that they're studying things that are so small that they make up everything. And I think biology has been a victim of that broader scientific movement. And I think anyone that lives life and observes it recognizes that almost everything that matters is emergent. Consciousness, your lived experience, disease, even obesity, something that's simply the accumulation of fat, is as much a disease of fat tissue as it is a disease of the brain and the gut.

46:52Viswa Colluru:And I think that broader movement edged the currents of biology, number one. The second is at the turn of the millennium, the molecular biology revolution had reached its zenith. So our ability to sequence genes and all of a sudden correlate mutations in genes, these were called massive GWAS studies, genome-wide association studies. And if you look at papers in the 2000s, that was what the most exciting labs were doing. And it was, for the first time, sequencing hundreds and then thousands of people and saying, oh, look, this gene here has a number of mutations that either protects from or predisposes you to this other disease.

47:39Viswa Colluru:And so it became very elegant to say that a single gene was responsible for something. And there are, like any good distribution, I think complex diseases that can be either treated or ameliorated by a single effector. And this became sort of the dominant way of thinking. But I do think that is also a result of technology. We invented a sequencer for genetics. And so that became the most voluminous form of data. And this data, I think, both became highly amenable to the scientific zeitgeist of trying to reduce problems down to really simple things. And I think the human predisposition towards correlation.

48:27Viswa Colluru:We love, our brains were wired for correlation, not truth. We're like, oh, I see a pattern behind in the bushes, that must be a tiger, right? And so I think these two things made it so that we said, oh, wait, most disease can and should be caused, and if not caused, at least treated by a single chemical or now, you know, other modalities like RNA that allow me to tweak this one protein, which is expressed in this one tissue or is expressed in the diseased tissue of interest in order to cause this balance between benefit and risk. And if you think about it from an evolutionary perspective, going back to genetic diseases, the lesson lies right there that most of these genes and proteins exist for a reason.

49:15Viswa Colluru:So perhaps completely ablating their function is walking a very tight rope physiologically, which is what we go on to find out. And because so much of life is emergent, life exists essentially to turn your breakfast into you, to make energy cycle and matter flow. or the other way around. And all of that happens through a deeply coordinated symphony. And so symphonies are rarely one protein shows, right? Or one musician shows. And I think that is, those are the things that are driving some of the low success rates that we see today. So we have, I think, a rich shape of the problem here of, you know, all of this energy directed through one paradigm, stigma, where people, you know, are sort of maybe looking down at saying, take ginger for this or take willow bark for this.

50:09And then, you know, this evidence of, or this absent evidence. Did you have a shape in your mind of a solution at that point?

50:16Viswa Colluru:For me, it was very simple. As Charlie Munger says, you know, take a simple idea, but then treat it seriously. I just wanted to say, look, if there's hidden chemistry, that's interesting, it is not the first time that chemistry would teach us biology. So you mentioned the willow bark, which gave us the molecule that would go on to become aspirin. We didn't find aspirin because we studied inflammation through and through. In fact, the study of aspirin taught us about inflammation. And that same pattern holds true for rapamycin, teaching us about metabolism and then eventually immunity and aging.

50:52Viswa Colluru:It also holds true for warfarin, which comes from the University of Wisconsin, stands for Wisconsin Alumni Research Foundation, WARF, where a Wisconsin farmer made observations that would give us a blood clotting medicine that was the mainstay till about half a decade ago, where warfarin taught us about the role of vitamin K in blood clotting, not the other way around. And I said, it wouldn't be the first time that we learn biology through chemistry because this chemical pool that nature has made is deeply evolutionarily selected for activity. And so there's a reason that molecule exists in that shape and form.

51:28Viswa Colluru:And understanding how it mediates its function in a biological system has on average given us a Nobel Prize every other year. We make a big deal of the AlphaFold Nobel Prize and a big deal of the CRISPR one, but discovering vitamin D, for example, which was the active form was discovered at the University of Wisconsin, led to a Nobel Prize. Discovering cholesterol led to a Nobel Prize. Like understanding how plants make cholesterol, make their equivalent of cholesterol and how humans share that biosynthetic pathway, I think was another prize. Yeah. So this for me was very interesting. Going back to things that work in the lab don't work in people.

