None of the stuff that you suggested has worked for any animal.
Has anyone done 2500 edits in the brain cells of an animal? No. The graphs are meant to illustrate the potential of editing to affect IQ given a certain set of assumptions. I think there are still significant barriers that must be overcome. But like… the trend here is pretty obvious. Look at how much editors have improved in just the last 5 years. Look at how much better our predictors have gotten. It’s fairly clear where we are headed.
Also, to say that none of this stuff has been done in animals seems a bit misleading. Here’s a paper where the authors were able to make a desired edit in 60% of mouse brain cells. Granted, they were using AAVs, but for some oligogenic conditions that may be sufficient; you can pack a single AAV with a plasmid holding DNA sufficient to make sgRNA for 31 loci using base editors. There are several conditions for which 30 edits would be sufficient to result in a >50% reduction in disease risk even after taking into account uncertanties about which allele is causal.
Granted, if we can’t improve editing efficiency in neurons to above 5% then the effect will be significantly reduced. I guess I am fairly optimistic on this front: if an allele is having an effect in brains, it seems reasonable to assume that some portion of the time it will not be methylated or wrapped around a histone, and thus be amenable to editing.
Regarding lipid nanoparticles as a delivery vehicle for editors: Verve-101 is a clinical trial underway right now evaluating safety and efficacy of lipid nanoparticles with a base editor to target PCSK9 mutations causing familial hypercholesterolemia.
There are other links in the post such as one showing transcytosis of BBB endothelial cells using angiopep conjugated LNPs. And here’s a study showing about 50% transfection efficiency of LNPs to brain cells following intracranial injection in mice.
it’s technically challenging if not impossible
Technically challenging? Yes.
Impossible?
Obviously not. You can get payloads into the brain. You can make edits in cells. And though there are issues with editing efficiency and delivery, both continue to improve every year. Eventually we will be able to do this.
if we want to achieve a true revolution in cognition, we need to target brain development not already developed brain!
If your contention is that it is easier to get a large effect by editing embryos vs the adult brain, I would of course agree! But consider all the conditions that are modulated by the timing and level of protein expression. It would be quite surprising to me if intelligence were not to modulated in a similar manner.
Furthermore, given what is happening in AI right now, we probably don’t have 25 years left for the technology for embryo editing to mature and for the children born with its benefits to grow up.
Imagine a monkey thinking of enhancing its abilities by injecting virus in its brain—will it ever reach a human level cognition? Sounds laughable. Who cares about +5 points to IQ
I have doubts we can enhance chimpanzee intelligence. We don’t have enough chimpanzees or enough intelligence phenotypes to create GWAS for chimp intelligence (or any other mental trait for that matter).
We could try porting human predictors but well… we already see substantial dropoff in variance explained when predictors are ported from one genetic ancestry group to another. Imagine how large the dropoff would be between species.
Granted, a lot of the dropoff seems to be due to differences in allele frequencies and LD structure. So maybe there’s some chance that a decent percentage of the variants would cause similar effects across species. But my current guess is few of the variants will have effects in both species.
Also, if I expected +5 IQ points to be the ceiling of in-vivo editing I wouldn’t care about this either. I do not expect that to be the ceiling, which is reflected in some of the later graphs in the post.
For >40 years, way before the discovery of CRISPRs and base editors, we’ve been successfully genetically engineering mice, but not other species. Why only mice? Because we can culture mouse embryonic stem cells that can give rise to complete animals. We did not understand why mouse cells were so developmentally potent, and why this didn’t work for other species. Now we do (I’m the last author):
Highly cooperative chimeric super-SOX induces naive pluripotency across species—ScienceDirect
I’ve spent the better part of the afternoon reading and trying to understand this paper.
First, it’s worth saying just how impressive this work is. The improvement of success rates over existing embryogenesis techniques like SCNT. I have a few questions I wasn’t able to find answers to in the paper:
Do the rates of full-term and adult survival rates in iPSC mice match that which could be achieved by normal IVF, or do they indicate that there is still some suboptimality in culturing of tetraploid aggregated iPSC embryos? I’m not familiar with the normal rates of survival for mice so I wasn’t able to tell from the graph whether there is still room for improvement.
How epigenetically different are embryos produced with Sox2-17 compared to those produced through the normal IVF process?
If this process or an improved one in the future were capable of inducing embryo-viable iPSC’s, would you be able to tell this was the case in humans with the current data available? If not, what data are you missing? I’m particularly wondering about whether you feel that there is sufficient data available regarding the epigenetic state of normal embryonic cells at the blastocyst stage.
