YouSaid · the spoken record

Jacob Kimmel

lines on the record: 109
first: 2025-08-21
most recent: 2025-08-21
sittings or episodes: 1
sources: podcast

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“Who is like a thousand times smarter than me? And she's one of the people who invented this technology and has a big group doing this sort of work there. So it's not like every pharma takes that view, but I think that's sort of a general trend.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Another disintermediation. And part of the reason for that difference in cost is they're running most of the trials. Most people partner with Pharma to run trials where a lot of the costs are incurred. So it's not just that, oh, all large farmers are horribly inefficient or anything like that. I think some of them would tell you these ideas are really exciting. We have an external innovation department. If we don't have one internally or we're collaborating with a startup that's doing something similar. And so you can kind of think of a market structure like you have a bunch of biotechs, which are kind of like the startups in your ecosystem. And then they're working with something like an oligopsony of pharmas where it's like a limited number of buyers for this particular type of product, which is a therapeutic asset that is ready for a phase one, phase two trial. And so there's a very liquid market for the phase one, phase two assets, and that's the point at which these partnerships can come to fruition. And so I think that's what a lot of those leaders would say. Now, some of them, by contrast, for instance, Roche bought Genentech back in 2013. R&D is currently run by Avivor Gev, one of the scientists I admire most in the world.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“About some of the modern pharmas a bit like venture capital firms, where they've over time externalized a lot of their R&D. And so they often have divisions of external innovation, which you can kind of think of as like the Corp dev version of venture capital. They work with the biotech ecosystem to have a number of smaller nimble firms explore really pioneer ideas, like the types of things we're working on, and then eventually partner with them once they have assets that are later downstream. And so I think the industry has sort of bifurcated where smaller biotechs like ours take on most of the early discovery. The stat I'm going to get a little bit wrong from memory, but it's 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 dollars of R&D spend on the balance sheet and it's like largely in big pharma.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, so I'll just correct one thing to make sure I'm not overstating. We have way more data for a particular limited subproblem we're tackling, which is overexpressing TFs in combinations. I think we have way more data than anyone on full stop there, but even more specifically, I feel very, very confident we have more data than anyone looking at trying to reprogram a cell's age. So that's where we're way larger than the rest of the world. When we think about just general single cell perturbation data, various flavors, then I think there are other groups which have very large data sets as well. We're still differentiated because we do everything in human cells with the right number of chromosomes, whereas it's very common to do things in like cancer cell lines, which have 200 chromosomes. So that human, I don't know, depends on how you actually quantify these things. So then if you're going to go ask the leaders of some of the traditional pharmaceutical firms, like, are you trying to build a general model? I think some of them have in-house AI innovation teams that are working on this. They're really smart people there. But I think as a general trend, I think you can think.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“That keeps your liver or your immune system younger. I think on net, that actually starts to drive healthcare spend down because you're sort of shifting some of that burden from the administration system to the pharmaceutical system. And the pharmaceutical system is the only piece of healthcare where technology has made us more efficient. As drugs go generic, actually the cost of administering a given unit of healthcare is going down. And the grand social contract is that they eventually go generic. That's the way our current IP system works. So I think if you were to get the question of when would you like to be born as a patient? You always want to be born as close to today as possible. Because for a given unit in terms of pharmaceuticals, for a given dollar unit of expense, you can access more pharmaceutical technology today than has ever been possible in history, even as healthcare costs everywhere else in the system have shot up. And so pharmaceuticals are the one place where because of the mechanism of things going generic and the fact that our old medicines continue to work and persist over time, you're actually able to get more benefit.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I think the latter is much more How will this affect the total amount of health care that will need to be delivered? If you have more of these, what I like to think of as sort of like medicines for everyone, medicines that keep you healthier longer rather than medicines that only fix a problem once you're already very sick, I think you actually avoid a lot of the types of administration costs, not just administration like admins at hospitals, but the cost of administering existing medicines and therapies to you going down. One doubt on why I think that's true. Something like a third of all Medicare costs are spent in the final year of life, which is shocking when you realize that the average person on Medicare is, I don't know the exact number, but probably a decade plus covered by it. And so there's an incredible concentration of the actual expenses once someone is already terribly sick. Meaning something like an inpatient hospital visit, if you can prevent even just a couple of those visits over a long period of someone's life with a medicine like an increment medic, like a reprogramming medicine.