Jacob Kimmel

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.

One other really cool thing about transcription factors is that the endogenous biology is very favorable for drug development.

the expression level of transcription factors in your genome relative to other genes is incredibly low.

If you just look at the rank ordered list of what are the most frequently expressed genes in the genome by the count of how many mRNAs are in the cell, transcription factors are near the bottom.

And that means you don't actually need to get that many copies of a transcription factor into a cell in order to have benefits.

And so 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.

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 like the first principles back to the reality of like 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, you know, hundreds of years if you want to take the example of a bowhead whale, which uses the same mechanism.

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 hothouse where you're just trying as hard as you can to break this mark down 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.