The Quest to Cure Alzheimer's | Sacha Schermerhorn, Babylon Bio

0:00There are a lot of clues about Alzheimer's. I think there's enough clues for us to understand what is actually causing the cognitive impairment. Often these clues come from very disparate fields. The shingles vaccine, there was a group in Wales where if you were born after this cutoff date, you were eligible for the vaccine. And if you were born just before you were not, they basically stratified those patients and followed them over time. And they found that people that had the shingles vaccine were 20 % less likely to develop Alzheimer's or all cause dementia within seven years. Why? We have no idea.

0:27And that's because, again, these are very distinct fields of science that don't interface with each other directly. So with these elements kind of taking off, can we basically like get very smart scientists to train these models to approximate some heuristic that they use and then just deploy these on like the knowledge graph of science to try and connect off? That seems really tractable. And like we have more than enough clues to figure out like the perfect target for something like Alzheimer's or other diseases. today i have the pleasure of sitting down with sasha skirmahorn and he is the founder and ceo of babylon bio they are currently trying to find a cure for alzheimer's i think over the last like many decades uh tens of thousands of people have been basically working on a cure for alzheimer's billions and millions of dollars have been spent and almost no progress has been made what about that got you excited so i i would actually disagree with the premise that uh the no progress has been made i think a lot of progress has been made but by showing us things that don't work more than things that do um so there's no existence proof that this is like uh attainable which to me is extremely exciting um and i think yeah the past several decades of failure have um given the perception of intractability and if you were to take the second order implication of that intractability i think it's super interesting because it actually makes it a more tractable problem to go after if everyone else thinks it's a graveyard um that to me at a meta level as like obviously fertile grounds for for actual innovation um yeah i mean i think like you know we we've kind of still looking at this disease through the prism of like dr alzheimer from 1906 which is definitely a good thread we should talk about because he had a crazy story but yeah like this is um we are kind of focused on two pathologies we have no idea kind of how they're related but i think we've had enough clues in the clinic and uh on the diagnostic side and prognostic side to understand that um you know a little more parts of the picture that you know maybe the the field hasn't updated their os on do you want to just go through some of the approaches that have been tried and why they didn't work yeah all right let me let me actually start with the the dr alzheimer thinks it's just it's crazy and it's a very good like backdrop um so uh dr alzheimer was this this dude from like way back when he was born in the late late 19th century um and got super super interested um well first of all his degree uh his medical degree and his research during that was um on earwax um so like you know started in the world of earwax um and was was kind of lost kind of like you know just a roaming intellectual not really you know didn't have hadn't set his sides on anything yet um but he got um uh when he was doing it i think i think it was his residency he was got introduced to august demeter who was a patient who was in her late 50s i believe and had this like disorientation, discombobulation, general cognitive impairment.

3:15People thought she was crazy. People didn't know what was going on. Maybe she had a mind virus. And anyway, he spent a long time with her, characterized her very well clinically. When she eventually passed, he ended up doing histopathology on her brain. And he found these two, he used basically some variant of a silver stain, which was a way to visualize these proteins in her brain. and he was punched in the face by these two extremely large structures that shouldn't have been there. And it was what he called plaques at the time and neurofibrillary tangles inside of certain neurons. And obviously the right conclusion from that was if this is not in a healthy brain and is present in the brain of a patient with what was then to be called Alzheimer's, you know, these are clearly causing the symptoms that she had.

