#495 James Peyer on Longevity and Curing Cancer

James Peyer, PhD is the Founder and CEO of Cambrian Biopharma, a Distributed Drug Discovery Company developing therapeutics targeting the biology of aging. Cambrian builds, finances, and manages a pipeline of therapeutics. In this conversation, we discuss the nine hallmarks of aging, molecular damage, how to add healthy years to your life, prevention vs reversal of diseases, and distributed drug companies. ======================= Exodus is an absolute game changer in the crypto wallet space, and we’ve teamed up to offer an exclusive discount for you, as listeners of the podcast. Sign up for Exodus today using my promo code http://exodus.com/pomp This is a no brainer for both newcomers and crypto heavyweights - go sign up today. ======================= With over 5 Million users, Crypto.com is the easiest way to buy, and sell over 90 cryptocurrencies. Download the app at Crypto.com and get $25 with my code: POMP. When it’s time to spend your crypto, nothing beats the Crypto.com Visa Card, which pays you up to 8% back instantly, with no annual, or monthly fees to worry about! Get $25 when you download the Crypto.com App today using the code “POMP” ======================= Download the top-rated DraftKings Sportsbook app NOW and use promo code POMP when you sign up to Hammer the Over on Sunday night’s basketball game when LA takes on Denver. For every ONE THOUSAND people that bet the over in Sunday’s game, the line will decrease by one point. Yes, this is your2 chance to improve the odds of the over hitting, so tell your friends and family, this is a team effort! Hammer the over and improve your odds of doubling your money. That’s promo code POMP.… for a limited time, only at DraftKings Sportsbook! =======================

• 0:02Speaker 00

  What's up everyone, this is Anthony Pompliano. Most of you know me as Pomp. You're listening to the Pomp Podcast, simply the best podcast out there. Let's kick this thing off. James Pyer is the founder and CEO of Cambrian BioPharma, a distributed drug discovery company, developing therapeutics targeting the biology of aging. Cambrian builds, finances, and manages a pipeline of therapeutics. In this conversation, we discuss the nine hallmarks of aging, molecular damage, how to add healthy years to your life, prevention versus reversal of diseases, and distributed drug companies. I really enjoyed this conversation with James, and I hope you do as well. Before we get into the episode, though, I want to quickly

• 0:44Speaker 00

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• 1:27Speaker 00

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• 2:10Speaker 00

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• 2:49Speaker 01

  Anthony Pompliano is a partner at Morgan Creek digital all opinions expressed by pomp or his guests on this podcast are solely their opinions and do not reflect the opinions of Morgan Creek digital or Morgan Creek Capital Management you should not treat any opinion expressed by pomp as a specific inducement to make a particular investment or follow a particular strategy but only as an expression of his opinion this podcast is for informational purposes only

• 3:20Speaker 00

  all right guys bang bang I've got a very special treat for you today about James here thank you so much for doing this

• 3:26Speaker 02

  um thanks for having me this is gonna be fun

• 3:29Speaker 00

  absolutely let's just jump right into your background we're gonna talk about all kinds of crazy stuff today but I just kind of give people context in terms of what you've done previously and kind of what got you into the longevity space

• 3:39Speaker 02

  absolutely so yeah James Peyer I started my career as a scientist so I did a PhD focused on the stem cells in the blood worked on leukemia worked on stem cell transplants then knew that I wanted to get into drug discovery so switched consulted for some big pharma companies for a while launched a VC fund which was the first VC fund to focus on longevity

• 4:09Speaker 02

  Or to build companies around around this longevity topic. And then now for the last couple of years, we just came out of stealth a few days ago. I teamed up with a co-founder Christian Angermeyer to start this company called Cambrian, which is, we call it a distributed drug discovery company, or a disco focused on aging. I got into this space actually really early in my life. When I was a teenager, my grandfather was dying of cancer and, and I, you know, was a hotshot, kind of arrogant, know it all, and tried to, to learn whatever I could about his disease. And I came to this really depressing conclusion, which is that we were treating

• 4:52Speaker 02

  all the diseases of aging like cancer, wrong, that we were waiting for these diseases to happen to us, and only then trying to use medicines to unwind them. And that was fundamentally the wrong way to approach these diseases, that we should instead understand them, try to attack them before they appear, and only then could we cure them. And so I've been spending my entire life chasing that idea.

• 5:16Speaker 00

  So let's get into a little bit, when we talk about disease, there's a lot of people who just say, hey, we get older. Of course, that happens to everyone. I think that the conversation is changing a little bit to this idea of like aging is a disease. But I want to break down like what exactly is happening as you age, and kind of why there's a growing portion of people who believe that we can actually treat that, prevent it, delay it, you know, kind of all these different aspects. And so first, let's maybe start with like the nine hallmarks of aging. I know that you guys have done a ton of work of identifying these and explaining them and kind of elaborating on it. But what does it mean when you talk about the nine hallmarks of aging?

• 5:54Speaker 02

  Yeah. So I think this is really the right place to start. So the nine hallmarks of aging are basically nine different types of molecular damage that build up in our bodies as we get older. And so, you know, we don't just, you don't just get cancer, right? The moment, you know, it doesn't just appear. It happens over a very long period of time Different aspects of our bodies are breaking down little by little. In the case of cancer, you have DNA mutations that accumulate one after the other, creating an evolutionarily selective pressure for some cells to outcompete others until you kind of, you know, run this cycle long enough that you have this uncontrolled tumor.

• 6:39Speaker 02

  And but the the damage that starts all of that, that are mutations in our DNA that happen randomly, even, you know, in our twenties and thirties that are constantly happening way before we get cancer. And there are nine of these types of damage that include, you know, chronic inflammation that happens, you know, just more and more as we get older. Build up of aggregates like the aggregates that called that cause Alzheimer's disease. But there are more than just amyloid and tau aggregates that are building up all the time. And the machinery that machinery that we have, the recycling mechanisms for chewing up those aggregates, degrades over time as our cells and our tissues get older.

