Jacob Kimmel

And so evolution has optimized for being able to just swap one TF in or swap one TF out of a combination.

and get pretty different effects.

And so you have this sort of like local change in sequence or gene set space leading to a pretty large global change in output.

And then likewise, many of these TFs again are duplicated in the genome.

And because mutations are going to be random and they're inherently small changes at the level of sequence at a given time,

Evolution needs a substrate where in order to function effectively, these small changes can give you relatively 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 that does something interesting.

And so I think we're actually in most cases in biology, due to that evolutionary constraint, small edits need to lead to meaningful phenotypic changes in a relatively favorable regime for generic gradient-like optimizers.

You know, it would be maybe a little bit overstating to say evolution is like using the gradient, but there is a system kind of like if you've heard of evolution strategies, where basically the way you optimize parameters is you can't take a gradient on your loss, so you make a bunch of copies of your parameters, you randomly modify them,

And then you compute a gradient on your parameters against your loss.

And so you can take a gradient in that space.

That's kind of how I imagine evolution is working.

And so you need lots of those little edits to actually lead you to have meaningful step sizes in terms of the ultimate output that you have.

And to think like, you know, why would transcription factors... Maybe this is getting a little bit too gigabrained about it, but like, why does the genome even have transcription factors?

Like, what's the point?

Why not just have every time you want a new cell type, you like engineer some new cassette of genes or some new totally de novo set of promoters or something like this?

I think one possible explanation for their existence rather than just an appreciation for their presence is that

Well, having transcription factors allows a very small number of base pair edits at the substrate of the genome to lead to very large phenotypic differences.

If I break a transcription factor, I can delete a whole cell type in the body.

If I retarget a transcription factor to different genes, I can dramatically change when cells respond and have, you know, hundreds of their downstream effector genes change their behavior in response to the environment.