4:03Anyway, he ended up giving a talk, I think it was in Frankfurt. And it was a big seminar in front of all these people. And he presented the first case of Alzheimer's, what was then to become Alzheimer's. He was expecting a standing ovation. Absolute crickets. People walked out in the middle of it. They just took their bathroom break. They didn't care at all. They came back to the next presentation to a completely packed house, which was on chronic masturbation. So that was about summarizes, you know, the level of respect that he had. He kind of died, you know, a bit of a, you know, I don't want to call it a a scientific pariah but he didn't get the credit he deserved like any good scientist he basically did did did some really good research and then no one cared in his time yes basically um it's just such an insane like the following they kicked him off stage basically no follow-on questions to hear this fabled talk uh on chronic masturbation um so uh so anyway and then fast forward you know i think um the field really rightfully was saying well these things are not present in a healthy brain let's get rid of them and that was many decades of research and yeah the craziest thing is like we eventually had data to suggest that we finally had these these drugs that were able to reduce amyloid in the brain the amyloid plaques is the plaques are made up of a thing called beta amyloid and that's you know was supposed to be this this incredibly toxic thing and the reduction of these you can basically deplete this in the brain of an alzheimer's patient and have relatively de minimis efficacy um and aducatumab famously reduced amyloid pet i can't remember if i think it was 76 percent um and had no impact on cognition whatsoever isn't the amyloid cascade basically what people have spent i don't know roughly half of alzheimer's research and dollars have been spent on that it seems like a fair approximation 100 i mean this is a huge like it has been the dogma over many decades and you know my kind of like hot take within the alzheimer's space is like amyloid you know because people have basically seen that hey we reduce amyloid has relatively trivial efficacy in patients therefore it seems reasonable to conclude that that's actually like we've debunked the hypothesis but i actually think that's wrong and i think you know a lot of the biomarker development over the past like 15 years even has revealed that amyloid starts to pausing in the brain 20 to possibly 30 years before you develop symptoms and so that pre-clinical phase is like clearly amyloid is causative and it's necessary um but it may not be sufficient um and eventually after 20 to 30 years you develop this like you transition into the clinical phase and um uh and so like if you were to go into a burning house um it doesn't matter what started the fire right it doesn't matter if it was a match or a toaster or whatever it is on fire it's on fire so like you should put it out right and you should figure out clever ways of doing so and i think that's where the field you know maybe maybe has like you know lagged a little bit behind is like not um not updating their priors that like the cause is actually not the thing that you need to target um uh like if you're developing a drug you should probably not go after the cause unless you want to run a 30-year trial um which like it already costs quite a quite a pretty penny anyway so um uh you want to keep them as small as possible so if you're not going after the cause what are you going after um so so i think there's like many ways to tackle that problem i think um you know the thing that we spent a very long time thinking about and like i personally have thought about quite a bit was um this like transition period like how do you basically have this dormant stage for 30 years and all of a sudden you wake up and you start forgetting your you know where your keys are and you know that leads to this cascade and um it's just become abundantly clear that um fossil related tau is definitely a linchpin in that process um and so the thing that um dr alzheimer kind of conceived of us these neurofibrillary tangles um actually turn out to be uh uh like the number one predictor of the onset of cognitive impairment so they're not the predictor of whether you'll develop Alzheimer's period.

7:48Amyloid is like a very good marker to suggest early kind of development. But if you look at the AUCRC of like all the biomarkers you could imagine, there's a thing called P tau 217, which is a fragment of these tau tangles that, yeah, proves to be the most predictive of when you'll develop Alzheimer's. I should say the cognitive impairment phase. For you yourself, like why did you kind of make this the thing that you wanted to work on for the next like 25 plus years? I think like it was a parallel track of these two things. I basically, um, uh, I was very excited on the scientific side. I was, you know, very big reader when I was growing up.

8:27Um, and I was kind of like a music and art kid and not really into science. And then when I was about 13, um, I was also a big troublemaker, uh, stole a book from my library. Um, my, my middle school library on neuroplasticity was called the brain that changed itself by norman doidge and uh and i was like a kid horrible kid yeah um and uh i was just like absolutely engrossed by this thing i mean i devoured the entire book and the the top guy that they talked about um uh was this guy michael merzenich who was like the godfather of cortical plasticity he was the first one to really show that um your brain can rewire itself in these fundamental ways um and so uh i emailed him just being like you know i found out he was in san Francisco where I grew up I emailed him no response and like you know just bombarded him basically until he finally met with me we stayed in close touch and then when I was about 15 I started interning with him working it happened to be on Alzheimer's and around the same time my grandmother had gotten diagnosed with Alzheimer's and I think just like you know as I progressed on the research side and I went to college was doing a lot of research there and seeing these like what I conceived of as these breakthroughs in the lab and seeing the incongruity with like that and my grandmother having not a single drug.

9:36This was pre-lucanumab, pre-aducanumab, all these other drugs that came out. And yeah, that just like crystallized my desire to eventually do something. I felt angry to say at least, let down. What kind of gave you the conviction that this was a solvable problem? If people have been working on it for decades and it hasn't been solved, that's you know a very big hurdle as i spent a lot of time asking pretty fundamental questions to these very very very top people who i respect tremendously by the way they like set the stage for a lot of really important research um i mean even in the first like seven months of babylon i probably met with 500 people i was flying all over the world emailing cold emailing every single person i'd read papers you know i was reading maybe 10 15 papers a day emailing all the authors of the papers I thought were good and just going down that rabbit hole.