• 7:24Speaker 02

  And so there are this this group of scientists in this emerging field called gerassience, right? The study of what makes us age have mapped out way more than nine particular mechanisms, but they fall into these nine categories that we call the hallmarks of aging, which define the different types of damage. And and what we've been able to do with those nine categories, which were only kind of distilled into a single thesis about seven years ago to 2013, 2014. What we've been able to do since then is you pick one of those types of damage and you tweak it, right? Either preventing it from building up or removing it from an already aged animal.

• 8:07Speaker 02

  And we see this amazing thing happen, which is you can take a mouse, for example, tweak one of these hallmarks of aging and it just lives longer and healthier than it ever would in the past. So instead of living, you know, for a mouse like two and a half years, it's living three or more years instead. And instead of getting sick at two years, so that it dies at two and a half years, it's only getting sick at, you know, two and a half or close to three years. And and that Change is fundamentally what gets me excited about this space because that would mean, you know, if we could translate that into human biology, like it would be way better than like a magical cure for cancer or something like that. As far as like the

• 8:52Speaker 02

  number of extra healthy years of life we could distribute to the population. We can talk about that a little bit more.

• 9:00Speaker 00

  Yeah. So what I want to talk about is just, you know, at a very high level, when you talk about molecular damage, just explain that very quickly for people because I think that that's somewhat table stakes in the kind of the scientific community and the longevity community. But there's a lot of people who won't understand what that actually means.

• 9:15Speaker 02

  Sure. So, you know, we're all just collections of cells. Cells are bags of fat containing water, protein, DNA, and, you know, and other molecules, right? And the molecules that make up our bodies are changing dynamically all the time. And so, so we are constantly being assaulted with, you know, UV rays from the sun or crap that we put into our bodies that we eat, or even just like random changes as we get older. We're like our, the bags

• 9:52Speaker 02

  that are our bodies are not designed to live or to function forever in an unchanging state. And as, as these different, you know, environmental and natural impacts affect our, our cells and our tissues, things change over time. So let me try to do a better job of explaining what molecularly we mean here, right? And I think that would actually help to maybe touch on the nine hallmarks of aging really, really briefly, just so we know what, what we're talking about. At Cambrian, we separate these into three categories of changes that

• 10:34Speaker 02

  we think of as like changes inside the cell. So I already mentioned in cancer, we have mutations to the DNA, but also as our cells divide, the ends of our chromosomes called the telomeres, which you and some of the listeners may have heard of, they get shorter every time a cell divides, right? And so that's another kind of molecular damage in a way, because our cells are becoming less able to do more divisions every time they divide. So. Then there's also inside the cell, a loss of what's called epigenetic information. So this is some of the markers on top of the DNA. That, yeah, that change which genes are expressed in which cells at which time.

• 11:19Speaker 02

  And the more information is lost there, the less well the cells perform the job that they're supposed to do. Then we have a second category of like whole cellular level dysfunction. So cells themselves can become old and dysfunctional. We call this cellular senescence, where they were supposed to die, but actually failed to do so. And they operate, they, they start operating in this different program that spews inflammatory cytokines. So basically inflammatory molecules out into the environment. And they can cause quite a lot of havoc, even if you only have one, one out of every hundred cells being in this senescent state. And similarly, another kind of like whole cellular level dysfunction.

• 12:05Speaker 02

  We have the power plants in our cells, the mitochondria that make energy. Those start working less and less well over time as our bodies get older. And so those might, the, the, the power plants can become dysfunctional. And there's a few different types of molecular damage that can make mitochondria not work well. So this is kind of a second theme of cellular level dysfunctions. And then the final theme is tissue level dysfunctions. So we have stem cells in our tissues, right? That are trying to regenerate, especially when we're young, regenerate injured organs. Our liver is super good at regenerating. For example, our bone marrow, our immune systems are super good at regenerating.

• 12:47Speaker 02

  But as we get older, the stem cells that are fueling all of that, they get worn out over time. And, and they be, are able to regenerate less and less well. Another one that's in this kind of like organismal level or, you know, whole tissue level is the topic of chronic inflammation. So. Long-term chronic inflammation does horrible things to a tissue. It turns it from being very flexible and, and flexible and regenerative to what we call fibrotic. Basically, we become more and more like a scar as we get older, not just on our skin, but in all of our tissues.

• 13:29Speaker 02

  And so we're spending a lot of time thinking about this increased scarification that happens not just in our skin, but in our liver, in our kidneys, our hearts, our lungs, as we get older, and what molecular tools we could use to reverse some of that, to, to make our tissues more, more flexible, more able to regenerate, instead of hardening up. So that gets into a little bit of scientific detail, but hopefully gives a sense of like the types of damage that we are thinking about in this neuroscience field.

• 14:04Speaker 00

  Yeah. And what's so interesting about this, I think that there's a sequence that people may or may not understand, which is that a lot of this molecular damage happens in what most would consider your healthy years. And then it actually shows up, you know, 10, 20, 30 years later. And so maybe talk through a little bit of like that sequencing around the, when the damage happens, but then also like when it shows up and how that's not actually happening simultaneously in most cases.

• 14:29Speaker 02

  Exactly. I think that that's the key to understanding this whole field is that when, like, when someone is diagnosed with a disease like Alzheimer's, let's say, that, that Alzheimer's diagnosis is, it's like not the start of the disease. It's one inflection point of a really long process that's been happening in that person. And, and so what this field of aging biology or neuroscience is helping people think about is that

• 15:06Speaker 02

  If we can understand all of the damage that's building up 10 years, 20 years, 30 years before what we call a phenotypic effect, right? So before someone is actually losing their memory, or unable to walk, or unable to eat, or something like that that can happen to a patient with Alzheimer's, or in the case of, you know, cancer, before you see a big tumor, that's metastasizing. If we can understand that damage in the 10, 20, 30 years leading up to it, measure that damage, and then use a biomedical intervention to either stop it or reverse it before we get a disease, then it's a much easier problem to solve than it is to try to react to a disease once it's already happened.

