Intelligence Enhancement (Monthly Thread) 13 Oct 2023

All good questions.

1. Using a targeting ligand like angiopep attached to the outside of a lipid nanopaticle. There are papers where researchers have already done this.
2. Yes, probably, though I don't think it will be particularly common. The way to avoid this is just to incorporate a bunch of predictors for other traits into your allele selection criteria.
3. Obviously yes, though hopefully we just wouldn't need to flip those alleles in the first place. I'm still uncertain about the maximum effect size.
4. Maybe? Our predictors for the genetics of personality still aren't very good, so it would be hard to evaluate the expected effect size.
5. I'm not sure what that would mean in this context. I think the first human trials would probably target polygenic brain diseases like Alzheimer's. If the delivery platform works, you could use it to dramatically adjust someone's polygenic risk score for many diseases. So you might as well do the first trials on people who are going to die from a degenerative brain disease with no cure or effective treatment, for which in-vivo editing might offer a solution.
6. I don't know the answer to this yet. Most of the pioneering work in this field has happened in the US, so my suspicion is it would start here. Pretty much every step except perhaps the human trials could be done in the US.
7. I would have to think about this one more. If this tech actually works it would become incredibly valuable. Because you could use the delivery platform to basically target any disease of your choosing by adjusting someone's polygenic risk score. There are still questions around whether you can repeatedly dose someone with the editing agent without provoking an immune response, but there are plausible solutions to all the problems I've looked at so far. My biggest concern though relates to AI; I really don't want this tech to be used to speed up development of world-conquering AI. The main reason I'm interested in the tech is because I think it could potentially result in people capable of solving some of the more difficult problems in AI alignment and coordination around its appropriate use. If I were to open source it I would lose control of that.

And I think in reality there will be a lot of stakeholders in the technology so the decision won't be mine alone. If I want to bring something like this to market, I'll need to raise quite a bit of money and work with a lab to run animal trials. So there will be many other stakeholders with input into that decision. I suspect open-sourcing the tech would also diminish the financial gain. 8. Hard to answer, but my default assumption is they would be just like an elderly person with a very high IQ. 9. I'll let you know when the main post goes up.

Would you do challenge trials? 

What do you mean by challenge trials in this context?

In the vaccine context, a challenge trial is a trial where you expose people who get the vaccine to the virus. 

That makes little sense in the context of intelligence improvement. 

This is a bit of a tangent but what made you pick those 'experiences' instead of just watching some lectures from  biology profs and reading some books?

Do we have a good (or any) sense of the mechanisms by which these genetic variants work -- how many are actually causal, how many are primarily active in development vs in adults, how much interference there is between different variants etc?

No, we don't understand the mechanism by which most of them work (other than that they influence the level of and timing of protein expression). We have a pretty good idea of which are causal based on sibling validation, but there are some limitations to this knowledge because genetic variants physically close to one another on a chromosome are highly correlated, by which I mean if you can usually predict the value of one variant using the value of the other. Maybe the simplest way to describe this would be to say that we know the approximate location of causal variants, but aren't always certain exactly which of a few neighbors is causing the effect.

86% of all genes are expressed somewhere in the adult brain, so I think it's quite likely we can have a significant effect on brain function via editing. Ideally we would be able to establish some kind of prior on the expected effect size of editing a genetic variant in an adult brain (perhaps based on the timing of its peak level of expression throughout the lifespan?), but the tech could still work without this. It would just take more edits to achieve the desired benefit.

I also don't think this effect could be replicated by medications because the effect genes have on cellular functioning can take into account the current cell state in a way that medications cannot.

how much interference there is between different variants etc?

As I wrote in my post on "How to have Polygenically Screened Children [LW · GW]", there are very few measurable non-linear interactions among genes that vary within the human population. The reason for this is actually pretty simple: genes with linear effects have an easier time spreading throughout a population.

It's possible there are more interactions than we currently believe and that our sample sizes simply aren't large enough to detect them, but the fact that we've found so few indicates that their influence must be small relative to simple additive effects.

I am also not an expert at all here -- do we have any other examples of traits being enhanced or diseases cured by genetic editing in adults (even in other animals) like this? It seems also like this would be easy to test in the lab -- i.e. for mice which we can presumably sequence and edit more straightforwardly and also can measure some analogues of IQ with reasonable accuracy and reliability. Looking forward to the longer post.

I'll talk about this in more detail within the post, but yes we have examples of monogenic diseases and cancers being cured via gene therapy.

That’s a decent idea. I had thought to do it with cows or some livestock animal for which we do have decent polygenic predictors, but mice are of course the obvious first step for animal trials.

Significantly better due to base editors and prime editors, neither of which induce double-stranded breaks

I also think that getting adequate funding and permissions for doing this research, even just on animal subjects, within a 5 year time frame, is a substantial hurdle.

Agreed. Hopefully the post I'm working on may catalyze interest among funders.

To get approval for human testing? Whoa.

You can do almost all the human testing necessary to prove this technology in the context of other diseases and mental conditions.

Tier 1 would be pretty simple: find someone with a monogenic brain disease and try to get an editing agent into their brain to fix it.

Tier 2 would be to attempt to modify polygenic risk score. For example, imagine someone has treatment-resistant depression that doesn't respond to therapy or medication, and they are suicidal as a result. We could potentially modify their genes to reduce the propensity for depression (particularly if their polygenic risk score is already unusually high).

Once you've done something like that, pretty much all of the pieces are in place. You will have tested literally everything except the genetic predictor for intelligence.

one needs to only make a low-hundreds number of edits to one cell to make someone smarter than any human that has ever lived.

This is probably not true unless you start out with an embryo that already has a very high polygenic score for intelligence. To a first approximation, 15 IQ points = 75 edits of causal variants. And since we aren't precisely sure which variant is causal, the needed number of edits will be higher (perhaps 100-300).

Am I just wrong here? Is somatic gene therapy really robust and error-free enough to safely edit billions of cells?

It depends heavily on your editing vector and your target site. Base editors and prime editors have significantly higher ratios for on-target / off target edit rates. They also don't introduce double strand breaks like CRISPR does, which means you won't randomly get entire cells being eliminated if the DNA repair machinery doesn't work.

I am writing a more detailed post about this that will answer most of these questions. In short, the answer to your question is maybe. It is much more plausible we could make edits in billions of somatic cells than I would have though even two months ago.