When you engineer stem cells rather than adult animals, all of those concerns you listed are gone: low efficiency, off-target mutations, delivery, etc. Pluripotent stem cells are immortal and clonogenic, which means that even if you get 1 in 1000 cells with correct edits and no off-target mutations, you can expand it indefinitely, verify by sequencing, introduce more edits, and create as many animals as you want. The pluripotent stem cells can either be derived from the embryos or induced artificially from skin or blood cells. The engineered pluripotent stem cells can either be used directly to create embryos or can be used to derive sperm and eggs; both ways work well for mice.
You are of course correct about everything here. And if we had unlimited time I think the germline editing approach would be better. But AGI appears to be getting quite near. If we haven’t alignment by the point that AI can recursively self-improve, then I think this technology becomes pretty much irrelevant. Meat-based brains, even genetically enhanced ones, are going to be irrelevant in a post-AGI world.
One would need to start with animals. I propose starting with rats, which are a great model of cognitive studies
How exactly do you propose to do this given we don’t have cognitive ability GWASes for rats, don’t have a feasible technique for getting them without hundreds of thousands of phenotypes, and given the poor track record of candidate gene studies in establishing causal variants?
Do the rates of full-term and adult survival rates in iPSC mice match that which could be achieved by normal IVF, or do they indicate that there is still some suboptimality in culturing of tetraploid aggregated iPSC embryos? I’m not familiar with the normal rates of survival for mice so I wasn’t able to tell from the graph whether there is still room for improvement.
Using tetraploid complementation, it is possible to achieve up to 70% of full-term development, which is similar rate of mouse natural conception. And this was before we understood how it works. I believe that soon we will be able to outperform nature and achieve close to 100% full term development and survival (I’ve seen 90% efficiency in some experiments). For human, only 30% of naturally conceived embryos are born, and only 10% of IVF, so superseding nature for human will be even easier than for mice.
How epigenetically different are embryos produced with Sox2-17 compared to those produced through the normal IVF process?
In figure 4 we demonstrate that the mice are healthy, and can breed giving rise to healthy progeny, which is the highest bar for the quality of the cells. Again, our current IVF practice has only 10% success rate—the bar is pretty low. Also, the biggest advance of the paper is not creation of Sox2-17, but understanding the mechanism of naive pluripotency in mammals, which gives the unprecedented access to mammalian germline. Before, it was only accessible for mice and rats.
If this process or an improved one in the future were capable of inducing embryo-viable iPSC’s, would you be able to tell this was the case in humans with the current data available? If not, what data are you missing? I’m particularly wondering about whether you feel that there is sufficient data available regarding the epigenetic state of normal embryonic cells at the blastocyst stage.
This is just the first paper on the true nature of naive cells. Mouse is always first. The paper is unusual in the way that it contains 4 more species, including human. The next step would be to achieve tetraploid complementation for non-rodents, such as pigs, cows, sheep, dogs, monkeys, etc. If we could generate various animals and they are heathy and give normal progeny, then only we could think of humans. For humans, the first edits will address horrendous genetic diseases, rather than enhancements.
FYI, your iPSCs would give rise to your clones rather than children, which might only be okay for individuals with high value for society (eg. Einstain-like intelligence). I think it makes more sense to derive ESCs from IVF embryos, edit them in the dish, do QC, then use to create the embryos again—those will obviously be your children. Another option is to use iPSCs for in vitro gametogenesis (IVG), so basically your edited iPSCs are used to derive sperm/eggs. This rout will take longer to perfect, because so far very few mice have been born from IVG.
Do you know a study that has demonstrated enhancement of intelligence by editing adults? It would be a cool study, definitely worth to pursue, but there’s a big change it won’t work at all. I would bet on cell therapy for adults rather than gene therapy.
On the other hand, multiple studies have already shown enhanced intelligence for mice and monkeys by engineering the germline.
AGI will hopefully not kill all the humans. With such pessimism we can just give up and watch tv. If there are any humans in future it makes sense to enhance their intelligence and other talents. I did not suggest enhancing monkeys, I was just trying to say that if we want to achieve a chimp-to-human level transformation for human, we need to target the development.
Has anyone done 2500 edits in the brain cells of an animal? No. The graphs are meant to illustrate the potential of editing to affect IQ given a certain set of assumptions. I think there are still significant barriers that must be overcome. But like… the trend here is pretty obvious. Look at how much editors have improved in just the last 5 years. Look at how much better our predictors have gotten. It’s fairly clear where we are headed.