• 15:47Speaker 02

  And I actually have like a kind of nerdy scientific way that I, example that I like to use to think about this. So as a VC in, in bio, we invest in companies like cancer companies, for example, right? And one of the ways that drugs are tested in cancer companies is you give a mouse a tumor, and then try your experimental treatment to see if the mouse can clear out its tumor, right? And so it's, you know, pretty standard practice, you're giving mice, mice cancer, curing the cancer, and then you can like use that as a justification for trying it in humans later. But as a VC, one thing that we all do is we make sure in these mouse models of cancer,

• 16:30Speaker 02

  that before we try our experimental treatments, that the, the mouse has been injected with a tumor, and the tumor has like grown big and scary enough that, you know, it's going to be hard to, for the, for the treatment to clear out that tumor. Because if you treat the mouse too early, when the cancer is just developing, we know that almost every anti-cancer treatment works really, really well, and you get like 100% cure rates, but that doesn't then translate into good results for patients, human patients that have advanced tumors. And so It's this fascinating situation to me, and I guess, you know, a bit nerdy here, that like, we're turning the thinking on its head, where like, a lot of the VC and

• 17:15Speaker 02

  investment thesis in how we think about mouse models has been, how do we make sure we can replicate advanced-stage human disease in the mice, so that the mice that we're treating look more like the patients that we're treating? That's one way to think about this investment thesis, but this neuroscience hypothesis almost turns it on its head, which is like, if we know a way that we can cure cancer almost every single time, why don't we start thinking about how we treat our human patients in the way that works almost every time in our mouse models? And I think that that kind of flipping of the script is the powerful, one of the powerful ideas behind this.

• 17:54Speaker 00

  One of the most fascinating things to me in all of this was when I learned about Brett Weinstein and kind of a lot of the controversy around the mice and the shortening of telomeres and kind of how a bunch of the mice came from the same place, and without getting, you know, super into detail about that whole situation, people can go Google it, but it really just showed that like, hey, this is still science, and if you don't get kind of a bunch of stuff right, the conclusion can be inaccurate. And so this whole idea of like, what's the framework you use, right? Do you try to replicate the human disease in a mouse and then go ahead and address it? Or do we just figure out how do we cure mice, and then should we bring that to the humans is a fascinating way to kind of look at it. What I want to talk about next is this idea of healthy years. And Christian

• 18:39Speaker 00

  and I have talked a ton about this, and I think that a lot of people, when they think of longevity, they just simply say, okay, well, if the average human lifespan is 77, 78 years, whatever it is now, how do we get that to 80? And then how do we get that to 85, 90, 100? And, you know, that makes sense, because you just want to live more years. But actually, there's a difference between living for an extra 20 years at the healthy or unhealthy state of a 90-year-old versus living an extra 20 healthy years that might actually be more like, you know, what you feel and how you operate at 45, not actually feeling the effects of older age until maybe you're 65, and then being able to kind of

• 19:23Speaker 00

  capture those healthy years. So talk a little bit just how you think about healthy years versus maybe non-healthy years, and why it's so important to focus on the former rather than the latter.

• 19:33Speaker 02

  Yeah, and I think you nailed our thesis right off the bat there, which is if we only extend unhealthy, the unhealthy period at the end of life, we're doing a disservice rather than a service to the population at large. So, anything that's worth doing has to extend the number of healthy years. And like, that's our ultimate readout. So whenever we talk about it, we actually avoid the term lifespan altogether unless it has the term healthy put before it. Or, you know, I think the most popular term among people in our field is actually to talk about it in terms of health span as one word. Or,

• 20:13Speaker 02

  my favorite, again, kind of wonky term, which is Qualys, the Quality Adjusted Life Years, where this is kind of how insurance companies think about, you know, quantifying human life happiness, kind of that cross-product. And, and so, the positive news here is what we've seen both in humans, as our lifespans have risen from 35 at, you know, 120 years ago, at the start of the 1900s, to close to 80 now. We've seen, as human lifespan

• 20:53Speaker 02

  has gone up, human healthy lifespan has also gone up dramatically. Obviously, because we're dying of these chronic and horrible diseases like cancer and cardiovascular disease and Alzheimer's now, there is a tail period of unhealthiness that most of us experience at the end of our lives. But, but in humans, we have been able to extend that healthy lifespan portion out very significantly. And in mice and other model organisms that we've been able to use drug interventions to extend those healthy, the healthy lifespan of those animals, you're basically never able to increase just the unhealthy portion

• 21:34Speaker 02

  of life. Because, one of the conclusions, or I guess the assumptions from this damage theory of aging, is that Once you've got a critical amount of damage that's going to send you kind of tumbling downhill, which will ultimately result in your, in the organism's death, like you can't undo that, that hill from that inflection point. So it's a much simpler idea to extend the time before you reach that, that turning point that starts you tumbling downhill. And so when I talked a little bit about like the mouse life extension earlier, you extend like the way that essentially all of these treatments work is you extend that healthy period. And then the period of decline that ultimately ends in the death of the organism

• 22:18Speaker 02

  actually stays fairly constant because once you've reached that big threshold, then there's almost just nothing you can do and it's a matter of time.

• 22:25Speaker 00

  Got it. Let's think through a little bit. There's multiple, I think, schools of thought around prevention reversal. And then maybe I'll just call it treatment, right? Like you're already kind of old and we're just going to make it as, as painless as possible and as enjoyable as possible. How do you look at those three buckets, right? Kind of prevention reversal or treatment? And is one better than the other? Is it kind of, no, we need to do all three at the same time to get the best outcome? Just what's the framework you use to think through that?

• 22:58Speaker 02

  It's a really good question that we could probably spend an hour talking about to, to give justice. But, but I will put it in, in kind of almost like an easiest to hardest term, sort of terms where prevention is always scientifically the easiest thing to do. But from a, a treatment perspective, both getting drugs approved through the, you know, regulatory system like the FDA, but, but also in like choosing which patients to treat, prevention is the hardest. So scientifically easiest, practically the most difficult. Treatment is scientifically, in some ways, the hardest.

