Jacob Kimmel: evaluation

Transcript context

…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. What is the answer to what is the general purpose thing where every marginal discovery increases the odds you make the next discovery?…

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