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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?*1-3

A statistical-significance threshold is irrelevant NHST mumbo-jumbo. What you care about is posterior probability of the causal variant's effect being above the cost-safety threshold, whatever that may be, but which will have nothing at all to do with 'genome-wide statistical significance'.

I'm aware of this, but if you're just indiscriminately shoveling heaps of edits into someone's genome based on a GWAS with too low a sample size to reveal causal SNPs for the desired trait, you'll be editing a whole bunch of what are actually tags, a whole bunch of thing... (read more)

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6gwern
What I said was "What you care about is posterior probability of the causal variant's effect being above the cost-safety threshold". If you are 'indiscriminately shoveling', then you apparently did it wrong. Pretty much all SNPs are related to something or other. The question is what is the average effect. Given the known genetic correlations, if you pick the highest posterior probability ones for intelligence, then the average effect will be good. (And in any case, one should be aiming for maximizing the gain across all traits as an index score.) If they're irrelevant, then there's no problem. No it's not. If you're using common SNPs which already exist, why would it 'have no chance of working'? If some random SNP had some devastating effect on intelligence, then it would not be ranked high.
Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?40

I might end up eating my words on the delivery problem. Something has just come out a few days ago that renewed a bit of my optimism, see here. According to the findings in this pre-print, it is possible to shield AAVs from the immune system using protein vaults that the immune system recognizes as self. It is not perfect though; although VAAV results in improved transduction efficiency even in the presence of neutralizing antibodies, it still only results in transduction of ~4% of cells if neutralizing antibodies are present. This means you'd need to cros... (read more)

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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?10

I wouldn't call it magic, but what makes FSIQ tests special is that they're specifically crafted to estimate g. To your point, anything that involves intelligence (SAT, ACT, GRE, random trivia quizzes, tying your shoes) will positively correlate with g even if only weakly, but the correlations between g factor scores and full-scale IQ scores from the WAIS have been found to be >0.95, according to the same Wikipedia page you linked in a previous reply to me. Like both of us mentioned in previous replies, using imperfect proxy measures would necessitate m... (read more)

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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?30

The SAT is heavily g-loaded: r = .82 according to Wikipedia, so ~2/3 of the variance is coming from g, ~1/3 from other stuff (minus whatever variance is testing noise). So naively, assuming no noise and that the genetic correlations mirror the phenotype correlations, if you did embryo selection on SAT, you'd be getting .82*h_pred/sqrt(2) SDs g and .57*h_pred/sqrt(2) SDs 'other stuff' for every SD of selection power you exert on your embryo pool (h_pred^2 is the variance in SAT explained by the predictor, we're dividing by sqrt(2) because sibling genotypes

... (read more)
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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?10

The problem could potentially be solved by conducting GWASes that identify the SNPs of things known to correlate with the proxy measure other than intelligence and then subtracting those SNPs, but like you mention later in your reply, the question is what approach is faster and/or cheaper. Unless there is some magic I don't know about with GSEM, I can't see a convincing reason why it would have intelligence SNPs buoy to the top of lists ranked on the basis of effect size, especially with the sample size we would likely end up working with (<1 million). ... (read more)

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gwern125

The problem could potentially be solved by conducting GWASes that identify the SNPs of things known to correlate with the proxy measure other than intelligence and then subtracting those SNPs

More or less. If you have an impure measurement like 'years of education' which lumps in half intelligence and half other stuff (and you know this, even if you never have measurements of IQ and EDU and the other-stuff within individuals, because you can get precise genetic correlations from much smaller sample sizes where you compare PGSes & alternative methods ... (read more)

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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?51

I am more optimistic than you here. I think it is enough to get people who have already gotten their genomes sequenced through 23&Me or some other such consumer genomics service to either take an online IQ test or submit their SAT scores. You could also cross-check this with other data such people submit to validate their answer and determine whether it is plausible.

I think this could potentially be done for a few million dollars rather than 50. In fact companies like GenomeLink.io already have these kind of third party data analysis services today.

Als

... (read more)
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gwern*101

You could elect to use proxy measures like educational attainment, SAT/ACT/GRE score, most advanced math class completed, etc., but my intuition is that they are influenced by too many things other than pure g to be useful for the desired purpose. It's possible that I'm being too cynical about this obstacle and I would be delighted if someone could give me good reasons why I'm wrong.

This is just measurement error and can be handled by normal psychometric approaches like SEM (eg. GSEM). You lose sample efficiency, but there's no reason you can't measure ... (read more)

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4kman
What if 23&me offered a $20 discount for uploading old SAT scores? I guess someone would set up a site that generates realistically distributed fake SAT scores that everyone would use. Is there a standardized format for results that would be easy to retrieve and upload but hard to fake? Eh, idk, maybe not. Could a company somehow arrange to buy the scores of consenting customers directly from the testing agency? Agree that this seems hard. This seems unduly pessimistic to me. The whole interesting thing about g is that it's easy to measure and correlates with tons of stuff. I'm not convinced there's any magic about FSIQ compared to shoddier tests. There might be important stuff that FSIQ doesn't measure very well that we'd ideally like to select/edit for, but using FSIQ is much better than nothing. Likewise, using a poor man's IQ proxy seems much better than nothing.
Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?74

I posted my reply to this as a direct reply to the OP because I think it's too huge and elaborate to keep hidden here.