• 23:40Speaker 02

  Like it's much harder to unwind these diseases after they've already appeared. And, but from a regulatory perspective, it's much easier because that's how our healthcare system is set up today. It's set up to be reactive, waiting for someone to get sick. And then now we know like we can approve a drug to see if, you know, it can, you know, shrink your cancer or something like this. But the sad reality is that we haven't developed enough drugs that can work.

• 24:10Speaker 02

  Worked that well in a lot of people. So like if you look at the past 75 drugs that have been approved in to treat cancer over the last 10 years, the average amount of extra time a cancer patient gets when they go on to one of these drugs is about two and a half months of extra life, right? Not a huge bonus for the fact that we're spending hundreds of billions of dollars a year conducting clinical trials in cancer therapy. And so it's not zero progress at all. And there's tons of good discoveries being made, but it's just such a scientifically harder problem than than prevention. And then the final one around reversal, like this

• 24:53Speaker 02

  is, in some ways, you know, in some contexts, you could think of reversal as treatment. And so let's say in the context of cancer, reversal probably isn't an option, right? Like, once you've got a cancer, you can't just like reverse the damage that caused the cancer from being there, because if you would, it would just be a treatment for the cancer. So reversal is really something that you have to think about in a tissue specific or a disease specific sort of way, where it's like, before you have something that's going to definitely kill you, but when there's still time to undo the damage. So it kind of sits somewhere in between treatment and prevention. And so I'll give

• 25:38Speaker 02

  like a couple of examples here. Like, let's say I'm getting into my 70s or 80s, and my muscles are becoming way weaker, right? And my bones are becoming way weaker. So this is now already happening to me. I'm getting less less robust, and we could try to use a therapy to strengthen my muscles, to strengthen the structure of my bones, so that I don't continue to get more frail, kind of like resetting me back to the point where I was in my 40s or something along those lines. From a scientific point of view, that's harder than the the prevention aspect, but not as hard as trying to, you know, put

• 26:20Speaker 02

  me back together once I've had a fall in my late 80s and my hip is shattered.

• 26:26Speaker 02

  And then from a regulatory perspective, it actually looks a lot like the prevention part because again, when we're weakening, but we haven't been diagnosed with a major disease, the FDA kind of looks at all of that in the same, in the same way. And so a lot of what we focus on is this reversal and prevention ideas. And we kind of bundle those together into one way of thinking about like medicines that we can use before a true disease happens. That's either preventing damage from building up or reversing it once it's there. That's the same category for us.

• 27:02Speaker 00

  Everything you're talking about is incredibly complex and there's a lot of really, really smart people working on it. And there's a lot of people who are doing it for what I'll call kind of the right reasons in terms of they want to make a difference. They want to increase life. They want to have people live healthier lives. There's also people who are doing it from a for profit kind of perspective and profit is kind of the number one thing that they're focused on. I don't think, neither do I think that you nor Christian believe that those two things have to be mutually exclusive. Like I actually think that there's a world here where you could take a capitalistic perspective and the capitalism

• 27:42Speaker 00

  or the pursuit of profits actually drives revenue, which then can be reinvested to further kind of the, the health impact and probably is the most sustainable model that we've seen so far. But you guys have a spin or kind of a variation of how to finance a lot of this work. And one of the things that I think is fascinating to me is that most of the people in this space come from the science side, right? They, they look at it from a very scientific perspective and there's a constant cat and mouse game. How do I get funding? How do I get a grant? How do I get some level of financial kind of backing so that I can actually spend time both mentally and, and kind of with resources to actually make an impact.

• 28:27Speaker 00

  You guys are looking at this and kind of this drug discovery company model. So maybe talk a little bit about this DISCO, D I S C O that you guys talk about a lot. And then talk through what are the variations or changes that you think of from a financing perspective that should lead to kind of a better outcome and a more kind of sustainable platform?

• 28:49Speaker 02

  Yeah, so there's, there's a lot of threads that I can pick up from there. But, but maybe before we jump deep into the, the DISCO model, I want to just emphasize one of the pieces that you're talking about around like doing this for the right reasons, kind of how drug discovery in general works. Because there are a few different ways that people have been doing this. And I think that as you articulated, the biggest problem for folks trying to think about developing a drug for anything is the funding question, that a lot of drugs that start clinical trials ultimately end up failing. And that those failures are usually very expensive to figure out because it takes,

• 29:31Speaker 02

  you know, tens or even hundreds of millions of dollars to run a phase one, then a phase two, and then a phase three clinical trial. We've seen that, you know, with, with the COVID vaccines that everyone has paid attention to. These are incredibly expensive human experiments to run. And so, um, one of the cool things about the pharmaceutical industry as it exists in the free market for all of its flaws, and it has many, is that once you start going down a path that's going to cost a hundred million dollars plus to get you from the idea stage to an approved drug, that at the end of that, it really never makes sense to start

• 30:14Speaker 02

  to say like, oh, well, this is just going to be for one small group of people, right? That you, you actually want to get those drugs to as many people as possible.