52:08Viswa Colluru:Let's just start with things that work in people. That requires us to put chemistry, not biology, back at the center of the process. Those were maybe like the three legs of the stool. Okay. Okay. And so you set out to do this new business yourself. I think you raise a very small pre-seed round to do something this ambitious. $225 ,000, right? That's right. And the first check-in was mine, which was the entirety of my life savings, which was$55 ,000, which felt like a tremendous amount of money. By that time, I had out-earned my father his entire career. So it did feel like an incredible amount of money.

52:44Viswa Colluru:But yes, it was a very small amount for a biotech. How did you get to the stage that you needed to get to to get this off the ground? Winning one match at a time. Yeah. It was very clear to me that, you know, I was just going to always have to out execute what people would expect in order to get the capital needed to brandish an old idea. You know, new ideas are hard to sell, but old ones even harder. And so very practically, it became very clear that the kind of answers I would need to provide to people's latent questions were, are there interesting medicines to be found? Interesting defined as potent for big markets, right?

53:28Viswa Colluru:in this overlooked area of chemistry. No matter what layers of priors you use, whether it is ethnobotanical use, whether it's geographical diversity, whether it's chemical diversity, it doesn't matter. I think it was very clear that I had to prove that there were powerful medicines still left to be found. And what is the best way to do that without completely burning a hole in your bank account is to actually take reasonably reliable mouse models of disease where whether or not they perfectly translate to humans, they allow you to benchmark against existing medicines. So I took some of the biggest markets, pain, neurodegenerative disease, inflammatory disease, and I said, even though I may not find the precise molecule like the salicin in the willow bark, can I at least prove that this mixture of compounds has efficacy through unique mechanisms that beats existing standard of care in efficacy or safety or convenience, which are the three things you really care about in terms of product attribute.

54:34Viswa Colluru:And I said, there's no way you can generate, you know, mouse studies in these big conditions with a quarter of a million dollars. The only way you can is if you own the vivarium. Because I just, you know, pulled out a scratch pad and did the math on how many mouse biologists I would need, what these chemicals would cost to induce the disease, and then what the plant extracts would cost. And the math wasn't adding up to what I was being quoted by CROs. I was being quoted 150 ,000 US dollars to do a single study. And so I said, wait a minute, like, you know, what if we just somehow did this ourselves?

55:11Viswa Colluru:So I got on a 40 hour economy flight to India, you know,$700, and interviewed multiple people I had cold messaged on LinkedIn in hotel lobbies. Many folks didn't respond. and then many of whom did didn't show up because they're like, wait, are you a real company? Why do you want to meet me in a coffee shop or a hotel lobby? That's not the culture in India, but ended up finding, you know, three brave, intelligent souls that said, you know, find us a lab and we're in. And through a funny twist of fate, after looking at multiple cities, I would find Enveda's first home a kilometer and a half from the home we were living in when my mother who first got diagnosed with cancer.

55:53Viswa Colluru:And it was a bunch of ex-U.S. trained biotech entrepreneurs that decided that India needed a strong biotech ecosystem and started a lab, and we would be their first tenant. So$150 ,000 is the sticker price. What did it end up costing you to do, let's say, one of these studies? We did about 10 studies with that money. Wow. I'm sure it's a parallel you're familiar with, but it reminds me so much of the story where Elon Musk gets quoted the sort of first prices on the rockets, and then he's on the, you know, the plane ride home with his spreadsheet and figuring out, you know, this doesn't make sense.

56:27I can do this myself. Okay, so you run these 10 studies. How does the, you know, to sort of bring people into that process, how do you then sort of whittle down towards the one and now maybe two things that you've really ended up focusing on?