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Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?261

Me: "I don't think this therapy as OP describes it is possible for reasons that have already been stated by HiddenPrior and other reasons"

kman: "Can you elaborate on this? We'd really appreciate the feedback."

Considering the enormity of my response, I figured I would post it in a place that is more visible to those interested. First I'd like to express my gratitude for you and GeneSmith's goal and motivation; I agree that without some brain-machine interface solution, intelligence enhancement is certainly the way forward for us if we'd like to not only kee... (read more)

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4who am I?
I might end up eating my words on the delivery problem. Something has just come out a few days ago that renewed a bit of my optimism, see here. According to the findings in this pre-print, it is possible to shield AAVs from the immune system using protein vaults that the immune system recognizes as self. It is not perfect though; although VAAV results in improved transduction efficiency even in the presence of neutralizing antibodies, it still only results in transduction of ~4% of cells if neutralizing antibodies are present. This means you'd need to cross your fingers and hope that 1) the patient doesn't already have naturally extant neutralizing antibodies and 2) they don't develop them over the course of the hundreds/thousands of VAAV you're going to give them. In the paper, it is stated that AAV gets packaged in the vaults only to an extent rather than completely. So, more than likely, even if you're injecting 99% VAAV and 1% naked AAV, if you do this 100 times you are almost sure to develop neutralizing antibodies to that 1% of naked AAV (unless they have a way to completely purify VAAV that removes all naked AAV). One way to combat the transduction problem post-innocuation though is using multiple injections of the same edit in order to approximate 100% transduction, though I'm pessimistic that this will work because there is probably a good reason that only 4% of cells were transducible; something might be different about them than the rest of cells, so you might receive diminishing transduction returns with each injection. They also still need to demonstrate that these work in vivo and that they can be routed to the CNS. Nonetheless, I'm excited to see how this shakes out.
4kman
Thanks for leaving such thorough and thoughtful feedback! The SAT is heavily g-loaded: r = .82 according to Wikipedia, so ~2/3 of the variance is coming from g, ~1/3 from other stuff (minus whatever variance is testing noise). So naively, assuming no noise and that the genetic correlations mirror the phenotype correlations, if you did embryo selection on SAT, you'd be getting .82*h_pred/sqrt(2) SDs g and .57*h_pred/sqrt(2) SDs 'other stuff' for every SD of selection power you exert on your embryo pool (h_pred^2 is the variance in SAT explained by the predictor, we're dividing by sqrt(2) because sibling genotypes have ~1/2 the variance as the wider population). Which is maybe not good; maybe you don't want that much of the 'other stuff', e.g. if it includes personality traits. It looks like the SAT isn't correlated much with personality at all. The biggest correlation is with openness, which is unsurprising due to the correlation between openness and IQ -- I figured conscientiousness might be a bit correlated, but it's actually slightly anticorrelated, despite being correlated with GPA. So maybe it's more that you're measuring specific abilities as well as g (e.g. non-g components of math and verbal ability). Another thing: if you have a test for which g explains the lion's share of the heritable variance, but there are also other traits which contribute heritable variance, and the other traits are similarly polygenic as g (similar number of causal variants), then by picking the top-N expected effect size edits, you'll probably mostly/entirely end up editing variants which affect g. (That said, if the other traits are significantly less polygenic than g then the opposite would happen.) Getting old SAT scores could be much cheaper, I imagine (though doing this would still be very difficult). Also, as GeneSmith pointed out we aren't necessarily limited to western countries. Assembling a large biobank including IQ scores or a good proxy might be much cheaper and mor
6GeneSmith
I am more optimistic than you here. I think it is enough to get people who have already gotten their genomes sequenced through 23&Me or some other such consumer genomics service to either take an online IQ test or submit their SAT scores. You could also cross-check this with other data such people submit to validate their answer and determine whether it is plausible. I think this could potentially be done for a few million dollars rather than 50. In fact companies like GenomeLink.io already have these kind of third party data analysis services today. Also, we aren't limited to western countries. If China or Taiwan or Japan or any other country creates a good IQ predictor, it can be used for editing purposes. Ancestry doesn't matter much for editing purposes, only for embryo selection. Would the quality of such tests be lower than those of professionally administered IQ tests? Of course. But sample size cures many ills. I briefly looked into this and found these papers: Adeno-Associated virus induces apoptosis during coinfection with adenovirus I asked GPT4 whether adenoviruses enter the brain: I also found this paper indicating much more problematic direct effects observed in mouse studies: AAV ablates neurogenesis in the adult murine hippocampus Also:  So it sounds like there are potential solutions here and this isn't necessarily a showstopper, especially if we can derisk using animal testing in cows or pigs. This is an update for me. I didn't previously realize that the mRNA for a base or prime editor could itself trigger the innate immune system. I wonder how serious of a concern this would actually be? If it is serious, we could potentially deliver RNPs directly to the cells in question. I think this would be plausible to do with pretty much any delivery vector except AAVs.  I don't really see how delivering a plasmid with the DNA for the editor will be any better than delivering mRNA. The DNA will be transcribed into the exact same mRNA you would
Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?31