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I think that's correct. So I think the stat is something like drugs are roughly 7% of healthcare spend. I could be a little bit wrong on that, but the oom is right.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“When not involved, you know, some intermediary compounder in the middle that might not even make your molecules properly. And I think as these medicines develop that have actual consumer demand because you feel it in your daily life, you're actually seeing a benefit from it. It's not just something that your physician is trying to get you to take, that that model will start to dominate. And that means that this sort of like payment over time for some of these long-term benefits might be able to be abstracted away from our current payer system where it churns every few years. And now a sort of like payment over time plan the same way we finance other large purchases in life seems very feasible.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“In post affordable care act in the US where pre existing conditions no longer really exist so patients are able to freely move between pairs and you could sort of treat the presence of one of these therapeutics lowering this patient's overall health care costs the same way we treat a pre-existing condition I think this is something that the system is still overall figuring out so what I'm saying here is one hypothesis about what the future might look like but I think there are alternative clever approaches people might think about for reimbursement I also think over time we're going to move more toward a direct-to-consumer model for many of these medicines which preserve and promote health rather than just fixing disease you're seeing what I think are really some of the most innovative examples of this right now from Lily around the incridimetics where they actually launched Lily Direct so for the first time rather than going to a pharmacy which interacts with a PBM which interacts with your primary care physician now you can get a prescription from your doctor go straight to Lilly the source of the good stuff and you're able to order high quality drug from them”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“And so I think there are a couple models here that can make sense. One is something called pay for performance, where rather than reimbursing all of the cost of the drug upfront, you actually reimburse it over time. So say you get a medicine that just makes you generically healthier and you can measure the reduced rates of heart attack and reduced rates of obesity and various other things. And you get this one dose and it lasts for 10 years. Each year you would pay something like a tenth of the cost of the medicine contingent on the idea that it was actually still working for you and you had some way of measuring that. So that's 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, these are things like gene therapies where you can just measure the expression of the gene and like, okay, the drug is still there. But it gets more complicated when you have some of these sort of longer term net benefits. And the idea would be that then each insurer is incentivized to just pay for the time of coverage that you're on their plan. And we already have a framework for this.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Consider that to be a tremendous concern writ large. I do think the broader point of if you have medicines with very long-term durability, how do you reimburse them? Or if just the benefits are very long term and sort of accrue in the out years, a challenge we have in the US system is that the average person churns insures every three to four years that number fluctuates around, but that's the right order of magnitude. And that means that if, for instance, you had a medicine which dramatically reduced the cost of all other healthcare incidents, but it happened exactly five years after you got dosed with it, no insurer is technically, economically incentivized to cover that.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“The gray market piece will maybe put aside and say that's sort of an IP enforcement at a geostrategic level that I'm maybe not qualified to speak to, but I do think it comes down to IP enforcement effectively. I think for that gray market piece, another reason that sort of the traditional pharmaceutical industry, I think, will still continue to reap the majority of rewards here is that most of the payment in the United States, which provides most of the revenue for drug discovery in the world, goes through a payment system that is not just direct consumer. It goes through payers. And so if you have the opportunity to either order a sketchy vial off of some website from some company in Shenzhen, or you can go through your doctor and get a prescription with a relatively low copay for Trazepitide, the real thing. I think most patients will go for Trazepatide. I think you and I probably live in a milieu of people who are much more comfortable with ordering the vials from Shenzhen than most people might be. But I don't.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Every possible gene perturbation in every possible cell type. And then building the first products based on that, and then expanding from there. And so we think that's necessary because of where we are today. There isn't this internet-like equivalent of data that everyone can go out and reap rewards from.