56:41Viswa Colluru:Yeah, the short answer is like, you know, we would go on to develop now what I think is over 18 candidate medicines. Three things in clinical trials. Got it. But initially, the idea was to just show the breadth of what this could do. And we found in very obvious places that didn't take a lot of complex reasoning in the first order, potential medicines that could improve immunity against cancers, against infectious disease that doused inflammation, that improved pain responses, and that improved memory. And these were some of the big problems facing the medical field today. And so the question really was, okay, if we have this substrate that's hidden in these plants, the big bet we're taking is that a majority of that could be reduced to a single compound.

57:36Viswa Colluru:And that felt like a reasonable bet given the history of the field because plants make a lot of similar compounds because if effectively plants don't have an adaptive immune system, as one of my favorite authors of these reviews had once written, plants can't stand up and walk away from a problem. So they have to produce all potential solutions to future problems. And so they make a lot of interesting chemistry. And just like you make a lot of interesting T cell receptors for all future viruses, plants make a lot of chemistry to modulate everything from the bees that pollinate them, you know, to the herbivores that eat them, to the humans that they either want to attract or not attract.

58:16Viswa Colluru:And so it was a reasonable bet, in short, to make that, you know, we can find a single exemplar chemical that would reduce that molecule. But the question was, how? So that was a big question, which is, how do we find the needle in nature's haystack, quite literally? And the two things that you need to kick off a drug discovery campaign is the structure and the function. And if you can do that and say, oh, I actually want to find the one compound in here that's anti-inflammatory or neuroprotective, how do I do that? How do I find the functionally active piece? And how do I find the structurally attractive piece?

58:53Viswa Colluru:Those are the two things. So natural products or this, you know, history of looking within nature to find medicines has historically yielded tremendous successes, but it was unreliable when you considered the fact that many compounds that start off from nature end up not having the properties to make a good medicine, at least how we define it in modern times. And so how do you make this serendipitous endeavor systematic? And that is to be able to quickly weed out the ones that will fail, which means we need to find the structure and function of all of the molecules in that leaf in order for me to quickly say which one of these may one day be the next aspirin.

59:33Viswa Colluru:And if you take too long to find out the needle, then you may say, oh, I actually ended up with a strand of hay. It's the wrong structure. It's one that I don't think I can ever manufacture stably, or it's the wrong function. What I thought was active is actually not quite active. And the reason is that nature doesn't make individual compounds in neat vials. It makes thousands of molecules in one mixture, essentially. So that was the how piece. The where piece was also interesting. There's 400 ,000 terrestrial plants, I think, as defined by the Royal Botanical Society in terms of species. So how do you look, right?

1:00:10Viswa Colluru:And where do you look? So for us, it was very simple. We said different cultures must have all used plants that are similar. Let's find plants that different cultures used for similar symptoms. And we actually published a paper showing that, you know, the statistical likelihood that two plants were used for similar symptoms is actually fairly high across different traditional medicine systems and benchmarked against randomness, the odds are extremely low that that would have happened. And so that was the two simple things that we needed to figure out is, what are the best plants if I want to treat pain, for example?

1:00:48Viswa Colluru:And once I know what those are and I know they're active, how do I find the needle in the haystack, which means annotating the structure and the function. And this problem had a parallel that we talked about, which is sequencing. So genetic sequencing allows you to take any sample and ask what the genes are and what they do by quickly identifying, you know, what one nucleotide does relative to the other, right, where it sits in the sequence. So we had to essentially build a sequencer for life's chemistry instead of life's genes. And that was the definition of the problem that I would take maybe about a year, year and a half to figure out.

1:01:26Viswa Colluru:Wow. Yeah. And so just to sort of put a finer or rather maybe even a coarser, uh, rougher version of this, you're, you're looking, you know, saying people in China for centuries, millennia have been using this plant for pain, pain management. People in, uh, you know, Peru have been using this. People in Europe have been using this. What is sort of like the, the, the connective tissue here? What's the unified, uh, function and structure and what can we learn from that such that we can then maybe hone in on something? Yeah. What are the common chemicals between those related plants? And then you say, great, like, let me go take, test them out and explore the chemistry of those plants more fully.

