May 5Liked by Abhishaike Mahajan

How much is toxicity a function of the drug itself (eg small molecule, antibody, or -- stretching the meaning of drug here -- a particular gene edit) versus a joint function of the drug, formulation, delivery mechanism, etc? In other words, is toxicity something that can be answered at the target discovery stage, or will you always have to solve all the other steps and then check whether the final result is toxic? I realize the answer is probably fairly context dependent, but I'm curious whether there are broad trends among various drug, disease, or tissue types.

Expand full comment

this is just one owls opinion but i suspect all the information you need to derive small molecule toxicity is available at the development stage

but for anything biologics-based, it's fuzzier, because the creation process behind the biologic starts coming into picture (e.g. antibody aggregation) + they often have more complex delivery mechanisms (e.g. LNP-based inflammation)

Expand full comment

the real underlying problem is that biologists, chemists, bio-informaticists lack a causal model of any part of the body. so we rely on assays, 'expert' labels and shitty statistics for 30 years as a basis for a trillion dollar industry. this might take five years to play out (synthetic multi-level labels, consumer verbatims, raw input of in vivo experiments) but the entire field needs an enema (perhaps 'medical physics' will help). i say this as coming from the mobile space, where Jobs was nice enough to give us an enema, and society benefited

Expand full comment