• 30:25Speaker 02

  At the right price. And so there's this old joke in the pharma industry that it takes a billion dollars to make your first pill, and it takes a fraction of a penny to make your second one. And that what that means for supply and demand curves is that when a medicine is applicable to a large fraction of the population, it drives the price way, way, way down. And so the closest thing that exists today to what we would think of as one of these Gero protective or age slowing drugs is actually the drug Lipitor. So these statins that reduce cholesterol. That's the closest, the closest equivalent to what's been on the market so far. And those drugs at their highest point never cost more than

• 31:05Speaker 02

  four or $5 a day. Right? And it was the most profitable drug of all time, because it reached so many people. And so when we think about doing this for the right reasons and kind of like the mixing and matching of the profit motive with the with drug development, I think there is actually kind of a positive story there. So I just wanted to pick up on that thread. The, the second piece that you talked about is, as it relates to how we fund drug development today. We've actually been in this really interesting, quiet revolution, where two things are changing a lot in science. And the first part is that universities and

• 31:48Speaker 02

  like academic research scientists, because of all of the genetic sequencing tools and like advances in chemistry, advances in genetics that have been happening. So you can do so much more now in a university lab than you could 20 or 30 years ago, as far as making a drug. And so almost all, like the majority of new drugs are actually discovered at universities, spun out into biotech companies, and then are eventually acquired by big pharmaceutical companies that do the late stage clinical trials. Because this is working so well, on the flip side, the big pharma companies are actually powering down their R and D,

• 32:26Speaker 02

  and, and relying more and more on gobbling up through M and A, these small research companies, right? And so the intersection of those two things means that there's tons of good ideas inside of academia that need to do the research and development work to prove to a big pharma player that their idea is worth a damn. And so they're constantly fighting for funding. And so the VCs, the funders have kind of become the gatekeepers in this.

• 32:59Speaker 02

  And you have this really kind of messy mixture of like CEOs coming into a biotech company, pitching a VC to try to get funding. And then, you know, getting a little bit of data, pitching more VCs, bringing more in, until you can kind of like finally roll a big enough snowball to get absorbed by a pharma company. But it's really messy. It involves a lot of hype generation and like a lot of like who you know sort of conversations. And ultimately, what we've seen is that it can get disconnected from the value of the underlying science. And so when Christian and I came into this field, what we wanted to do was build an organization that could have the scale to take a lot of different shots on goal so

• 33:44Speaker 02

  that some of them would ultimately succeed. And then at the individual asset development level, make our decisions exclusively based on the quality of the science, not on, you know, how hyped it was or what the last valuation was or who had invested before. And so with Cambria, we've been able to like absorb almost 15 different projects that started at universities into our umbrella. And now we can continue to resource the ones that are working with more and more money to kind of get them into clinical trials. And if an idea fails, like that's a tough message to deliver to that team, but it's

• 34:26Speaker 02

  better for us as the ultimate, like the organization that's footing the bill to make that decision early instead of trying to pull more and more capital and like hype it up and hype it up, try to like get it out the door and then have it ultimately fall on its face. And so that's a

• 34:43Speaker 02

  Bit of a, you know, a lecture on this and we can go deeper or stay at a higher level as how this model works, but changing those incentives around so that I can talk to my ultimate investors and not have to sell them a bill of goods around how this one technology is going to change the world, but instead say, hey, look, we have this thesis around how we're going to create this new category of preventative or proactive medicines targeting the hallmarks of aging. And if you believe that this hypothesis has merit to it, we're going to take enough shots on goal to get one, two, three, four things

• 35:22Speaker 02

  working. And we don't need every single project to ultimately be, you know, the golden goose. I think that's a very powerful idea.

• 35:32Speaker 00

  Absolutely. And so you guys recently came out of stealth. You've been working on this for, I think, about two years or so. What can you share in terms of who some of the investors are and kind of how you guys have been funded to date?

• 35:43Speaker 02

  Yeah. So Cambrian is a biotech company, not a VC fund. All right. So we actually have attracted investors that are traditional company investors. Started this together with Christian Angermeyer, who runs a Pyran Investment Group, who's also behind a few other really interesting projects, including one called A-Tie that is commercializing all of the psychedelics for use in mental health disorders and actually running clinical trials in those. So Christian is the biggest, a single investor in Cambrian. But then we've also attracted a really, really

• 36:25Speaker 02

  good group of other folks. I can't talk about all of them, but, but among them are Future Ventures, which is Steve Jervitson and Mariana Cyanco's fund. Steve was one of the early investors and on the board of Tesla and SpaceX. And it's just like, they are just really far thinkers about what the future is going to look like, have been huge supporters. Mike Novogratz, who is a, who's really big in the crypto space, as well as doing a ton of other smart investments, also involved in the psychedelics work.

• 37:00Speaker 02

  Brent Saunders, who's the former CEO of Allergan, which was acquired for 50-plus billion by AbbVie, is really interested in this space. And then a biotech-specific VC based out of Baltimore called Catalio also participated with us. So we've got this kind of like cool group of eminent tech investors, entrepreneurs, some folks from the crypto world, kind of like all coming together to to support this mission for Cambrian. And we've raised 60 million so far. But I can say, kind of like on this, not off the record, but like not on paper sort of format, that I've had the

• 37:43Speaker 02

  the luxury of being able to turn down about three times as much money as we've accepted, which is a really cool place to be.

• 37:50Speaker 00

  Absolutely. And so part of this is obviously, financing is an important part of the drug development and kind of distribution. And you've got a recent announcement, Sensei, and there's been a kind of a public market angle to this. So maybe talk a little bit about what is exactly is Sensei? How does that fit into the Cambrian model? And then talk a little bit, whatever you can share in terms of the public market.

• 38:13Speaker 02

  Yeah, absolutely. So Sensei is a cancer vaccines company that we started working with right when we started Cambrian. That was, had already completed a phase one clinical trial and needed funding to start its phase two clinical trial. We partnered with them around that.