1:02:07Viswa Colluru:So fun fact for you, you know, in an average sample, we only know one in 20 compounds. And, you know, if you think about the fact that 2 billion people will eat a tomato today before the sun sets. Yes. Right. The fact that we know approximately one in four compounds for a tomato, which is one of the best studied plants, is crazy. And, you know, we know maybe one in 10 compounds in human blood. So we know more about the genes of random viruses from the bottom of polar ice caps, literal study from 2024, where scientists went to Antarctica, took advantage of the thawing permafrost, sequenced ancient retroviruses, and they were able to map those genes contained in those genomes about 30 % of the time.

1:02:52Viswa Colluru:And if you take human chemical signal from blood, which should be the most studied matrix in the world, you end up with 10, 15 % of the masses actually being annotated. And our scientific co-founder, fun story if we go into that, the godfather of computational metabolomics, has, I think, in the last two, three years alone, doubled the size of the known human metabolome, which is essentially the chemical code that you produce as a result of metabolism, converting your food into you, and discovered hundreds of thousands of new compounds. Wow. Right. And so there's so much where this comes from, going back to my comment earlier of me not knowing how unfinished this idea was, how much of the world's chemistry was unknown and why that is deeply interesting.

1:03:41Viswa Colluru:Yes. And so how many to try and sort of understand the quasi pipeline here? How many of these plants did you have to look at to get to 18 candidates and three in trials? You know what's funny is that the first chunk of those, maybe about a dozen, came from us studying less than 80 plants. Wow. So there's really was good actual sort of the intuition or the sort of historical knowledge was there that you could target. And that it was very rich. There was a lot of not to push plant metaphors here, but low hanging fruit. And the best part is we don't see that running out anytime soon at all. So this was very interesting and very exciting for us as we saw the fruits of our labor.

1:04:28Yes, there you go. And so the three sort of leading products so far, maybe you can talk a little bit about those and how advanced they are and what you hope to see over the next few years.

1:04:40Viswa Colluru:So we didn't anticipate this, but the sheer volume with which we could find interesting molecules and turn them into medicines now about four times faster stable state. So a year in finding a first chemical hypothesis and finishing all of the studies required to call that a candidate and about 10 times cheaper. So about a million dollars instead of 10 to 15 million was something that would emerge naturally. So we didn't ever shoot for volume. We just wanted enough shots on goal that does justice to the idea on a risk-adjusted basis. This sheer breadth and depth of the pipeline would be something we would just come to enjoy as we realized that nature had done a tremendous amount of pre-work in making these molecules essentially compatible for life, for safety reasons, and then having utility for efficacy reasons.

1:05:36Viswa Colluru:So with that as background, it was very clear to us early on that, you know, one of the big things we're going to have to solve is inflammation. And early on, you know, we knew there was lots of ways we could target this, move it to different diseases. But as the market turned, and it became clear that, you know, the industry was moving towards medium-priced drugs for a large disease. So think obesity. And if you were paying keen attention to the trajectory of chronic diseases, it was clear that this was where the market was heading, especially if you were inside. And so we said, great, let's target inflammation, let's target a chronic disease, and let's target a big pain point.

1:06:19Viswa Colluru:And so one of the biggest inflammation diseases that has an open pain point is eczema. 25 to 30 million adults in the U.S. alone. And if you have anything but mild disease that requires what we call advanced therapies, you're stuck between a rock and a hard place. The rock is you can take medicines called JAK inhibitors. You've probably seen television ads if you visited America recently for drugs like RINVOK. They're called JAK inhibitors. And they're oral pills that are very effective. But they're the sort of things that require consistent lab monitoring, and they could put you in the ER. And dermatologists don't like that because they enjoy the only medical specialty where they don't need to go to the ER.

1:07:01Viswa Colluru:Have you ever seen a dermatologist in the ER? No. And so it's hard for the patients. It's not something doctors care about. It does work. And the rock was you can take drugs like Dupixent, which are injectables, which are biologics like Humira was for rheumatoid arthritis, and they work really well, but you also have to inject yourself frequently. And if you have skin as your primary pain point, then injecting yourself becomes something both physically and psychologically burdensome for patients. And so today, Dupixin only treats about 900 ,000 patients, I think, in the US, and still registers over$10 billion or so in revenue from that single disease.