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I don't know enough about the underlying mechanics to know if that would have been feasible, but it's a much more feasible problem than trying to create the most recent cursor agent or compete with modern cloud code. I think that's roughly the equivalent where the problem we're breaking off is a subset of the more general virtual cell problem. We're trying to predict what do groups of transcription factors do to the age of very specific types of cells. We only work on a few cell types at Nulamant because those are the only cell types where some of the only cell types today we believe we can get really effective delivery of medicines. And so we think they're just more important because we can act on them today if we solve the problem of what TFs to use. We can make a medicine pretty quickly. So in a way, we're 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 really amazing products unlike the world has ever seen. And over time, we can expand to this more general corpus of predicting”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, yeah. Maybe to play with the analogy a bit, imagine that you think about New Limit as an LLM company if I'm going to put us in the shoes of cursor, which, oh, so I wish. Imagine we're trying to, in 2018, create cursor tab, but we're not trying to create a full LLM. Right.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Of, like, you could detect roughly 50% of them, then the fraction of cells that would be correctly labeled is like 1 over 2 to the n where n is the number of genes you're trying to detect, and very quickly it's like more of your data is mislabeled than it's labeled. So there's lots of technical reasons like this that have gotten worked out over time. And so only now are we really able to scale up where we're able to run experiments that are in the millions of cells in just a single day at, for instance, a small company like New Limit. There was a point even just six or seven years ago where the companies that made these reagents were publishing the very first million cell data set just as a proof of concept and only they could do it as the constructors of the technology and now two scientists in our labs can degenerate that in an afternoon.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Sound like a trivial sort of technical piece, but imagine you're running this experiment the old fashioned way where you test different groups of genes and different test tubes on a bench. Now imagine you hired someone who every other tube labels it wrong. So when you then collect data from your experiment, you basically have no idea what happened because you're just randomized all your data labels. You wouldn't do much science and you wouldn't get very far that way. So a lot of those technologies have improved to the point where you had a number of processes which are pretty inefficient and you multiplied a lot of these things together and ended up with like a very small outcome of successful cells you could actually sequence. 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, turning on more than just one gene at a time, which it turns out is much, much harder for the same reason we're just alluding to. Imagine you're having trouble figuring out which one gene you put in this cell and turned on or off. Now imagine you have to do that five times correctly in a row. Well, if you start out with the original sort of performance,”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Explains why this didn't all happen earlier. One, the actual readout, ripping the cells open and sequencing them used to be pretty bad, and it used to be really expensive. And it's gotten much better over time. So the metric people often think about here is like cost per cell to sequence. It used to be measured in dollars and now it's measured in cents and down to the fractions of cents because that cost curve has made dramatically. The cost of sequencing has likewise come down. So even beyond the actual reagents necessary to rip the cell open and turn its mRNAs into DNAs that are ready for the sequencer, now the sequencer is cheaper. The other piece is actually getting these genes in and then figuring out which ones are there started out pretty bad. So when we started with this technology, it was a beautiful proof of concept, but I don't think anyone would tell you it was 100% ready for prime time. When you sequenced a cell, only about 50% of the time could you even tell which perturbation you put in? Sometimes you just wouldn't detect the barcode and you'd have to throw the cell away or you detect the wrong barcode and now you've mislabeled your data point.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Why is this taken so long? Yeah, yeah. Good questions. So the original procedure was created by a bunch of brilliant folks. There's a group in Edo Ahmed's lab at the Weisman Institute, Aviv's lab at the Broad where Trade Dixa, a friend of mine, helped work on this. And then Jonathan Wiseman's lab at UCSF, where Brit Adamson did a lot of the early work. They all constructed this idea where you can go in and you label a perturbation that you're delivering to a cell. So this is typically a transgenic perturbation, meaning you're integrating some new gene into the genome of a cell, and that turns another gene on or off. They used CRISPR, but there's lots of ways to do it, and the concept's pretty general. And then you attach on that new trans gene, that new gene you put into the genome of the cell, some barcode that you can read out by DNA sequencing. So now when you rip the cells open, you're able to not only measure every gene they're using, but you also sequence these barcodes and you know which genes you turned on and which are off. So you can then start to ask questions like, well, I've turned on genes A, B, 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”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“This one looks really great. I love that one potentially, potentially. It's more like developmental biologists locked in a room, my friend Cole Trapnell would say.