10:24And I would just ask these very basic questions. You know, why do you think tau fibrils are toxic? No answer, you know, no answer. And again, I don't blame them. There was not enough information for us to be able to have these answers, but it just felt like there were enough of these like, you know, axioms of this disease that we just like had not yet characterized. And that gave me a lot of confidence. That was the part of the reason I got into neuroscience to begin with was like the fundamental pillars of this entire field aren't even there yeah it's fertile grounds for innovation or discovery that's super exciting and on that like when you were kind of coming up to speed on how everything worked like what was your process for doing that yeah i mean look i think like um i i think a part of it is just like constantly challenging your priors and like you know one of the benefits i suppose like it was a luxury that i was afforded that i had not been in the field for 20 30 40 whatever years like i was this young uh uh kind of you know very very very hungry to learn kind of guy and like i was always always asking questions always willing to update my priors i i would say like there were certain points where i was almost myopically focused on very specific biology that i thought was relevant and then you know i'd go deep enough down the rabbit hole realize it's not zoom back out and there was no ego in that process it was kind of like obviously i'm going to be wrong like definitionally like you know even like the the term alzheimer's expert for me is like almost oxymoronic um you know if if if there were real experts in the alzheimer's space i think we we would have a uh we'd have a lot more answers um so uh yeah i think just realizing like no one was an expert and then that um i was in a unique position to just like you know rewrite how i think about this disease from the ground up was like a pretty compelling prospect you basically have talked a number of times about updating your priors what kind of paths have you gone down in the past just over the past couple years where you thought that there might be something you know some gold negative gold at the end of the tunnel and then realized that's just the wrong direction and turned around um okay so so like i got really obsessed with axon degeneration for a while and thinking that that was you know the cause of of alzheimer's uh specifically the cognitive impairment due to Alzheimer's.

12:33And that was a very deep rabbit hole. I met all the people who published the seminal papers there. And I still think it's incredibly compelling. I think, you know, sometimes you'll kind of hit a dead end insofar as it relates to the drug ability of that pathway. And so for that work, it was very compelling. A lot of evidence showing that the rate of cognitive decline, meaning the slope of your decline once you actually become symptomatic, that varies significantly as a function of specifically what are called white matter hyperintensities in these long range tracks in the brain. And, um, uh, and I went very deep, very deep, very deep.

13:07And I just realized, you know, drug ability of that pathway was, was really hard. There were no drugs that people had developed to actually intervene in that pathway and doing it to novo would have been like, you know, that's like a 10 year academic project, let alone then transition into something that you could have, could have approximate a drug. Um, so yeah, I think there were a lot of these, I mean, you know, honestly, our first program for Alzheimer's we worked on, I think the biology, I still think the biology is really compelling. It was a completely novel target that no one had ever, you know, tried drugging.

13:35And we got really excited about some of the some of the biology there. And, you know, in the end, we basically found the, you know, we knew the biological risk was like the highest percentile you could imagine. But the kind of like drug ability ended up being in the first percentile. And that was just a really bad quadrant for us to be in. And so we pulled the plug. But I still think that's like a super exciting protein, just a bad target for Alzheimer's. There's been a huge amount of capital deployed into trying to solve Alzheimer's and it hasn't happened. How did you kind of structure the way that Babylon operates so that you can actually get to a point where you're able to solve it?

14:09I think the first program gave me scar tissue that if you like Alzheimer's is such a hard thing that any individual program, it cannot be existential for the company. If you're a single asset company trying to go after Alzheimer's just like you know definitionally a moon a moonshot is something where like you're almost certainly you're starting to fail right and I think like you know it had me thinking a lot about like ways to kind of hedge against that um because you don't want to scale down the ambitions of what your goal is obviously um in favor of like you know increasing the POS but um but at the same time uh you need to be realistic about like no one's gonna you know just bland yeah I mean I'm not Elon Musk I can't go raise tens of billions of dollars tomorrow so I think like you know to really um you have to get creative around that problem and you know it had me going very deep down the rabbit hole of like portfolio theory and like ways to kind of like hedge against this at the portfolio level and um uh yeah like more upsets to come in the future there but like i think just financializing the process of self-financing alzheimer's moonshots that's something we've tried to be super thoughtful about and um uh yeah you know the goal is just to amortize the risk of those moonshots basically and uh come up with clever ways to do so are you able to go into any of those um all right like i mean i think at the highest level um there are a lot of opportunities out there that are um not per se like venture exit size um and when i say opportunities like in the context of the pharma land like i'm talking about drugs um and so there's a lot of drugs sitting on the shelves um that's like you know roi vent obviously you know famously kind of spearheaded this where they were like there are these multi-billion dollar blockbusters but you have to de-risk them significantly through several successive stages to get them to the inflection point that warrants that acquisition size.