1:07:40Viswa Colluru:So we recognize delivering a safe oral medicine for a disease like eczema, which could also extend into similar diseases like asthma. They're all called atopic diseases. There hasn't been a non-steroid approved for asthma since Singulair, which was 20 years ago. So we said this was a big market. And so we took one of the plants that was used to treat symptoms of atopic dermatitis and asthma, or diseases that we now call those things, and identified a potent anti-inflammatory molecule and showed that it worked via mechanisms that we didn't quite understand, but had the efficacy of a JAK inhibitor, which is like, you know, those medicines that have the black box warning that could put you in the hospital, but didn't seem to have any of those liabilities and could be given once daily orally.

1:08:30Viswa Colluru:And so this became our first program. And we would go on to, you know, spend a lot of time understanding its unique mechanism, unique molecule, put it in patients, see that, you know, the safety was pristine, at least in early phase studies, we did a pet dog study because pet dogs are the best model for human eczema, and they have 100 % positive predictive rate for novel mechanisms. And in the pet dog study, we noticed that they had the efficacy of a JAK inhibitor, which is the best, most potent drug we've made. And we recently talked about this publicly, but in our first patient study, which was small, nine patients, we actually ended the trial early due to the extent of efficacy we're seeing.

1:09:14Viswa Colluru:by some measures, we actually exceed a JAK inhibitor while still retaining the safety profile of a Dupixent injection, if not better, on both accounts. And so it's been a fun journey and goes back to my first crystallized idea, which is there are millions of people that would be unsurprised by this discovery. In fact, our chief medical officer is married to a Maliali woman. And when he was making a slide deck around this plant and first talking about the release of our data, he was putting a picture of the plant and his mother-in-law came. And she was like, oh yeah, like that plant was in our garden.

1:09:54Viswa Colluru:And we used to drink it when we had fevers and, you know, we had difficulty breathing or we used to make it into a bomb for skin rashes. And here we are today. And so what needs to happen now from, you know, these effective dog studies, this nine-person study. What does that pathway look like before you can really start to have it out in the open? We are in two phase two studies right now, and drug discovery and development usually goes from phase one for safety, phase two for a balance of safety and efficacy, and for you to figure out the right dose. And you do a phase three study. Sometimes you have to do two.

1:10:28Viswa Colluru:We'll see where the FDA lands on this. They're changing their tune. But you do large phase three studies to prove this benefit risk reward ratio for patients. And we expect to finish our phase two studies this year and the next and our phase three studies in the year or two after that. So we want to get this medicine to launch, you know, within this decade. Yes. And that would be huge. We think it is the second biggest consensus market in the world today is a safe oral for inflammatory diseases. The biggest one, of course, is obesity. Yes. Which is our second drug. And so, yeah, Yeah, maybe we can talk about that one's maybe still in phase one.

1:11:06Viswa Colluru:That one is in phase one as we speak. We haven't said much about the mechanism publicly, but what is very interesting is that it represents an evolution of our platform. I planted the seeds in this conversation, but, you know, most of human blood is unknown. And while we're all excited about peptide hormones and, you know, everyone has their peptide guy, nature's made hormones in two forms. and that is small molecules like melatonin, testosterone, estrogen, and peptides like GLP-1 and insulin. And everybody can identify, you know, peptide fragments floating around in the blood because they rely on traditional technologies of identifying in a mass spectrometer a peptide fragment and then just matching it to the DNA because all proteins come from DNA.

1:11:54Viswa Colluru:But you would need the Envada platform, which figures out how, you know, molecules break apart in a mass spectrometer to identify the structure of unknown molecules to discover new chemical hormones. So we said, why not discover new chemical hormones? And in the last few years, we've identified over four dozen new or interesting chemical molecules that seem to regulate different disease states, including everything from pain to feeding and satiety. So we turned one such hormone that's regulated after exercise and after eating that your body produces and said, what if we turned this into a medicine for obesity?