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Task that you're trying to optimize for in drug discovery, you would then need to know well, what are the cell states I want to engineer for? That's kind of the next generation of what a target might be beyond just which genes do I want to move up and down and which genes perturbations do I put in, you then need to know what cell state am I engineering for? What do I want this TCL to do?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, they do. I think the conceptual analogy is very apt. We don't actually use RL at the moment, so I don't want to overstate the level of sophistication we've got. But I think the general problem reduces down in a similar way. And so you can think about your earlier question of what does the general model look like that enables you to actually have compounding returns in drug discovery. Well, you might have something like this base model, which, as you said, just predicts this object function of how are these perturbations hitting these targets going to”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“A younger cell, and I'm going to select on that and train ahead to predict it where I can denoise across genes and then select for younger cells. But you could do that for arbitrary numbers of additional heads. What are some other states you might want? Do I want to polarize T cells to a less inflammatory state and somebody with an autoimmune disease? Do I want to make liver cells more functional in a patient who's suffering from certain types of metabolic syndrome? Be that maybe even orthogonal to the way that they age? Do I want to go in and change the way a neuron is functioning to a different state to treat a particular type of neurodegenerative disease? These are all questions you can ask. They're not the ones we're going after, but that is the more general broader vision.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, absolutely. So I think what we actually do both today. So we can train these models where basically the inputs are a notion of what that cell looked like at the starting place. Here's what a generic old cell looked like. And then representations of the transcription factors themselves. We derive those from protein foundation models. They're language models basically train on protein sequences. Turns out that gives you a really good base level understanding of biology. So the model is kind of starting from a pretty smart place. And then you can predict a number of different targets from some learned embedding the same way you could have multiple heads on a language model. And so one of those for us is actually just predicting every gene the cell is expressing. Can I just recapitulate the entire state and guess what effect these transcription factors will have on every given gene? And you can think about that as like an objective rather than a value judgment on the cell. I'm not asking whether or not I want this particular transcriptome. I'm just asking what it will look like. And then we also have something more like value judgments. I believe that that transcriptome looks like”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Back to something like healthy cells. So that's another version of what would an all-encompassing model look like where you actually have compounding returns in drug discovery.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Entrance I can find that I'm able to experimentally in the lab that shift one toward the other. And then the hope would be because you're not never going to be able to scan combinatorially all the possible groups of genes just to make that concrete. It's going to be round with it, but there's something like 20,000 genes in the genome. You can then choose however many genes in your combination you want. It's not crazy to think of hundreds at a time. That's what transcription factors control. That's how development works. So the number of possible combinations is truly astronomical. You just can't test it all. So the hope would be that by doing some sparse sampling of those pairs, your inputs are, here's what the cell looked like beforehand, here's the particular genes I perturbed, you have some measurement then of the state that the cell resulted in. So here's which genes went up. Here's which went down. And then you can start to ask, once I've trained a model to predict from the perturbations to the output on the cell state, what would happen for some arbitrary combinations of genes? And now in silico, I can search all possible things that one might do and potentially discover targets that take my disease cell.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“So there are multiple ways one might approach this problem. The most common today, this is often what people are describing when they talk about a virtual cell. This is sort of a very nebulous idea, sometimes numinous, if you'll let me describe it in that way as well. But I think most concretely what most people are trying to do is measure some number of molecules or some sort of perceived emissions like the morphology of a cell, and then perturb it many times, turn some genes on, turn some genes off, and measure how that molecular morphological state changes. The notion is that there's a lot of mutual information in biology. So if I measure something like most commonly, all the genes the cell is using at a given moment, which you can get by RNA sequencing, that I get a decent enough picture of most of the other complexity going on. And so that I can, for instance, take a bunch of healthy cells and a bunch of cells that are in a diseased or age state, and I'm able then to compare those profiles and say, okay, my disease cells use these genes, my healthy cells use these, are there NT interventions?