15:50But I think like there's actually an even larger number of these like assets where it's not going to be a multi-billion dollar exit, but like low nine figures for sure. Is that something that, you know, I think people should dedicate their lives to doing like absolutely not. Or maybe if that's your objective function, but, but for us, you know, if that went back onto the balance sheet, like the thought experiment was basically like a lot of those drugs, if that could go straight back onto the balance sheet, instead of getting circulated up back to the investors um uh sorry to the babylon investors then you know that's an amazing way for us to kind of like again financialize this process and sell funds so that by the time we have a drug on the market uh for alzheimer's that um you know we were able to take it away take it all the way through end to end without needing to kind of partner up at the very last stage right like how shitty would it be to run a marathon and you know you're you're three feet away from the finish line and then you have to you know hold hand in hand with a second place who was 10 minutes behind you.

16:43That would just feel super defeating. And so we don't want to give 50 % of our drug or whatever at the very finish line just because we ran out of money or we weren't able to take it through or what have you. The way I think about it is it's almost like a complex way of creating a new Google search where you just have this huge cash cow and you're able to siphon all the cash from it into the research angle. Sure, yeah. Commercial intermediates are things that I think people who are thinking on a, like founders specifically, who are thinking on a long time horizon should be very thoughtful about.

17:08I remember Viagra at one point was like a heart medication and then someone realized that there was another application for it um and so they repurposed it and now it's worth you know billions of dollars i think a year yeah how many drugs are like that out there okay you have already the research has already been done and you can just repurpose them for another use for another use um you know it's not as simple as the mechanism of action is you know i think um oftentimes like conceivably targeting the same target so like you know most molecules have a single target um and that target is um uh hopefully the thing that like elicits the salubrious effect if you target it um and so the the idea that like that same target um uh like you know for instance like sildanafil which is viagra um uh targets um i think it's a phosphatidesterase 4 inhibitor um but that target alone actually is relevant for Alzheimer's, which is super interesting, like totally makes sense.

18:05Because it's like proliferative in nature, it actually leads to like, you know, cell outgrowth and neurite outgrowth. And like, these are very good things in the context of Alzheimer's, where you're getting this degeneration, and you're actually stimulating regrowth. And so there was actually a study that well, okay, to close that point real quick. It does not mean that the PK itself, like the pharmacology of the drug may be totally different, maybe it doesn't even get into the brain. So whereas it could conceivably be efficacious by targeting the same thing. It's not going to actually get into the brain.

18:33So I guess that's my like non-answer, you know, avoidance of your question. Like, I don't know what the exact number really is and what the like Fermi estimate of that would be, but like I have to imagine there's probably hundreds, high hundreds of those opportunities out there where it would actually be a very good drug for the other thing. But probably the super majority of those are just like off patent and like there's no market there for you to actually advance it. Um, but I will, uh, say so, so, um, in the context of sildenafil, which is Viagra, I think there's a very interesting story, which is there was a study that basically, um, did, uh, look through electronic health records.

19:10And, uh, you know, there, the goal was like, look through the prism of epidemiology, see if you can see these trends and then like use that as a repurposing angle. um and so they found that people who took sidenafil were 69 percent less likely to develop alzheimer's um it was all caused dementia but um then then people who did not and this is like i mean it's just the the number alone is hilarious that viagra you know reduces your risk by that number but the um the overall was uh uh the conclusion was that okay well viagra should be repurposed for alzheimer's follow-on studies were not able to reproduce it there's probably some like bias in terms of people who take viagra need to have you know healthy hearts healthy hearts probably better you know overall like anti-hypertensives are also good for alzheimer's so like long term that's probably what happened there but um but still i just think there's a lot of these like provocative stories out there and there's an ai element to that as well we can get into if you're interested yeah i'm i'm down okay yeah so i mean i think like there was an information scientist called uh don r swanson um who did this thing called swanson linking which was like his whole thing was basically that um there are a lot of medicines uh out there that um can basically be discovered uh just based on information we already have not new information that we need and i i'm like totally in on that concept i think it's like you know in the graph theory formalism of it it's like you don't need to add a new node to the network to feel like you know that that will unlock new biology that you uh can drug it's like there's probably a lot of medicines out there that can come from just drawing edges between pre-existing nodes.

20:43And so he took that to the max. And this was like at a time where information gathering, scraping, all these things were like super analog. So like kudos to him. But there was a few examples like magnesium and migraine. But the big one that he did was for a thing called Raynaud syndrome, where he basically saw that Raynaud syndrome was linked to blood viscosity and that blood viscosity was also linked to fish oil. And so, you know, he therefore posited that fish oil would be good intervention to intercept or remediate the, the, the renaud syndrome, blood viscosity issue. And, you know, that was like a big paper that I believe did ultimately prove to be efficacious.