1:12:36Viswa Colluru:And what we would go on to find out is that it modulates this really interesting signal in your brain called the leptin system that tells you when you're full. So just like insulin has two types, you have type 1 diabetes when you don't have insulin and you have type 2 diabetes when your body stops listening to insulin, leptin is very similar. Initially, it was discovered in patients that had a rare genetic form of obesity where they ate a lot because they didn't have any leptin enzyme. But most of us today are walking around with way too much leptin, like type 2 diabetes, like type 2 obesity, where your body doesn't recognize the leptin signal anymore.

1:13:16Viswa Colluru:And so we're very excited to maybe make perhaps one of the only, if not the first, molecule to go into humans with this mechanism. Given the interest in that space and also the level of competition, what is the rock and the hard place that you see there that you're trying to sort of find the sweet spot on? So today it's become very obvious that GLP-1s, for one reason or another, do not provide a long-term solution. There was a study that came out, I think, literally this past week where they looked at over 3 ,000, if not 30 ,000, thousands of adults that had access to$11 copay GLP-1. And they traced cardiovascular risk and overall treatment adherence.

1:14:04Viswa Colluru:And, you know, their study also found that the vast majority of people start dropping off, you know, in month three, six. And by the end of the year, they're off treatment, even though they can afford it and have access to it. And that when they do, their cardiovascular risk comes back to make it worse than before. Wow. So you have to use it for three years, I think they said, to have an 18 % cumulative risk in cardiovascular events. But if you stop using it at the end of year one, you start reversing that and you actually end up in a worse place where you have 4 % or 5 % greater risk of cardiovascular events.

1:14:40Viswa Colluru:So two takeaways. People are stopping for one reason or another. Because it's injections primarily? Probably injections. There's some degree, maybe even outside of this cohort of affordability, but it's likely a combination of both of those and the side effect profile. Yes, right. The side effects don't really go away. And in fact, every time you dose escalate, you feel them. But over time, people have reported everything from either not responding at all, despite having the side effects, to the response essentially going away. So you have this combination of factors that make the drug not something sticky, right?

1:15:15Viswa Colluru:And not being sticky could be worse off for you than not starting in the first place. So those are the two big takeaways. Now, if you study chronic diseases that have a similar etiology that we all know, and if you're South Asian, have multiple relatives that suffer from, it's two other diseases of a similar scale, magnitude, and time mark. It is high blood pressure, right? And high cholesterol, Hypertension and hyperlipidemia. Now, both of those are treated not by a highly effective pill that has a deep side effect profile or an injection. They're treated by a safe once daily oral that your doctor can start you on in somewhere on year two or three of your five-year journey of having high lipids, right?

1:15:58Viswa Colluru:And so we think that as much as GLP-1s are extremely exciting, they play a very perfect role for induction, which is you make a fat person less fat. But there's a big arc of time where you need to keep that person not fat for a long time. Or ideally, you would have caught them before they become BMI 30 or 32, and you give them something that allows them to stay on it for a long time, right? Like you take your statin before you have an atherosclerotic vasculature, and that leads to a stroke or a heart attack. So two years ago, we said what the world needs is a once daily oral that's complementary to GLP-1 that has an extremely low side effect profile that allows preservation of muscle and does not cause nausea, vomiting, or diarrhea.

1:16:49Viswa Colluru:And so we went and made that. Ben, it was, again, not cool to do that. And today we're very, very glad we did. We're reaching the end here, but perhaps very briefly, you can tell us a little bit about what this third sort of advanced candidate is, and then maybe a little bit about what you hope the next 10 years look like. What does Invada look like in 2036? Absolutely. So our third candidate very quickly comes from a plant. Long history of being used to treat symptoms of what we now know as ulcerative colitis. We went after a very interesting inflammatory pathway, and long story short, discovered a once-daily pill, similar rock and heart place to atopic dermatitis.