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Hook as you put it in order to do that. It's a relatively short list. What you're not going to get is anything approximating the panoply of human pathologies that develop. And you can actually look for this. There are some existence proofs you can look for out in the universe, which is to say, if the only problem was that we didn't have the ability to drug something using current therapeutics that we can put in humans, we should still be able to treat it in the best animal models of that disease because we can use things like transgenic systems. You can go in and you can engineer the genome of that animal. And so this gives you all sorts of superpowers that you don't have in patients, but allow you to, for instance, turn on arbitrarily complex groups of genes in arbitrarily specific or broad groups of cells in the organism at any time you want, at any dose you want in the animal. And for the majority of pathologies, we just don't have many of those examples.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, in this particular case, if 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 by which you can drug some of these genes. And I would say, I don't have a formal way of explaining this, but if you were to write out a list of well-known targets that many, many folks would agree are the correct genes to go after and to try and inhibit or activate in order to treat a given set of diseases. And the only reason we don't have medicines is that we can't figure out a trick in order to be able to drug them. It's a fairly small list. It would probably fit on a single page. Whereas the number of possible indications that one could go after and the number of possible genes that one could intervene upon, especially when you consider their combinations, is astronomical. I think the experiment you could run here is if you lock 10 really smart drug developers in a room and you tell them to write down some incredibly high conviction, target disease pairs where they're sure if they modulate this biology, these patients are going to benefit. And all they need is some molecular”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Gene to go after, and most of the risk is not in how do I make an antibody to treat my particular target, it's in figuring out what to target in the first place”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“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 Earth. So we need to find a way to be able to route toward medicines that address these very large populations. The second piece then is how do we actually build models that enable us to take the success in one medicine we've developed and lead that to an increased probability of success on the next medicine? Traditionally, we haven't been able to do that. Maybe you're better at making an antibody for gene Y because you made one for Gene X five years ago, but it turns out making an antibody isn't really the hard part of drug discovery. Figuring out what to make an antibody to target is the hard thing about drug discovery. What gene do I intervene upon in order to actually treat a disease in a given patient? Most of the time we just don't know. And so that's why even if a given drug firm becomes very good at making any bodies to gene X, they have a successful approval, when they then go to disease Y, they don't necessarily know”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Traditionally, when we've developed medicines, we go after fairly narrow indications, meaning diseases that fairly small numbers of people get. And that's actually increased in terms of the narrow scope of what medicines are addressing as we've gone forward in time. And so there's sort of an ironic situation where we've gone from addressing pretty broad categories of disease like infectious disease to narrower and narrower genetically defined diseases that have small patient populations because these only affect a few people if you think about the value function of a medicine is how many years of healthy life does it give how many people if how many people is pretty small it just really bounds the amount of value you're able to generate”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Of potential beneficial spin. So I think there are a few different versions of this you could imagine, but I'll address the first point. How do you get to a place where you're actually able to generate more revenue per medicine so that potentially the outputs you're generating are more valuable, even if each output might cost a bit more?”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“To eventually replacing large fractions of white collar intelligence. In biotech, when you're traditionally able to develop a medicine in a given indication, I was able to treat disease X. It doesn't necessarily engender you to be able to then treat disease Y more readily, typically where these firms, biotech firms in general, have been able to develop unique expertise is on making molecules to target particular genes. So I'm really good at making a molecule that intervenes on gene X or gene Y. It turns out that the ability to make those molecules more rapidly isn't actually reducing the largest risk in the process. And so this means that the ability to go from one or two outputs one year to then going to four the next is much more limited. And so this brings us then to the question of what would the general model be in biology? And I think it kind of reduces down to how do you actually imbue those two properties that create the ML scaling law curve of hope and bring those over to biology so that you can take the EROMs law curve and potentially give it the same sort of”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Okay, I'm going to slightly dodge your question first to maybe analyze something really interesting that you highlighted, which is you have these two phenomena, again, ML scaling and then scaling in terms of the cost for new drug discovery. Why is it that the patterns of investment have been so different? I think there are probably two key features that might explain this difference. One is that the returns to the scaled output in the case of ML actually are expected to increase super exponentially. You actually reach AGI. It's going to be a much larger value than just even a few logs back on the performance curve that people are following. Whereas in the life sciences thus far, each of those products were generating further and further out on the EROOM slot curve as time moves forward haven't necessarily scaled in their potential revenue and their potential returns quite so much. And so you're seeing these increased costs not counterbalanced by increased ROI. The other piece of it that you highlighted is that unlike building a general model where potentially by making larger investments, you're going to be able to solve a broader addressable market moving from solving very narrow tasks.