21:23So I think there's a lot of these, I think there's a lot of these, and I think LLMs have unlocked a new ability to actually be able to do that in high throughput. It's definitely something we've been exploring. I will see if it bear fruit, it bears any fruits, but I'm very bullish on that general concept of just like a is connected to b b is connected to c therefore a is probably connected to c um uh yeah is there any other like neurodevelopmental or like neurodegenerative diseases that are able to kind of be cured in the process of trying to solve alzheimer's oh interesting um if you believe that um phosphor-related tau and tau fibrillization is like causative for the cognitive impairment in alzheimer's which i certainly do um then uh uh absolutely there's there's like other tauopathies where that's the predominant pathology because part of the problem with alzheimer's is yes it's tau pathology but it's also amyloid pathology it's also neuroinflammation like there's a litany of different things going wrong in the brain um as you could imagine um and so uh it's much harder to kind of isolate the thing that is very much causative on the other hand you have like frontotemporal dementia you have pick's disease psp these other things where they are what are called tauopathies and that's like the predominant pathology in all of those is tau fibrillization um so uh yes it's definitely conceivable that like depending on how you target tau that could be efficacious and other diseases that are also rare and can also get accelerated approval and things like this and there's definitely companies out there doing that but um uh but yeah oftentimes like for something like alzheimer's you know if you have a rare disease where you have 100 chance of developing the pathology and you know going into this neurodegeneration i think you'd be fine with like you have a much higher tolerance for for toxicity you have probably you know a lot of these drugs are intrathecal so they have to inject into your spine basically um which i imagine is like a high bar barrier for sure and so um but people are trying this directly in alzheimer's there's a drug called bib 80 um from biogen and ionis and it's a talia so and that's intrathecally delivered And so, I mean, I don't know.

23:26Imagine giving your grandmother, you know, a spinal injection. It just, you know. You have to do this like multiple times? Yeah, multiple times. Yeah, dosing will vary. Eli Lilly has a tau siRNA as well. That's like similar thing, just intrathecal. And I think these things will be really important proof of concepts and like an existence proof that you can actually really stop progression of Alzheimer's because I do think we'll see the best efficacy so far. Like that's my prediction for this year is BID 080. is going to be the most efficacious drug for Alzheimer's yet. The readout is slated to be in May of this year, but I have a strong suspicion it'll be probably Q4 just because recruitment's really hard for things like that.

24:06People drop out because, again, they don't want to keep coming back and getting a spinal injection. But I think it'll be maybe not an amazing drug, but it'll definitely be an amazing proof of concept. And for the drugs that have shown to be somewhat efficacious for Alzheimer's, what's been the process for actually developing those? okay so rightfully so people as kind of mentioned previously were going after this like beta amyloid because that's the thing that's the most present or kind of salient pathology in the brain of an alzheimer's patient um and so monoclonal antibodies are a good modality because they're highly specific um uh if if they're like humanized then like you know it's there's no foreign agent that you're introducing into your body so there's no you know like minimal likelihood of getting an immune reaction things like this um and so uh the benefit of these antibodies is they get to where they need to go uh very efficiently well more on that in a second but um they they are highly specific and um highly efficacious once they target uh the the protein the problem is uh 0.1 of the antibody that you put into your body will actually get into your brain because there are these massive entities that are trying to be shuttled across the brain and so the first generation of these were like you know the first drug um so like alzheimer's field had um memantine in 2003 which was like basically a symptomatic treatment 19 years later you had aducanumab as it was like nothing for 19 years and then aducanumab which was considered a breakthrough biogen famously um and later infamously put this on the market despite not showing any cognitive improvement in these patients and um reverse you know fda adcom had i think it was 14 people on the panel zero of them approved it all of them rejected but it was submitted anyway there's a whole nother conspiracy around that we'll save that for you know people can google that if they're interested um but yeah it had an amazing job at removing these plaques absolutely no efficacy and um uh and the later generations got better and better so denanamab lakanamab which now is marketed as lakembi and then denanamab which is now marketed as kasunla and um and the latest one that i'm most excited about is a thing called trontinimab which actually hijacks a shuttle the transfer receptor in your brain so you have the blood brain barrier which is protecting things from coming in which makes sense you don't really want anything that's going into your body to go straight into your brain especially pathogens but this is basically hijacking that shuttle that allows for this active transport into the brain and it increases significantly the amount of antibody that can get in there and so trontinimab has like the best efficacy in terms of amyloid clearance ever um and uh i'm like super excited about that one especially a subcutaneous formulation because again going in every every other week or every month to get an iv i hate needles generally but like an iv going into an infusion clinic like when you're seven years old i don't know it just it's tough i remember i remember my uh my sister getting shots as a kid and she it was like the worst experience she was just like horribly crying and stuff and she really really hated it she had like ptsd from getting any shots yeah for the first like 18 years of her life um and and that was uh that was a very big barrier i just have to get my blood drawn yesterday i almost passed out really it's my biggest fear in life yeah i had uh i had a blood draw where they took like 28 vials of blood in in one go was this a like one of these health wellness this was it was like a full blood panel and um that was that was pretty rough i definitely almost passed out and threw up um i believe you from that so when you when you started this company you've been at it for about three years what was kind of the first few months or year like what what did you decide to go after excruciating for sure um i i mean you know to be fair on the investors i was going out pitching you know i basically was telling people we're gonna go cure this undruggable disease um uh i don't have a phd um and uh uh and i know there's all these failures but like trust me bro um and And and by the way, it's just me in my bedroom in New York line up.