• 38:31Speaker 02

  Before touching a little bit on like what their product specifically does, I want to put it in the context of like why this fits in Cambrian. And so every program that we put together has to have two features. The first feature is that it has to target one of our hallmarks of aging, right? And, and if it targets one of the hallmarks of aging, you know, we think it can ultimately be used as a preventative or a, you know, either a prevention or reversal therapy somewhere down the line. But the key is somewhere down the line. It has to also, on the other hand, be able to be built as a real biotech company that can deliver. You know, short to medium term value for investors today within the existing regulatory

• 39:16Speaker 02

  environment. And so what got us excited about Sensei is that these guys had figured out how to make a cancer vaccine that you could give to patients with an already established cancer. They would kind of like do some sequencing, kind of measure some of the genes that were overexpressed in that tumor, make a cancer vaccine to, that could boost the person's immune system to attack the cancer cells, and it was working, right? And we don't have to go too much into the specific details, but, but basically, at the, you know, not the 30,000 foot level, but at the 1,000 foot level, in order to

• 39:58Speaker 02

  turn your immune system on to attack cancer cells, you need to trick it into thinking that, that the cancer cells are virally infected. And so what these guys have done is they've taken a hollowed out virus that normally infects bacteria, doesn't affect human cells, and layered cancer proteins on top of it, injected it into a person, that person's immune system noms on that bacteriovirus with the cancer proteins, first realizes, oh, hey, I've been, like, it looks like there's a viral infection here, what should we respond to? And as it chops up all of the different pieces, it shows the immune system all of these cancer proteins, which then, as the immune system starts to look around the body for like where

• 40:41Speaker 02

  these quote unquote virally infected cells are, it finds all the tumor cells. And, and that, that is kind of like a, something that people in the cancer immunotherapy field have been trying to do for 15 years. And I haven't seen done as successfully until I met Sensei and discovered their platform. So that's, that's kind of like how, how this works. But the really cool thing about this is in addition to treating people with stage four metastatic, you know, cancer, people who have no other options left, which is the people that Sensei has been treating right now, and actually been able to help a substantial fraction of them, we think.

• 41:22Speaker 02

  In addition to that, the platform has this really cool potential, which is, I don't know how much you and your listeners have paid attention to some of this stuff, like there's this thing called a liquid biopsy that's been developed just in the last couple of years, which is like before you could even detect a tumor in your body, you can start detecting like single cell, single tumor cells circulating in the blood. And people have been able to pick up, oh, can we use advanced sequencing techniques to like find those tumor cells in the blood? And so in the longer term, we could imagine using this vaccine technology, not just to treat people with no hope left, but to actually

• 42:06Speaker 02

  go in for like regular checkups to see if there's any little bits of tumor cells in our body, vaccinating ourselves there before we even detect a tumor to prevent a tumor from happening. And then even in the long term, to use a technology like this, the same way that we have HPV vaccines to prevent cervical cancer, why couldn't you do this with other proteins to prevent lots of different types of cancers? It is very theoretically possible. And it's just a matter of building a platform that's both powerful enough and we think safe enough to justify doing that. And so that's where Sensei's long-term vision is. So that's, yeah, a little bit of an overview there of what got us excited about it.

• 42:47Speaker 00

  And talk a little bit about the public market aspect to it and why that's so important.

• 42:51Speaker 02

  Absolutely. So, so I talked a little bit already about this kind of change in supply and demand, right? As university program, university spinout programs and these small biotech companies have become the wellspring from which all new medicines arise. And, and so the natural history of these companies goes in one of two different directions. Either they get gobbled up by a big pharma company, or they raise a bunch of funding and can kind of go it on their own, which usually involves a path into the public markets. And Especially since COVID with, you know,

• 43:34Speaker 02

  clinical trial data being on the front page of the New York Times, the Wall Street Journal every day. Regular investors have started to get biotech so much more than they did in the past. And they're able to make informed decisions about what's, you know, what's, uh, what's working and what's not by looking at these clinical stage biotech companies. And so the IPO market for biotechs has exploded in the last couple of years. And so by bringing Sensei public, we can do a couple of things. Number one, we've been able to resource its clinical programs so that it can get all the way into what's called a pivotal trial.

• 44:15Speaker 02

  Right. The, the trial that would give it the ability to approve a drug all on its own with, with the money that we raised from IPO investors, which often is just like a much higher number because once you're publicly traded, those investors aren't stuck with an asset that they don't want, right? They can sell off their shares later if they want to. And then the, the second benefit is that from Cambrian's perspective, it was really valuable for us to take this affiliate company of ours into the public markets because it's kind of a validation for the way that we source, resource and build assets for our whole portfolio. So we were able to take this company that had, you know, a little bit of data, but like,

• 44:58Speaker 02

  was right at a point where we could accelerate it dramatically by getting involved and, and generated nearly $600 million of value in, you know, a year and a half, a little bit more by, by pushing the gas on this one asset. And, and that value is now validated in the public markets because this is what people are freely trading the stock at.

• 45:21Speaker 02

  And that's a cool place to be.

• 45:23Speaker 00

  What do you think is the kind of biggest lesson that you've learned over the last two years that would surprise people, right? The thing that you didn't expect or the thing that you didn't understand, but now you look back and you say, hey, here's the one learning that I've had that would be just absolutely fascinating for people to understand?

• 45:39Speaker 02

  That's a really good question. So I think the thing that's probably been most surprising to me throughout all of this is just how segmented and fractured the drug development ecosystem is, where like the university professors really can't even speak the same language as the guys at the pharma companies who are ultimately developing drugs. And there is such a wide gap of data and understanding there that the folks who are kind of like coming into the middle to fill in this gap and actually like build biotech companies

• 46:22Speaker 02

  that bridge this gap, it's way, way wider than I expected. And let's see if I can put this a little bit more concretely with a story here. So, and maybe I think it's useful to get into just like a little bit of the detail around this. So in order to get a drug approved, right? We talked about the three phases of clinical trials, but you also need to run all of these safety studies before you go into humans. And you have to validate that your drug is working in a million different ways. And when I was a PhD student working in the lab on mice, I didn't know and wasn't taught a single one of these things

• 47:04Speaker 02

  that had to be done, right? It was all about, could I generate like some interesting discovery that I could publish about in a paper and, you know, get it in some journal and then move on to the next thing that would be the next discovery. And so now that I'm in the middle here, I see that there's about, you know, 500 experiments that need to be done from that first observation, which, you know, gets covered in the New York Times or whatever, like is, oh, wow, we've made this huge discovery in mice. There's about 500 things that then need to be done before someone at a pharma company will say, oh yeah, it looks like you have something really interesting here. And figuring out what those 500 things are

• 47:43Speaker 02

  and building the right teams together of chemists and toxicologists and pharmacologists and like, you know, Patients and all of these other people that have to come together to think about how we formulate this drug and how we treat it and how we've tested it in all the right ways, it's such an operation. And, and so that's really why this process, this process is so expensive to go from university to, to ultimately getting a clinical ready product, but also why there's so much opportunity for companies to add a ton of value there. Because there really is this, you know, really ripe landscape for, for picking great ideas

• 48:27Speaker 02

  out of universities. And if you can be that translation engine, both translation in the literal sense of like being able to speak the language of the, of the folks who will ultimately be working with you, but also, you know, translating the discovery from the mouse stage to the human stage, it's just a great business that's adding a lot of value to the healthcare system.