Yes, as someone who has worked both in CS and in neuroscience at the graduate level, I probably do know far more than you about this topic. At the risk of sounding more polemic than I am, it's posts like yours and others that make excessively reductive inferences about neurons and the brain that invariably end up polluting discussions of this topic and turn it into an unproductive cesspool of ML people offering their two-cents for topics they don't understand (most of the replies to the original post being the cases in point).

I will grant you that it is in... (read more)

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1kman
Can you elaborate on this? We'd really appreciate the feedback.
2dr_s
The bit about the personality was specifically in response to the idea that you could revert brains to childhood-like plasticity. That's like an additional layer of complexity and unlike gene therapy we don't know how to begin doing that, so if you ask me, I don't think it would actually be a thing anyway in the near future. My guess is: most of your intelligence, even the genetic component, is probably determined by development during the phase of highest plasticity. So if you change the genes later you'll either get no effect or marginal ones compared to what would happen if you changed them in embryos - that is, if it doesn't also cause other weird side effects. Experiments are possible but I doubt they'd be risk-free, or honestly, even approved by an ethical committee at all, as things are now. It's a high risk for a goal that would probably be deemed in itself ethically questionable. And the study surviving for example a cohort "gone bad" would be really hard in terms of public support and funding.
Significantly Enhancing Adult Intelligence With Gene Editing May Be Possible
who am I?94

This reply is hilarious in the context of your first one. At first you confidently assert that changing genes in the brain won't do anything to an adult, followed by your statement that "we understand still far too little of how brains work" to know what's going to happen following such a therapy along with other predictions like total memory erasure. Which is it?

While the vast majority of neurons are subject to mitotic arrest after adolescence, gene expression, the regulation of gene expression, and morphological/biochemical restructuring of individual ne... (read more)

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-2Valdes
I just want to point out that the sentence you replied to starts with an "if". "If those genes' role is to alter the way synapses develop in the fastest growth phase, changing them when you're 30 won't do anything" (emphasis mine). You described this as "At first you confidently assert that changing genes in the brain won't do anything to an adult". The difference is important. This is in no way a comment on the object level debate. I simply think Lesswrong is a place where hypotheticals are useful and that debates will be poorer if people cannot rely on the safety that saying "if A then B" will not be interpreted as just saying "B".
6dr_s
I mean, you sound like you know far more than me on it so I won't argue the specifics, but in general, "we know enough about this thing to not be able to safely mess with it, but to be reasonably sure that messing with it will have bad effects" is absolutely possible. It's in fact the default for really complex black boxes: while understanding their general function may be easy enough, if you don't know what you're doing messing with their internals, odds are that you'll break them rather than improve them. The prediction of "total memory erasure" was a response to a specific idea, the notion that if intelligence was really mostly determined in childhood/adolescence, then if you could push the brain to regain its original plasticity you could repeat the process with different outcomes, and as I said that sounds like it would change a lot about what a person is (unless you can somehow disentangle experiences and personality from intelligence gained through them). I don't expect that to be the case if one of the premises doesn't hold; I was just criticizing that specific strategy. Others would not have this downside. As for the rest, sure, it's possible that there might be gene changes that will simply improve neuron health. But if I had to bet I'd imagine it would be easier to gain traits like resistance to dementia and Alzheimer's or such by tweaking those, than a whole 40 points of IQ or such. I know brains aren't the same as ANNs, but to make an analogy, if you run GPT-4 on newer hardware it'll do the same things a bit better and faster, but it won't be able to make entirely new things out of whole cloth.
[SEE NEW EDITS] No, *You* Need to Write Clearer
who am I?70

While writing well is one of the aspects focused on by the OP, your reply doesn't address the broader point, which is that EY (and those of similar repute/demeanor) juxtaposes his catastrophic predictions with his stark lack of effective exposition and discussion of the issue and potential solutions to a broader audience. To add insult to injury, he seems to actively try to demoralize dissenters in a very conspicuous and perverse manner, which detracts from his credibility and subtly but surely nudges people further and further from taking his ideas (and t... (read more)

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ryan_greenblatt113

I agree that EY is quite overconfident and I think his argument for doom are often sloppy and don't hold up. (I think the risk is substantial but often the exact arguments EY gives don't work). And, his communication often fails to meet basic bars for clarity. I'd also probably agree with 'if EY was able to do so, improving his communication and arguments in a variety of contexts would be extremely good'. And specifically not saying crazy sounding shit which is easily misunderstood would probably be good (there are some real costs here too). But, I'm not s... (read more)

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