28:02And it was so hard, so hard to raise money. I mean, like literally no one took me seriously. People were laughing at me. People, you know, fell asleep during calls. I had three people fall asleep during calls, like in the middle of calls. People would hang up after five minutes. People go. I mean, it was like really, really brutal. I'm glad I can laugh about it now because it was like I mean, it was just hilarious. Like I just kept like chewing glass and I was like it just became a game at a certain point. You know, it's kind of like, um, uh, and I had so much conviction in what I was doing. I put, I was self-financing all the experiment.

28:32I mean, it wasn't like I was going to stop any of the experiments. So paying for everything personally, um, you know, I think similar to you, just like credit score, like in the, to the toilet. Um, but, um, but yeah, I just like, it just made a lot of sense and like, I wouldn't do it any other way. Um, and I'm super grateful for that because it, it just like, you know, probably just crystallized the like general, you know, I'm incredibly strict on the finances and we're, relatively you know very lean by most comparisons um i would say and uh yeah a lot of that just came was birthed from like the pain of paying for you know everything with my personal credit card or like you know we do a high throughput screen and they'd be like you know hey please send your you know have your cfo send a po and like you know for the 59 000 wire and i was like you know do you take credit card yeah so it's like did you put a 59 000 wire on a credit card i ended up wiring it correctly for my savings.

29:21But yeah, it was, uh, did you have a lot of money to start this or not really? Not, not really. I would say like, you know, there was a brief period of like, you know, software ventures that I did. And, um, one of them became lucrative enough that it gave me the liquidity to do it. But I mean, I, for the most part had been paycheck to paycheck, like literally since starting the company, because I put all of that into the, that was like the pre-precede money of the company. What was different about the story that you were telling back then? Cause I know you kind of threw a whole bunch of no's and people falling asleep I imagine that you realize that something about this like if you want to get that money it's probably you probably have to tell a slightly different story than you're telling in order to to do that what what changed what shifted um it's funny I think like you know as someone who I'd like to pride myself on like updating my priors constantly um uh weirdly at the time I was relatively like stringent about this like I I think there was like you know maybe local fluctuations in terms of like I'd meet with the Boston investors and they'd be like hey your science is really cool but like who the hell are you and like why should we give you a penny um uh and you know and so maybe i kind of like spoke a little more formally or tried to be a little more you know present in the way that i thought was like necessary i'm very glad that that like you know i equilibrated and like yeah i just went back to just being me um but um but yeah i think like i was i was pretty strict about not like succumbing to that pressure because i really wanted people who were going to join the mission for the right reasons and if they were joining because they thought it was a like a very high probability thing or whatever like that was not the right partner i wanted to have for for the rest of my life and so um uh thankfully like long journey came in they were the first ones to observe the same set of facts and be attracted to them versus like repulsed by like you know maybe i won't name names but like one of the people at long journey when i told him about the life savings thing um he was like that is awesome it was the first person who was not like you're an absolute idiot what are you doing you know that's going to go to zero um it was someone who like actually saw the dedication and actually appreciated the fact that i was so committed and um uh so yeah thankfully they came in and you know since then uh thanks to to the efforts of the team like it's been our fundraising has gone much more smoothly since then that was the hardest round to ever raise um but uh but yeah i'm super grateful for it obviously in retrospect so if you have most people that you meet just immediately are basically turned off by i mean at least in the early days the idea that there's this like super low probability bet that will require a ridiculous amount of capital to actually even have a like reasonable shot in like a huge amount of time, maybe like 10 plus years.

31:50How did that kind of enable you to find and attract the right types of individuals to be supportive of the mission? That's a very good question because I think, I think again, a lot of the advice I was getting from the more like, you know, Boston biotech like archetypes was like, you need to, you need to work backwards from compensation, you need to go as high percentile as your burn allows you to, you need to, you know, and they gave me all this advice about winning the great talent over with the amount of equity and whatever else. And it just did not sit well with me. I just was like, you know, my goal is again, to assemble a team of best in class people that are missionaries, not mercenaries.

