I’m a software developer by training with an interest in genetics. I currently run a startup working on multiplex gene editing technology.
GeneSmith
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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.
It’s possible I’m misunderstanding your comment, so please correct me if I am, but there’s no reason you couldn’t do superbabies at scale even if you care about alignment. In fact, the more capable people we have the better.
I’m having trouble understanding how concretely you think superbabies can lead to significantly improved chance of helping alignment.
Kman may have his own views, but my take is pretty simple; there are a lot of very technically challenging problems in the field of alignment and it seems likely smarter humans would have a much higher chance of solving them.
First of all, no one has really done large scale genetic engineering of animals before, so we wouldn’t know.
Almost all mouse studies or genetic studies in other animals are very simple knockout experiments where they break a protein to try to assess its function.
We really haven’t seen a lot of multiplex editing experiments in animals yet.
But even if someone were to do that it would be hard to evaluate the effects on intelligence in animals.
The genetic variants that control IQ in humans don’t always have analogous sequences in animals. So you’d be working with a subset of possible edits at best.
The first proof of concept here will probably be something like “do tons of edits in cows to make them produce more milk and beef”. In fact, that’s one of the earliest commercial applications of this multiplex editing tech.
We’re hoping to show a demonstration of this in the next couple of years as one of the first steps towards demonstrating plausible safety and efficacy in humans.
Well we have it in cows. Just not in mice.
I think many people in academia more or less share your viewpoint.
Obviously genetic engineering does add SOME additional risk of people coming to see human children like commodities, but in my view it’s massively outweighed by the potential benefits.
you end up with a child whose purpose is to fulfill the parameters of their human designers
I think whether or not people (and especially parents) view their children this way depends much more on cultural values and much less on technology.
There are already some parents who have very specific goals in mind for their children and work obsessively to realize them. This doesn’t always work that well, and I’m not sure it will work that well even with genetic engineering.
Sure we will EVENTUALLY be able to shape personality better with gene editing (though I would note we don’t really have the ability to do so currently), but human beings are very complicated. Gene editing is a fairly crude tool for shaping human behavior. You can twist the knobs for dozens of human traits, but I think anyone trying to predetermine their child’s future is going to be disappointed.
The tremendous effort involved in trying to fit the child to the design parameters betrays a lack of belief in the child’s inherent value as themselves, and they will be able to tell.
The thing about this argument is you could easily apply it to other interventions like medicines or education. “The tremendous effort involved in trying to fit the child to the design parameters through tutoring and a specialized education program betrays a lack of belief in the child’s inherent value as themselves, and they will be able to tell.”
Does working hard to give your child the best shot of a healthy, happy and productive life show a lack of true affection for them? I think it shows the exact opposite; you loved them so much that you were willing to go to extra lengths to give them the best life you could. I think this is no different than parents moving to America to give their child a chance at economic opportunity, or parents working extra shifts to send their children to a better school.
But no “super” people can exist in an ethical system where people are of equal intrinsic worth.
The term “super” is not a description of the relative moral worth of these future children. It is a description of their capabilities and prospects for a healthy life.
Good genes enable human productivity and happiness. They don’t determine moral worth. That exists independent of ability.
Confering a genetic immunity to HIV on a child might help them out, but it does not, for example, license them to win the trolly problem.
Agreed. I don’t get the sense we have any disagreement about the moral worth of people being tied to their genetics.
It’s written to explore the principle that there are no bad genes, only genes badly adapted to their environments, and our heroine is an aspiring apprentice baby designer with sickle cell. While it’s a challenging position to take, I’m not sure it’s a bad guiding principle for somebody made of genes.
I think we need to separate judgment of genes from judgment of the people who have them. You are not your genes. Sure they shape you and influence your experience of the world, but I think a lot of these kinds of books make the mistake of starting with the mistaken premise that our worth IS determined by our genes, and then ask how we can still be equal.
I think the premise is just wrong. It’s like saying that you are your trauma, or you are your leg injury. People are much deeper than their experiences or their predispositions, even if all those things have a strong influence on their behavior.
I would love to try this in mice.
Unfortunately our genetic predictors for mice are terrible. The way mouse research works is not at all like how one would want it to work if we planned to actually use them as a testbed for the efficacy of genetic engineering.
Mice are mostly clones. So we don’t have the kind of massive GWAS datasets on which genes are doing what and how large the effect sizes are.
Instead we have a few hundred studies mostly on the effects of gene knockouts to determine the function of particular proteins.
But we’re mostly not interested in knockouts for genetic engineering. 2/3rds of the disease related alleles in humans are purely single letter base pair changes.
We have very little idea which specific single letter base pair changes affect things like disease risk in mice.
MAYBE some of the human predictors translate. We haven’t actually explicitly tested this yet. And there’s at least SOME hope here; we know that (amazingly), educational attainment predictors actually predict trainability in dogs with non-zero efficacy. So perhaps there’s some chance some of our genetic predictors for human diseases would translate at least somewhat to mice.
We do need to do more thorough investigation of this but I’m not really that hopeful.
I think a far better test bed is in livestock, especially cows.
We have at least a few hundred thousand cow genomes sequenced and we have pretty well labelled phenotype data. It should be sufficient to get a pretty good idea of which alleles are causing changes in breed value, which is the main metric all the embryo selection programs are optimizing for.
Yes, I pretty much agree with this
I’m not saying his experiments show germline editing is safe in humans. In fact He Jiankui’s technique likely WASN’T safe. Based on some talks I heard from Dieter Egli at Colombia, He was likely deleting chromosomes in a lot of embryos, which is why (if I recall correctly) only 3 out of about ~30 embryos that were transferred resulted in live birth. Normally the live birth rate per transfer rate would be between 30 and 70%.
It’s also not entirely clear how effective the editing was because the technique He used likely created a fair degree of mosaicism since the editing continued after the first cell division. If the cells that ended up forming hematopoietic stem cells DIDN’T receive the edits then there would have been basically no benefit to the editing.
Anyways, I’m not really trying to defend He Jiankui. I don’t think his technique was very good nor do I think he chose a particularly compelling reason to edit (HIV transmission can be avoided with sperm washing or anti-retroviral drugs to about the same degree of efficacy as CCR5 knockout). I just think the reaction was even more insane.
It doesn’t make sense to ban germline editing just because one guy did it in a careless way. Yet in many places that’s exactly what happened.
I’d be interested in hearing where specifically you think we are doing that.
Yes, the two other approaches not really talked about in this thread that could also lead to superbabies are iterated meiotic selection and genome synthesis.
Both have advantages over editing (you don’t need to have such precise knowledge of causal alleles with iterated meiotic selection or with genome synthesis), but my impression is they’re both further off than an editing approach.
I’d like to write more about both in the future.
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.