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Iram's law is a funny port mentor created by a friend of mine, Jack Skinnell, where he inverted the notion of Moore's law, which is the doubling of compute density on silicon chips every few years. So Moore's law has graciously given us massive increases in compute performance over several decades. And Eroom's law is the inverse of that because in biopharma, what we're actually seeing is that there's a very consistent decrease in the number of new molecular entities, so new medicines that we're able to invent per billion dollars invested. And this trend actually starts way back in the 1950s and persists through many different technological transitions along the way. So it seems to be an incredibly consistent feature of trying to make new medicines.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“So, I think the eventual solution for something like that is likely that you need to program cells to states that are extra physiological. There might not be a cell in your body. It's not just like a young skin cell from a 20-year-old is better at making these fibers, as far as we can tell. They don't. But you could probably program a cell to be able to reinvigorate that polymerization process to run along the fiber and repair it in places where it's damaged. Obviously, these things get made during development, so it's totally physically feasible for this to occur. Maybe there's even a developmental state which would be sufficient to achieve this. I don't think anyone knows, but that would be the kind of state that one might have to engineer de novo, even if our genome doesn't necessarily encode for it explicitly.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Best evidence is that it's probably not cellular. So, the reason your skin sags is there's a protein in your skin called elastin, which does exactly what you'd think it would based on the name. It kind of keeps your skin elasticky like a waistband and holds it to your face. So you have these big polymerized fibers of elastin in your face. And as far as we understand it, you only polymerize it and form a long fiber during development. And then the rest of your life, you make the individual units of the polymer, but for reasons no one, as far as I can tell, understands, they fail to polymerize. And you can't make new long cords to hold your skin up to your face.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Efficient IPSC reprogramming so it could take somatic cells and turn them into pluripotent stem cells more effectively than you could with just the canonical Yamanaka factors which are OCT4, SOCS2, KLF4, and MIC. IPSC reprogramming never happens in nature, so there's no reason to necessarily believe that the natural TFs are optimal. And so even really simple optimizations, like just mutagenizing one of the four Yamanaka factors we already know about, or swapping some domains between a few TFs, seem to improve things dramatically. So I think that's a pretty good signal that actually”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I think it's less likely. I think you have a prior that evolution has given you a reasonable basis set for navigating the states that human cells might want to occupy. And in our case, we know that the state we're trying to access is encoded by some combination of these TFs. It does arise in development, obviously. We're trying to make an old cell look young, not look like some Frankenstein cell that's never been seen before. That said, we don't have any guarantees that the way aging progresses is by following the same basis set of these transcription factor programs in the genome that are encoded during development. So I don't think it's unreasonable to ask, would your eventual ideal reprogramming medicine necessarily be a composition of the natural TFs or would it include something like TFs from other organisms as you posit, or even entirely synthetic transcription factors as well? Things like Supers. SuperSox is a particular publication from Sergei, I might mispronounce his last name, Vilichenko, where they mutated the Sox2 gene and they made more”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“We don't have data like that today, so I don't want to overstate. 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 of what's possible, just from the data we have in hand now, that you could get doses every month, every few months, and actually have really dramatic benefits that persist over time rather than needing, for instance, to get an IV every day, which might not be tractable.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“And we also know that with very targeted edits, other groups have done this, folks like Luke Gilbert now at the Ark Institute, who I think of as like one of the great unsung scientists of our time, have been able to make a targeted edit in a single locus and then show that you can actually make cells divide 400 plus times over multiple years in an incubator in the lab. So imagine like a hot house where you're just trying as hard as you can to break this markdown and it can actually persist for many years. Other companies have actually now dosed some editors similar to the ones that Luke developed in his lab in monkeys and shown they last at least a couple years. So in principle, the upper bound here is really long. You could potentially have one dose and it lasts a very long time, potentially decades, as long as it took you to age the first time maybe.