32:25And that was also something where I felt like I was getting constant external pressure to hire the right people. Thankfully, I was uncompromising in that. I was just really like so insistent on only hiring people who are going to work for the right reasons. Um, you know, I probably, um, uh, will not reveal my kind of like proxies for what ends up being very predictive of that. Um, but I, I, I certainly am like, I've got a very long list of things that I'm looking for when I meet someone and I don't do conventional like hiring processes or whatever. It's very like, get to know the person over many, many months and see how they kind of fare.

32:59Um, and, um, and be very sober with them about like, you're going to work your ass off. Um, you know, you're gonna age much faster probably than you would otherwise I'm not gonna be able to pay you you know more than anyone else yeah and I think that's actually a really good test because a lot of like especially here in Silicon Valley a lot of the people that are getting hired that are really really smart today are basically just getting ridiculously massive compensation packages and I think it kind of sets the wrong tone for why are you even working here like why are you working on this problem is it for you know 20 million or is it because you care about the thing?

33:35I think the fact that you have seen a massive kind of exodus of a lot of really exceptional talent or like the constant, you know, velocity of like people moving back and forth, like that's indicative of enough of that. That model is actually like not the right way to go about this problem. And so I think to whatever extent you can kind of filter a priority for those kinds of people, you're in a much better position, at least if you're working on something, you know, if we were a pure hedge fund or we're some whatever, like maybe it's a different story. But for me, you know, thank God I was very insistent on this and very like, yeah, like it kind of like weirdly turns out that the best people on the planet just want to work on the hardest problems.

34:15And so, you know, there was an early process of me trying to recruit these drug hunters. And when I'd go meet with like very talented people and I'd be like, hey, you know, I'm going after Alzheimer's. They're like, sorry, Alzheimer's is just like that's impossible. Like, good luck to you. Or they'd be like, hey, I need if you want my advice on anything, you need to start paying me 15 minutes into the meeting. I was like, no worries, let's hang up here. So, you know, I had to like filter through a lot of people took me a very long time. And then like one thing kind of flipped for me in terms of like the hiring process where I, I basically started looking for people that were just like the secret geniuses behind a lot of the success stories that I respected the most.

34:50And so one of them was, you know, the example of that was a thing. So Biohaven was a company based in New Haven that licensed a drug from BMS called Remedupin, and it was a CGRP antagonist for migraine. And anyway, they sold it for, I probably shouldn't disclose the number, but a very low amount of money. And then after having a successful phase three and going on the market, they were bought by Pfizer for$11.6 billion. It's considered one of the great successes in recent history in the neurospace. And so everyone was celebrating the executives that took that forward. And to be fair, Vlad Korich, who's the CEO and founder of Biohaven, is exceptional, world-class.

35:27Um, but I was more interested in the geniuses who like the medicinal chemists who actually invented those mall, that molecule. And, um, and so I ended up reaching out to everyone on that patent, the composition of matter patent for measurement. Um, I was most impressed with the lead inventor, John Macor. And, um, and again, I think like when I met John for the first time, I basically told him like, we're taking the biggest swing you can possibly take. This is like very, you know, any individual program is a very low likelihood of success. But like my goal is to literally get like the Avengers of drug hunting, throw them in a room and just throw them at this incredibly meaty problem.

36:00And John was like, you know, sign me up. I mean, there was not a, again, I think these other, one of the proxies I look for is like the extent to which they'll negotiate, right? John could get paid way more than what he's getting elsewhere. And, um, you know, we've been lucky enough to, to have him kind of come out of retirement to be with us full time. And like, that was just a direct buy product, not of the money, not of the equity, not of anything, but like, because of the passion and the nucleation of talent that we we've been lucky enough to do have money is definitely one factor for determining or figuring out rapidly whether or not someone is more missionary, more mercenary.

36:30But what have been the other biggest like indicators or signal for you over the past like three years that you've developed for figuring out whether or not someone's a missionary? Okay. I will give one version of this, which is it's been very predictive. If someone is willing to just like jam with me on science and have no, you know, it's not a formal hiring process. it's literally just like hey two people who are super passionate about this space let's just talk for hours unscripted just like are they willing to do that and not only are they willing to do that once but are they willing to do that like many many many times over many months and for me the people who are like the right people at least for Babylon are the ones who basically are so passionate about what they do they do this for free and like the thought of getting paid is just like sure I mean like it's a secondary kind of thing like a byproduct of the thing but it's totally exactly at all front of mind absolutely i mean i think like you know um yeah like and it's so funny because it is almost like the midwit meme but like i've just found that like the the best people in the world really are just so down to just chat science they don't the money is not what drives them um and and you know there's probably like a skew towards like you know something in there in terms of like they have to have some financial stability etc but like yeah the best people in the world really just love what they do so much that they fail retirement multiple times they're like in their 70s they still just want to chat signs of a random 29 year old yeah totally i mean like you know john i'm pretty sure has failed retirement like two or two times maybe this is the first time no i think he i think but bill at least has failed retirement a few times and yeah these guys are indefatigable i mean like it's i've been super impressed with the stamina like it inspires me to work harder seeing how how much you know how they when they do the 12 hour days when they're you know sending me emails at 4 a.m on a saturday like these are the kinds of things that for me i just you know the command the ultimate respect like late 60s early 70s still working that hard like they must really love what they do and those are the kinds of signals i look for at least did this sort of process where you're really trying to optimize for these people that are working on the problem purely because they care about the problem did you basically have any other approaches at the very beginning where you went in another direction because you initially thought that that was the right mode of operation and then kind of worked backwards and said no this was a mistake i'm gonna go in a different direction um I think there is like a really tough balancing act between, you know, you may have acute needs that like you need to immediately reconcile.

