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Comment by zackmorris

1 day ago

I'm definitely outside my wheelhouse but I've been thinking about this lately.

I heard that CRISPR can only cut segments that match a pattern, so if there are other genes between the ends that are cut, then those are lost as well. So to do a proper substitution, we'd need to sequence the patient's genes between the cuts, and possibly the whole rest of their genome, to make sure that any patterns don't appear anywhere else, so that nothing important is removed elsewhere.

That sounds insurmountable, but it may not be. Human beings basically all have nearly identical DNA, so maybe we can just derive someone's diff from a known DNA sample. If I ever won the internet lottery, that's the sort of tool that I would want to invest in.

Then we probably need more vectors to get CRISPR where it needs to go. That sounds like more of an engineering challenge to me than having to invent something new. Or at least, the number of vectors found might correlate with R&D funding.

It's not that hard for me to imagine getting the recipe figured out to the point that it's 100% reliable and can even be delivered to specific parts of the body with a certain frequency of light, for example.

Then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.

I don't see too much mystery there, even if the final recipes seem byzantine to human understanding. But I wanted to be a genetic engineer before I got into computers when I was 12, so I've had a long time to think about it. If AI eats the programming world like it looks like it's going to, maybe we can find work in biotech. Then it's probably 5-10 years before gene editing is a solved problem.

Many misconceptions here, let's clear them up:

> if there are other genes between the ends that are cut

I think what you're saying is that if two sites on the same chromosome are cut, then everything in between is deleted. However, this isn't going to happen in practice. DNA repair systems will rejoin the cut DNA ends rapidly, just erroneously (with maybe a few dozen missing/incorrect bases typically). If the cut site is in the protein coding region, it will usually disrupt the sequence to make the protein nonfunctional. Sometimes this is the desired effect, but for most gene therapies you'll probably use base or prime editing, which don't create double strand breaks.

> we'd need to sequence the patient's genes...to make sure that any patterns don't appear anywhere else

While sequencing an individual patient's genome isn't going to happen in practice, the FDA does require gene editing companies to do in silico off-target prediction, where you scan the genome for sites that have similar sequences to the target. You then have to show that none of the off-targets are in dangerous regions (e.g. DNA repair genes), and also show experimentally whether those sites are cut at all (they usually aren't, fortunately, as there are thousands within reasonable thresholds).

The reason you don't need to sequence individual patients is because you just assume that any patient could have any variant that has ever been catalogued (there are databases with thousands of individuals and the differences between them and the reference genome). You then have to show that none of those variants could induce a new target in a dangerous region.

> then come up with an iterative process, probably using AI, to catalog and repair all major genetic disorders.

I don't know what AI would do for you here. Figuring out the change you need to make to revert a genetic disorder is trivial. The hard part is making it safe and effective, and proving to regulators that it's safe and effective.

> Then it's probably 5-10 years before gene editing is a solved problem.

Not even close. Ironically, while the technologies are pretty good in general, every edit requires a ton of engineering work. CRISPR systems are notoriously idiosyncratic - they might edit one target in 80% of cells, and 0% at another target, for no apparent reason. There are definitely open problems with base and prime editing, and those will probably get more-or-less solved in 5-10 years, but I'm reasonably sure there will be genetic disorders for which there is no treatment for decades.

It doesn't help that the one approved therapy isn't really making much money: https://www.biopharmadive.com/news/sickle-cell-gene-therapy-...

See also: https://blog.genesmindsmachines.com/p/we-still-cant-predict-...