1:17:29Viswa Colluru:But we discovered a once-daily pill that puts the power of three different biologic treatments in a single pill. And the story of how we discovered it, why that mechanism allows you to inhibit what it otherwise takes three proteins to do is a story for another time. But again, putting safety, efficacy, and or convenience in the hands of the patient is very, very important to us. And we think this treatment could be very exciting because in ulcerative colitis and Crohn's, you eventually develop resistance. And so it's this never declining pool from a market perspective, but it is very, very, I'd say, troublesome and challenging if you're a patient.

1:18:11Viswa Colluru:Yes. Because you have to cycle off of therapies and eventually you run out. Ah, wow. So instead of, you know, we think by putting multiple therapies and those mechanisms in a single pill, we'd be able to both cause deeper remission, but longer remission for patients. And that's in phase one studies, and we're very excited about what it'll do. Wow. So big diseases, first-in-class medicines, which is the opposite of where the industry is heading with China, which is to make slightly better medicines or combine two really well understood biologics in a single pill or a single biologic called bispecific.

1:18:44Viswa Colluru:Very different take on the industry. Ultimately, we think the industry is underwritten by convenience, but is transformed by innovation. GLP-1 was a new mechanism when it came by. And there are many, many, many stories. Imatinib, so the medicine that changed my mom's life, was a new medicine. And it's usually these first-in-class medicines that end up changing the world. And in a parallel to venture capital, it is companies that have these first-in-class medicines when they were first invented that end up capturing the vast majority of the life cycle of the return and becoming big enterprises.

1:19:25Viswa Colluru:So Merck with Keytruda, 30-something percent of Merck's EV. Sanofi with Humira and now Rinwok, I think combined 60 percent, Skyrizi. Sanofi with Dupixent, 30 percent even though they only own half the drug. Lilly is a trillion-dollar company, but 80 percent of their EV is Monjaro. These were all medicines that were written off, both mechanistically and for the market. Lilly, I think, famously at one point said obesity was$100 million market, not$100 billion market. So they were off by a thousandfold. Okay, so we think first-in-class medicines, especially if you can look beyond where other people can look and you can use chemistry to get to them, is an incredible place for 10x returns, 1 ,000x returns, power law returns.

1:20:12Viswa Colluru:We also think that you can realize these returns only if you end up owning these medicines. Right. The Dutch company that sold Humira, nobody knows of them. You know, the tiny startup that made Keytruda that eventually ended up at Merck, nobody knows of them. Large pharma can afford to miss the boat on innovation, as once someone told me, because they just buy the boat. So it's very clear to us that we need to be an integrated pharma company and we need to work on mega blockbuster markets. As long as we believe our thesis and our technology can deliver products that can create those markets. So over the next 10 years, Enveda hopefully becomes a company with multiple incredible molecules on the market and create markets.

1:21:02Viswa Colluru:Like imagine the remaining 20 million adults that will use their atopic dermatitis medicine because it's both convenient and it's efficacious. And so molecules that make markets and then we'll let the, you know, the forces of capitalism do the rest and hopefully use that to both preserve and respect culture and preserve and respect the fragile environment in which we live and create the incentive and the narrative to do both. Well, I always like to end with a sort of final wrap up question. If you had the chance to assign a book to everyone on Earth to read and understand, what would you what would you want to give people?

1:21:42Viswa Colluru:For me, that would probably be the vital question by Nick Lane. And Nick talks about this incredible black hole that lies at the center of biology, which is why is complex life the way it is? And he makes a very compelling argument that it is not genetics or information flow, but it's actually energetics and the flow of electrons and electrochemical gradients that dictate how complex life evolved. And so I highly recommend that. That's a new recommendation for the podcast. So I'm always glad for that. Thank you so much, Bispo. This was such a pleasure. Thank you for having me, Mario. That's it.

1:22:22Thank you for listening to this episode of The Generalist Podcast. Please subscribe on Apple Podcasts, Spotify, or your preferred podcast app. Ratings and reviews help others discover these discussions. So if you enjoyed the conversation, I'd be grateful if you could take a moment to leave one. For all past episodes and more, visit us at thegeneralist.substack.com. See you next time as we continue to explore the future.