I certainly hope we can do this one day. The biobanks that gather data used to make the predictors we used to identify variants for editing don't really focus on much besides disease. As a result, our predictors for personality and interpersonal behavior aren't yet very good.

I think as the popularity of embryo selection continues to increase, this kind of data will be gathered in exponentially increasing volumes, at which point we could start to think about editing or selecting for the kinds of traits you're describing.

There will be an additional question to what degree parents will decide to edit for those traits. We're going to have a limited budget for editing and for selection for quite some time, so parents will have to choose to make their child kinder and more benificent to others at the expense of some other traits. The polygenicity of those personality traits and the effect sizes of the common alleles could have a very strong effect on parental choices; if you're only giving up a tiny bit to make your child kinder then I think most parents will go for it. If it's a big sacrifice because it requires like 100 edits, I think far fewer will do so.

It may be that benificence towards others will make these kinds of children easier to raise as well, which I think many parents would be interested in.

In the last year it has really hit me at a personal level what graphs like these mean. I'm imagining driving down to Mountain View and a town once filled with people who had "made it" and seeing a ghost town. No more jobs, no more prestige, no more promise of a stable life. As the returns to capital grow exponentially and the returns to labor decline to zero, the gap between the haves and the have-nots will only grow.

If someone can actually get superintelligence to do what they want, then perhaps universal basic income can at the very least prevent actual starvation and maybe even provide a life of abundance.

But I can't help but feeling such a situation is fundamentally unstable. If the government's desires become disconnected from those of the people at any point, by what mechanism can balance be restored?

In the past the government was fundamentally reliant on its citizens for one simple reason; citizens produced taxable revenue.

That will no longer be the case. Every country will become a petro state on steroids.

I spoke with one of the inventors of bridge recombinases at a dinner a few months ago and (at least according to him), they work in human cells.

I haven't verified this independently in my lab, but it's at least one data point.

On a broader note, I find the whole field of gene therapy very confusing. In many cases it seems like there are exceptionally powerful tools that are being ignored in favor of sloppy, dangerous, imprecise alternatives.

Why are we still using lentiviral vectors to insert working copies of genes when we can usually just fix the broken gene using prime editors?

You look at gene therapies like Casgevy for sickle cell and they just make no fucking sense.

Sickle cell is predominantly cause by an adenine to thymine swap at the sixth codon in the HBB gene. Literally one letter change at a very well known spot in one protein.

You'd think this would be a perfect use case for gene editing, right? Just swap out that letter and call it a day!

But no. This is not how Casgevy works. Instead, Casgevy works by essentially flipping a switch to make the body stop producing adult hemoglobin and start producing fetal hemoglobin.

Fetal hemoglobin doesn't sickle, so this fixes sickle cell. But like... why? Why not just change the letter that's causing all the problems in the first place?

It's because they're using old school Cas9. And old school Cas9 editing is primarily used to break things by chopping them in half and relying on sloppy cellular repair processes like non-homologous end joining to stitch the DNA back together in a half-assed way that breaks whatever protein is being produced.

And that's exactly what Casgevy does; it uses Cas9 to induce a double stranded break in BCL11A, a zinc finger transcription factor that normally makes the cells produce adult hemoglobin instead of the fetal version. Once BCL11A is broken, the cells start producing fetal hemoglobin again.

But again...

Why?

Prime editors are very good at targeting the base pair swap needed to fix sickle cell. They've been around for SIX YEARS. They havery extremely low rates of off-target editing. Their editing efficiency is on-par with that of old-school Cas9. And they have lower rates of insertion and deletion errors near the edit site. So why don't we just FIX the broken base pair instead of this goofy work-around?

Yet the only thing I can find online about using them for sickle cell is a single line announcement from Beam Therapeutics that vaguely referecing a partnership with prime medicine that MIGHT use them for sickle cell.

This isn't an isolated incident either. You go to conferences on gene editing and literally 80% of academic research is still using sloppy double strand breaking Cas9 to do editing. It's like if all the electric car manufacturers decided to use lead acid batteries instead of lithium ion.

It's just too slow. Everything is too fucking slow. It takes almost a decade to get something from proof of concept to commercial product.

This, more than anything, is why I hope special economic zones like Prospera win. You can take a therapy from animal demonstration to commercial product in less than a year for $500k-$1 mil. If we had something like that in the US there would be literally 10-100x more therapeutics available.

I mean... I think adult gene therapy is great! It can cure diseases and provide treatments that are otherwise impossible. So I think it's more impactful than heated seats.

So I'm obviously talking my own book here but my personal view is that one of the more neglected ways to potentially reduce x-risk is to make humans more capable of handling both technical and governance challenges associated with new technology.

There are a huge number of people who implicitly believe this, but almost all effort goes into things like educational initiatives or the formation of new companies to tackle specific problems. Some of these work pretty well, but the power of such initiatives is pretty small compared to what you could feasibly achieve with tech to do genetic enhancement.

Nearly zero investment or effort being is being put into the latter, which I think is a mistake. We could potentially increase human IQ by 20-80 points, decrease mental health disorder risk, and improve overall health just using the knowledge we have today:

There ARE technical barriers to rolling this out; no one has pushed multiplex editing to the scale of hundreds of edits yet (something my company is currently working on demonstrating). And we don't yet have a way to convert an edited cell into an egg or an embryo (though there are a half dozen companies working on that technology right now).

I think in most worlds genetically enhanced humans don't have time to grow up before we make digital superintelligence. But in the ~10% of worlds where they do, this tech could have an absolutely massive positive impact. And given how little money it would take to get the ball rolling here (a few tens of millions to fund many of the most promising projects in the field), I think the counterfactual impact of funding here is pretty large.

If you'd like to chat more send me an email: genesmithlesswrong@gmail.com

You can also read more of the stuff I've written on this topic here

Cool! Are you working for an existing company or are you starting your own?

There is some overlap with adult enhancement. Specifically, if we could make a large number of changes to the genome with a single transfection, that would be quite helpful.

Population mean

I’ve seen this and will reply in the next couple of days. I want to give it the full proper response it deserves.

Also thanks for taking the time to write this. I don’t think I would get this level or quality of feedback anywhere else online outside of an academic journal.

I think superbabies would still have a massive positive impact on the world even if all we do is decrease disease risk and improve intelligence. But with this kind of thing I think the impact could be very robustly positive to an almost ridiculous degree.

My hope is as we scale operations and do more fundraising we can fund this kind of research.