38:56And like part of that is a, you know, ends up skewing you towards just like compromising your standards in favor of like moving very quickly and plugging the wound, so to speak. And like, you know, I'd be I'd be lying to say there haven't been like, you know, examples of that. But, you know, overall, I think our hit rate is really high. And like part of it honestly started with Laura, who's our first hire. She's the founding scientist of the team. She's just an incredible workhorse and was like so, so, so just like dedicated from day zero. Like I met her and, you know, to be fair, I think I'm audacious enough that like I just I'll have people do the work and, you know, see what happens.

39:35And so like first time I met her and I was still in New York at the time and I was super impressed. And I just said, you know, the next day I was like, hey, I'm stuck in New York. I need you to start going to all these different labs that I'm looking at in San Francisco. And by the way, some of them are like two hours outside of San Francisco. And like, by the way, I don't really have money to pay you. Uh, or I definitely didn't have money to pay her generally, but I definitely couldn't pay her to, um, uh, uh, even get the Ubers because all of my money was just like going straight to these, uh, these experiments I was running.

40:03And so, um, she, uh, yeah, just was like, okay, I guess, I guess, you know, sure. And, uh, you know, she helped out as a friend for a long time and then, uh, you know, things kind of worked out. And when she was finished with her postdoc at UCSF pulled her in full time but um yeah like that kind of dedication I think set the stage for everyone else and definitely like held my bar very high insofar as it related to future hires keeping the DNA right yeah keeping the DNA right and like it's like such a it almost feels platitudinous at this point when people say like well the first 10 hires will define like the rest of your company but it's like we're still super early days at Babylon like this isn't even chapter one in my opinion but it is um like I couldn't be more true um and I think just being like you know culture can only be defined by what you're willing to fire for in my opinion and i just think yeah people are like very scared to do that but but in doing so they actually it's like an adverse selection for future hires because if people feel like oh well the bar is kind of like all over the place like that's not going to hire the best people and so i think just being super super strict about that and uncompromising even if you really like the person is like really has been important for us at least so alzheimer's is something where there's very long feedback loops And I think this is going into it.

41:13You recognize that this is like a multi-decade journey where there's not really a very clear end date or like, you know, this is when we're going to solve it. How do you both maintain that very long term view while also keeping your foot on the gas as much as possible? I think a huge part of why the team works so hard is because, again, like I've I've just filtered for that up front and like, you know, maybe this is ignorant, but I'm very much of the belief and have come to the realization that the super majority of management problems are actually just high hiring problems that are kind of masquerading as something else.

41:47And so, you know, I don't have to like push the team to be working, you know, from, you know, early in the morning to late at night, like that is, that's a byproduct of the people that I've happened to have filtered for. And, and so I think like, you know, the, the burnout thing is like, um and again like three years in but like at least i personally have been working this way for pretty much my whole life like i think um when you're just incredibly passionate about something there's just like a infinite resource um that you can tap into and i think the burnout does come as a byproduct of like not having impact so that that definitely matters and that's been said before but like yeah again like how are you able to get like a 67 year old flying red eyes every other week from new jersey and like working 12 hours a day like i don't know i think it's just like hiring for someone who is just built like that, right?

42:34Like, Darion, our team is built different. Like, he's a beast. Sam Altman has talked about the idea of burnout in the past, and I think he basically said, like, work does not actually cause burnout. What causes burnout is losing. Absolutely. And if you're always winning, and you feel like there's momentum, you never burn out. Yeah, I'd probably, like, you know, fork that idea and put, like, a corollary to it, which is, like, maybe. But my revision, actually, of that would be that I think it's, like, a lack of agency that breeds burnout. it's actually not like losing. Because if you feel like you had agency over the decision and it blows up in your face, I still think like you internalize that differently than if something blows up in your face and it wasn't even like you had no control over the situation.