Dwarkesh Patel: uncertainty

Transcript context

…y narrow indications, meaning diseases that fairly small numbers of people get. That's actually increased, in terms of the narrow scope of what medicines are addressing, as we've gone forward in time. This is 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 as how many years of healthy life it gives how many people—if the “how many people” is pretty small, it just really bounds the amount of value you're able to generate. 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. 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. That's why even if a given drug firm becomes very good at making antibodies to gene X and they have a successful approval, when they then go to treat disease Y they don't necessarily know what gene to go after. Most of the risk is not in how to make an antibody to treat my particular target, it's in figuring out what to target in the first place. I'm not sure how to understand this claim that we know how to engage with the right hook, we just don't know what that hook is supposed to do in the body. I don't know if that's the way you describe it. Another claim that I've seen is that with small molecules we have this Goldilocks problem. They have to be small enough to percolate through the body and through cell walls, etc., but big enough to interfere with protein-protein interactions that transcription factors might have. There it seems like getting the hook is the big problem. 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. I would say–I don't have formal way of explaining this–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. The experiment you could run here is if you lock 10 really smart drug developers in a room. 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. All they need is some molecular hook, as you put it, in order to do this. It's a relatively short list. What you're not going to get is anything approximating the panoply of human pathologies that develop. You can actually look for this. There are some existence proofs you can look for out in the universe. 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. 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. For the majority of pathologies, we just don't have many of those examples.…

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