"You always have to start by asking yourself, did evolution spend a lot of time optimizing this? If yes, my job is going to be insanely hard. If no, potentially there are some lowhanging fruit. And so ..."

"aging. That's getting eaten by a tiger. That's falling off a cliff. That's like scraping your foot on a rock and getting an infection and dying from that. And so from the best evidence we have, the ba..."

"thesis. You know, I think in biology in general, when you're trying to engineer a given property, be it being healthier longer, be it making something more intelligent, and this is true even at the mi..."

"very intermediate goals that last an hour or a couple hours, it's actually surprising that any signal propagates across a 20 20 year horizon. Um, by the way, on the point about fluid intelligence spea..."

">> the third piece is basically optimization constraints so I think this is where another ML analogy is helpful which is something like well actually a two-layer neural network is technically a univer..."

"antibiotics. Yeah, it's actually an excellent question that I haven't heard posed before. Um so we think about where do antibiotics come from? To your point, we could synthesize them. They're just met..."

"getting there, is that bacteria and other types of microorganisms are very well adapted to building these complex metabolic cascades that are necessary to make something like antibiotics. And they are..."

"sequences. In mammals where I do know a bit better, we do have examples of this where there is this co-evolution of pathogen and host. Imagine you have some antiathogen gene A fighting off some virus ..."

"a situation where you can go in and take human cells and make just a couple edits in that trim 5 alpha gene and it's currently protecting against a virus which no longer exists and you can edit it bac..."

"a minimal number of mutations, but then you lose its original function. So we have this nice feature of the genome, which is it can just copy and paste. And so occasionally what'll happen in evolution..."

"instance, in trim 5 alpha for this particular phenomenon we're talking about for memory, but it's in like the tens. It's not it's not that you need massive kilobase scale rearrangements. It's actually..."

"Okay. Um, back to aging. You'll cancel your evening plans. I've got so many questions for you and I keep going. Um, so the second reason you gave which was that there's selective pressure against peop..."

"There's not going to be a singular magic pill, but rather you're going to have medicines that add multiple healthy years to your life, years you can't otherwise get back, but it's not going to fix eve..."

"All right, back to Jacob. All right, so um uh evolution didn't select for aging. What are you doing? What's your approach at New Limit that you think is um is likely to find the true cause of aging? >..."

"combinations of these transcription factors that are able to actually remodel the epiggenome so that they can bind to just the right places in the DNA and then shift the chemical marks back toward tha..."

"also measure any potential detrimental effects that that emerge. >> So there are canonical examples where you can seemingly reverse the age of a cell for instance at the level of a transcriptto but si..."

"question, but it will help me understand why an AI model is necessary to do any of this work. So, you mentioned the Yamanaka factors. From my understanding, the way he identified these four transcript..."

"imagine some arbitrary mappings as well. And so I think as you get to these more complex problems that don't have the same features that Sha benefited from, which were the ability again to measure suc..."

"large changes in phenotype. Otherwise, it would just take a very long time across evolutionary history for enough mutations to accumulate in some duplicated copy of the gene for you to evolve a new TF..."

">> Yeah, you're you're sort of hinting that uh if we analogize it to some code base, we're going to find a couple lines that are like commented out that's like daging, you know, and then like unhyen o..."

"what's occurring. And so that ultimately leads to transcription factors being some of the final aectors in these signaling cascades. So a lot of the drugs we have that for instance inhibit a particula..."

"think it's pretty exciting is we now have new nucleic acid and genetic medicines where you can for instance deliver RNAs to a cell that can get through using tricks like lipid nanoparticles. You wrap ..."

"types with lipid nanop particles. So even if nothing else worked for the next several decades I think companies like ours would have more than enough problems to solve and with the cells that we can a..."

"which is how do I patrol the body, find arbitrary signals in the environment, and then deliver some important cargo there when some set of events happens. how do I you know find a specific place and o..."

"think that's ultimately how delivery will get solved. We've got many many stepping stones along the way. But if I could like clone myself and work on an even riskier endeavor, that's probably what I w..."

"delivery folks credit, they're currently ahead. There are currently no reprogramming medicines for aging and there are medicines that deliver nucleic acids. So like they're still winning the race agai..."

"sort of implies the inverse may also exist. >> Is this related to why has so many downstream positive effects that seem even not totally related to its um effects just on making you leaner? Yeah, I th..."

">> Interesting. How big will the payload have to be? >> Uh, how many transcription factors? >> Yeah, >> I think just a countable number. I think some of those that we found today that have efficacy ar..."

"either. >> And is it would it have to be a chronic treatment or could it just be a onetime dose? >> In principle, it could be one time. I think that would be an overstatement for today, but I can sort..."

"don't want to overstate. Um, we do have data that these positive effects can last several weeks after a dose. And so you could imagine even without many leaps of faith up toward this upper bound limit..."

"about the effects of aging which are um okay so I don't know your skin starts to sag because of the effects of gravity over the course of decades. Is that a cellular process? How would how would some ..."

">> Interesting. Okay. What is Arum's law? Iram's law is a funny portman who created by a friend of mine Jack Scanell where he inverted the notion of Moor's law which is the doubling of compute density..."

">> So, you need to then be able to find medicines that treat most people. All of us will one day get sick and die. So, arguably the TAM for any really successful medicine could be everybody on planet ..."

"Yeah. In this particular case, if we we bound ourselves to we must use small molecules as our modality, then there are lots of targets which are very difficult to drug. There are many other modalities..."

">> So there are multiple ways one might approach this problem. the most common today. Um, this is often what people are describing when they talk about a virtual cell. This is sort of a a very nebulou..."

"that's another version of what would a all-encompassing model look like where you actually have compounding returns in drug discovery. >> Right. And you basically described um one of the models you gu..."

"These are all questions you can ask. They're not the ones we're going after, but that that is the more general broader vision. >> This is so similar to in LLMs. You have first imitation learning with ..."

"Potentially. It's more like developmental biologists locked in a room as my friend Cole Trapnel would say. >> Um, it seems like what you're describing seems quite similar to perturb. And we've had per..."

"ask questions like, well, I've turned on genes A and C. What did it do to the rest of the cell? So that's the general premise of the technology. And so it's useful to just set that up because it expla..."

"They've all improved to the degree where now you can actually operate at scale. And then groups like ours have had to do a bunch of work in order to actually enable combinatorial perturbations, turnin..."

"different companies that have um you know are doing these cheap uh perturb like experiments and building their own virtual cells or at least a couple um and then they're like leasing this out to other..."

"carving out a region of this massive parameter space and saying if we can learn the distribution of effects even just in this small region it's going to be really effective for us and we can make real..."

">> Interesting. And then um this is more more a question about the broader pharma industry rather than just new limit which is that in the future how are people going to make money if you have you kno..."

"measuring that. So that's a big a big challenge in this industry is like how would you demonstrate that any one of these medicines is still working for the patient. In the few examples we have today, ..."

"looked the numbers up, but the overwhelming majority of this is going to administering treatments that have already been invented. Um, which is good, but nowhere near as good as spending this enormous..."

"these are things that biotech probably isn't going to be able to solve as an industry alone. That's probably a larger a larger economic problem. But when you think about how will this affect sort of t..."

">> Okay, final question. Um, so pharma is spending billions of dollars per new drug it comes up with and surely they have noticed that the lack of some general platform or some general model has made ..."

"something like 70% of molecules approved in a given year come from originally small biotechs rather than large pharmas even though you look at the actual like dollars of R&D spend on the balance sheet..."