• 48:51Speaker 00

  What's the biggest obstacle or challenge? Obviously, you're an optimistic person. So am I. So is Christian. I think that we generally have confidence, given who the backers are, what you guys are working on, that there's a lot of progress that will be made here. But what would the argument of the detractors be? Or kind of what would be the identification of what those obstacles and challenges are?

• 49:12Speaker 02

  So, so the biggest, biggest obstacle for us, like as I have my eye on the next decade of what we need to do, is establishing the regulatory paradigms to do prevention. When we value Cambrian right now, it's entirely based upon what we can do with the drugs that we have in the existing regulatory regime, which is essentially entirely reactive. And so, so the biggest challenges that we're thinking about now are how do we create the

• 49:45Speaker 02

  Create the pile of data that we're going to need to convince these regulators, the regulators that we have to work with. And to the FDA's credit, they've been open to having a conversation with us on this. But how do we create the pile of data that will allow us to say, hey, we have this drug, it works in cancer, or it works in like some rare childhood disease, we want to see if it can slow down aging and actually get them to say yes. Because the way that the FDA works now is, they would allow us to run a trial for slowing down aging or preventing multiple diseases. But if you and I started taking, you start taking the drug, I start taking the placebo right now, it'll take

• 50:28Speaker 02

  30 or 40 years for us to know whether it worked or not. And even if you start treating people in their 60s, it would still take 10 or 15 years, whether you would know if it was working or not. And so what we need to do is find the right tools, like what was done with cholesterol and these statin drugs, where people could come in and say, oh, you have high cholesterol, let's put you on the drug. If your cholesterol goes down, we can actually approve the drug already, get it out into the market, get it into people's hands, but then follow up those patients for another 10 years to see if they actually get fewer strokes, actually get fewer heart attacks. We have to do the same sort of thing here. But that's just something that doesn't exist in the aging space yet. And we're going

• 51:10Speaker 02

  to be working very closely with the FDA, but also with other countries who are excited about exploring this kind of transformational technology.

• 51:22Speaker 00

  Before I go to the rapid fire questions to wrap up, what's the message to people? When they would think of Cambrian, when they think of the work that you're doing, what is that one thing that you want them to walk away for remembering, or what that mission is?

• 51:41Speaker 02

  What I would say here is that the 1900s in medicine were defined by our conquest of our biggest human predators at the time, which were viral and bacterial diseases. And the combination of vaccines and antibiotics led us into a new era where now our biggest predators are age-related diseases, heart disease, cancer, Alzheimer's, et cetera. And, and the way that we conquered those diseases in the 20th century is going to be applicable to how we conquer the age-related diseases in the 21st century by understanding

• 52:22Speaker 02

  what causes them before people completely break down from those diseases and devising treatments to, in some cases proactively, and in some cases at the very early stages of the disease, use the power of medicine to reverse them. And, and that's how in this century, we're going to overcome today's biggest predators. It's a, it's a, you know, a transition from being reactive to proactive that's going to happen at some point this decade, and we want to be on the cutting edge of, of eliciting that transition.

• 52:56Speaker 00

  That's fantastic. I always ask the same three questions to everyone before I let them go, and then you'll get to ask me when to finish up. The first is, what is the most important book that you've ever read?

• 53:05Speaker 02

  So my, oh God, I'll pick one. Probably Richard Dawkins, The Selfish Gene. I think that is for me, you know, I almost tell people it's the grounding of my philosophy in some ways to understand how the logic of evolution really works. And it's been incredibly impactful to me in thinking about this topic of aging and longevity, because, you know, we have to remember that evolution isn't here to serve us, our, you know, our bodies that are thinking and doing interesting things. It, it has, we have all evolved to serve our genes on an individual level. And the fact that we are able to, you know, think about the universe and have fun conversations

• 53:50Speaker 02

  like this one is an evolutionary accident in a lot of ways. And so we have to take responsibility if we want to preserve what, what we have here. Kind of like taking that into our own hands. So I would say, yeah, selfish gene with an honor, an honorable mention to a book called The Origin of Wealth by Eric Beinhocker, about how markets work with the same mathematical principles as the biology of evolution.

• 54:18Speaker 00

  I love that answer. Second question, a little bit more personal, brought to you by our friends over at Eat Sleep. They've got a thermo regulation bed that essentially allows for you to make it hotter or colder. I'm a really, really cold, get deep sleep and not feel much better. But I used to only sleep five or six hours. Now I sleep like eight or nine. What's your sleep routine and kind of how's that evolved over the years?

• 54:40Speaker 02

  So I'm also sleep cold, kind of guy, sleep, sleep cold, but with like a nice blanket. And, and I try to go to bed at the same time. Every single night, I go for like seven and a half to eight hours of sleep for me, although eight to nine, I definitely like, I think there's a lot of evidence that getting up into that range is way better for you. And yeah, and then I guess without taking too much time, my sleep has evolved quite a lot over my life. When I was a grad student, I tried to, you know, before a lot of this sleep research was done, I was trying to actually shorten my sleeping hours to get

• 55:22Speaker 02

  more done in the lab. And I got so, I became such an asshole to people when my sleep was getting down to like five or six hours a day, that I abandoned it and spent two years during graduate school, operating on a 28 hour circadian rhythm, where I would sleep for eight hours and then stay up for 20 and had six days in a week instead of seven. So I was up at like really weird, weird hours. And, you know, that was great when I wasn't dating anybody and didn't really have any friends and just needed to be working in the lab. But, but now I'm trying to be a little bit more disciplined.