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“In principle, it could be one time. I think that would be an overstatement for today, but I can sort of talk you through the evidence from the first principles back to the reality of what's the hardest thing we have in hand. So epigenetic reprogramming is basically how the cell types in our bodies right now are able to adopt the identities that they have. And the existence proof that those epigenetic reprogramming events can last decades is that my tongue doesn't spontaneously turn into a kidney. So these epigenetic marks can persist for decades throughout a human life or hundreds of years if you want to take the example of a bowhead whale, which uses the same mechanism.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Frequently expressed genes in the genome by the count of how many mRNAs are in the cell. Transcription factors are like near the bottom. That means you don't actually need to get that many copies of a transcription factor into a cell in order to have benefits. What we've seen so far and what I imagine will continue to play out is that even fairly low doses of these medicines, which are well within the realm of what folks have been taking for now more than a decade, are able to induce really strong efficacy. And so we're hopeful that not only will the actual size of the payload in terms of like number of base pairs not be limiting, but the dose shouldn't be limiting either.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“How many transcription factors? I think just accountable number. I think some of those that we found today that have efficacy are somewhere between one and five and that that's a small enough number that you can encapsulate it in current mRNA medicines. So already in the clinic today there are medicines that deliver many different genes as RNA. So there are medicines where, for instance, it's a vaccine as a combination of flu and COVID proteins and they're delivering 20 different unique transcripts all at the same time. And so when you think about that already as a medicine that's being injected into people in trials, the idea of delivering just a few transcription factors is seemingly quotidian. And so thankfully, I don't think we'll be limited by the size of the payloads that one can deliver. for drug development. The expression level of transcription factors in your genome relative to other genes is incredibly low. So if you just look at like the rank ordered list of what are the most”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“I still think that you're going to have the ability to add decades of healthy life to individuals by reprogramming the age of individual cell types and individual tissues.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, I think it's one example because it is a hormone and your endocrine system coordinates a lot of the complex interplay between your tissues. I don't think the story is fully written yet on exactly why GLP1 and GIP1 broadly anchored in mimetic medicines like Ozempic have so many knock-on benefits, but I think they're a great example of this phenomenon. If someone told you I'm going to find a single molecule and I'm going to drug it and it's not only going to have benefits for weight loss, but also for cardiovascular disease, also possibly for addictive behavior, and maybe even preventing neurodegeneration, you would have told them they were crazy. And yet, just by acting on the small number of cells in your body, which are receiving this signal, the interplay and the communication between those cells and the rest of your body seems to have many of these knock-on benefits. So it's just one existence proof of very small numbers of cells in your body can have health benefits everywhere. And so even if cellular delivery does not emerge by 2100, as I imagine it will, then...”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“And so we can compare old humans who get livers from young people or old people. In a way, I ask a pretty controlled question. What occurs as a function of just having a young liver? Is it that, for example, you can eat a lot of fatty food and drink a lot and be fine? Or is it that actually you see broader benefits? And in the latter seems to seem”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Just to give the delivery folks credit, they're currently ahead. There are currently no reprogramming medicines for aging, and there are medicines that deliver nucleic acids. So they're still winning the race against us right now. But to your point, I hope the lines cross. I hope we out-compete them. So I do think actually, even if you were able to only target some subsets of cells, it's not that you would see like this strange Frankensteinian benefit in health in some aspects and lack of benefit entirely in others. I think what we found across the history of medicine is that actually the body is an incredibly interconnected complex system. And if you're able to rescue a function, even in one cell type and one tissue, you often have knock-on benefits in many places that you didn't initially anticipate. One way we can get examples of this is through transplant experiments. So both in bone marrow and in liver, for example, we have fairly common transplant procedures that occur in humans.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source
“Yeah, the Red Queen race is like quite sophisticated. If you want to just like throw a new tool into biology, you somehow have to get around one side of that equation. Right.”
2025-08-21 · Dwarkesh Podcast · Evolution designed us to die fast; we can change that — Jacob Kimmel · IDENTIFIED FROM THE TRANSCRIPT · source