• 55:57Speaker 00

  I love the experimentation with sleep. I've even tried, I think they call it the everyman sleep schedule, which is like four hours of sleep, but split into an hour and a half, and then a couple of 30 minute abs and the whole thing. Polyphasic sleep, I think, or something like that. The third question is, is more fun. Aliens, are you a believer or a non-believer?

• 56:20Speaker 02

  I think that they have to be out there. The Drake equation is a very compelling reason to think that there are other life forms out there. It's just a matter of finding them. I, as a, as a, I don't know, fun little experiment in college at some point, a group of friends and I were thinking about alternative answers to the Fermi paradox, right? Which comes out of the Drake equation, basically like, do all evolved civilizations destroy themselves? And I actually think that there is, we don't have to get deep into this, but I think that there is another compelling explanation, which is because we've scanned so little of

• 57:02Speaker 02

  the sky for radio transmissions and these other things.

• 57:08Speaker 02

  There is a possibility that interstellar travel is just not often worth it, right? And that it's just so far and getting up to close to light speed is so freaking hard that even very advanced species end up just hugely colonizing their own, you know, stellar neighborhood, but not expanding like what Isaac Asimov once said, a ball of flesh expanding at the speed of light, that that just doesn't happen even for very advanced civilizations. So I'm, you know, a future optimist and an alien believer.

• 57:44Speaker 00

  I'm right there with you. They exist, we probably won't engage with them during our lifetime. Everything we look in the skies, you know, million years old, so we'll see.

• 57:54Speaker 02

  Depends how long our lives are, I guess.

• 57:56Speaker 00

  Very, very true. What's the one question you have for me to wrap up?

• 58:01Speaker 02

  So the question that I think I would ask you is, as you think about the future of technology and you ask yourself like, what are the most important changes that are going to happen to our civilization in the next 30, 40, 50 years? Like, how do you rank the, how do you rank the biggest impacts between, you know, automation of work, changes to the monetary system, climate change, as well as medical innovations? How do you think about ordering those things in terms of their impact?

• 58:36Speaker 00

  That's an impossible question.

• 58:39Speaker 00

  I don't think I could rank them in terms of like, you know, magnitude of significance. What I could say is, can I paint a picture of where I think the world's going? And of course, this gets labeled as kind of, you know, the sci-fi Silicon Valley view of the future. But I like to joke all the time and say like, well, technologists are right. And so I think that one, you get kind of bioengineered humans that are augmented by technology and computing power, either externally or internally. You get a ton of automation. Automation includes robotics all the way down to literally streaming payments and digital assets like, you know, tokenized stocks, bonds, currencies, commodities, et cetera.

• 59:22Speaker 00

  You get a multi-planetary species that involves travel, both domestically, internationally, and kind of multi-planetary. And then I think that what we're going to see is a drastic shift in the world to kind of clean renewable energy and to, you know, electric vehicles and kind of you just like go down the line, like all of this stuff that everyone's all excited about, like, yeah, sure, it takes longer than we probably want it to take, but it's all going to happen. And I think that the part that probably people are underestimating the most is how disruptive the disruption actually ends up being. And then also too, we like to think about, you know, humans are geniuses, we're going to build all this stuff.

• 1:00:03Speaker 00

  But I actually think one of the craziest, most exciting innovations is going to be as we disrupt ourselves, right? Meaning that when you start thinking about longevity and people living longer, healthier lives, when you start to think about an augmented human, literally with, you know, the brain-computer interfaces, when you start to think about just what carrying a supercomputer in our pocket did, well, imagine when that is reduced friction and things like AirPods, you know, and kind of what that has empowered. And so I think that it's just like, we're headed in the right direction. What's more important than the rest, like, it's all interconnected, right? And so I think that, you know, just people who are pessimists, I'd like to say, you

• 1:00:45Speaker 00

  know, pessimists are losers because they basically are betting against innovation, they're betting against progress, and I just tend to think that that's a really, really bad side of the trade to be on.

• 1:00:55Speaker 02

  Totally fair, although as someone who has a few pessimists on my team, I love the counterbalancing effect.

• 1:01:01Speaker 00

  No, they're losers. Tell them if you're a pessimist, you're a loser. Now, as much as I joke around about that, I think that, you know, it really is, yes, you do need some people with kind of rational belief, but I like to remind people that being rational doesn't mean you have to be a pessimist, like you can be a rational optimist. If you kind of think like the Matt Ridley view of the world.

• 1:01:22Speaker 02

  I was gonna say, great, another great book, that would be in my top five as far as recommendations.

• 1:01:27Speaker 00

  Yeah, and I think Matt's just done a great job of kind of, you know, look, being rational is important, being an optimist is important, but the whole idea of being a pessimist, especially somebody who hangs their hat on being a pessimist, or somebody who is, you know, I like to say a lot, a multi-time violator of pessimism. If you just, every time you see something, you're pessimistic, then, you know, it's just like, hey, man, jump over on the other side of the river, this side is a little bit more fun, and I think that rational optimism is the way to play the game.

• 1:01:58Speaker 02

  Awesome. Well, thanks for asking that, Pop, this was fun.

• 1:02:02Speaker 00

  Absolutely. Listen, Jay, thank you so much for doing this. I think people are really, really gonna enjoy this. Obviously, I'm a huge fan of what you and Christian are building here, and I think that longevity and a lot of the work is just super important to the human race, if you will. So, thanks so much for all the hard work, and I appreciate taking the time to have the conversation, we'll have to do it again in the future.

• 1:02:21Speaker 02

  Okay, fantastic. Look forward to that.