Also, to say that none of this stuff has been done in animals seems a bit misleading. Here’s a paper where the authors were able to make a desired edit in 60% of mouse brain cells. Granted, they were using AAVs, but for some oligogenic conditions that may be sufficient; you can pack a single AAV with a plasmid holding DNA sufficient to make sgRNA for 31 loci using base editors. There are several conditions for which 30 edits would be sufficient to result in a >50% reduction in disease risk even after taking into account uncertanties about which allele is causal.
Granted, if we can’t improve editing efficiency in neurons to above 5% then the effect will be significantly reduced. I guess I am fairly optimistic on this front: if an allele is having an effect in brains, it seems reasonable to assume that some portion of the time it will not be methylated or wrapped around a histone, and thus be amenable to editing.
Regarding lipid nanoparticles as a delivery vehicle for editors: Verve-101 is a clinical trial underway right now evaluating safety and efficacy of lipid nanoparticles with a base editor to target PCSK9 mutations causing familial hypercholesterolemia.
There are other links in the post such as one showing transcytosis of BBB endothelial cells using angiopep conjugated LNPs. And here’s a study showing about 50% transfection efficiency of LNPs to brain cells following intracranial injection in mice.
Technically challenging? Yes.
Impossible?
Obviously not. You can get payloads into the brain. You can make edits in cells. And though there are issues with editing efficiency and delivery, both continue to improve every year. Eventually we will be able to do this.
If your contention is that it is easier to get a large effect by editing embryos vs the adult brain, I would of course agree! But consider all the conditions that are modulated by the timing and level of protein expression. It would be quite surprising to me if intelligence were not to modulated in a similar manner.
Furthermore, given what is happening in AI right now, we probably don’t have 25 years left for the technology for embryo editing to mature and for the children born with its benefits to grow up.
I have doubts we can enhance chimpanzee intelligence. We don’t have enough chimpanzees or enough intelligence phenotypes to create GWAS for chimp intelligence (or any other mental trait for that matter).
We could try porting human predictors but well… we already see substantial dropoff in variance explained when predictors are ported from one genetic ancestry group to another. Imagine how large the dropoff would be between species.
Granted, a lot of the dropoff seems to be due to differences in allele frequencies and LD structure. So maybe there’s some chance that a decent percentage of the variants would cause similar effects across species. But my current guess is few of the variants will have effects in both species.
Also, if I expected +5 IQ points to be the ceiling of in-vivo editing I wouldn’t care about this either. I do not expect that to be the ceiling, which is reflected in some of the later graphs in the post.
I’ve spent the better part of the afternoon reading and trying to understand this paper.
First, it’s worth saying just how impressive this work is. The improvement of success rates over existing embryogenesis techniques like SCNT. I have a few questions I wasn’t able to find answers to in the paper:
Do the rates of full-term and adult survival rates in iPSC mice match that which could be achieved by normal IVF, or do they indicate that there is still some suboptimality in culturing of tetraploid aggregated iPSC embryos? I’m not familiar with the normal rates of survival for mice so I wasn’t able to tell from the graph whether there is still room for improvement.
How epigenetically different are embryos produced with Sox2-17 compared to those produced through the normal IVF process?
If this process or an improved one in the future were capable of inducing embryo-viable iPSC’s, would you be able to tell this was the case in humans with the current data available? If not, what data are you missing? I’m particularly wondering about whether you feel that there is sufficient data available regarding the epigenetic state of normal embryonic cells at the blastocyst stage.
You are of course correct about everything here. And if we had unlimited time I think the germline editing approach would be better. But AGI appears to be getting quite near. If we haven’t alignment by the point that AI can recursively self-improve, then I think this technology becomes pretty much irrelevant. Meat-based brains, even genetically enhanced ones, are going to be irrelevant in a post-AGI world.
How exactly do you propose to do this given we don’t have cognitive ability GWASes for rats, don’t have a feasible technique for getting them without hundreds of thousands of phenotypes, and given the poor track record of candidate gene studies in establishing causal variants?
Do the rates of full-term and adult survival rates in iPSC mice match that which could be achieved by normal IVF, or do they indicate that there is still some suboptimality in culturing of tetraploid aggregated iPSC embryos? I’m not familiar with the normal rates of survival for mice so I wasn’t able to tell from the graph whether there is still room for improvement.
Using tetraploid complementation, it is possible to achieve up to 70% of full-term development, which is similar rate of mouse natural conception. And this was before we understood how it works. I believe that soon we will be able to outperform nature and achieve close to 100% full term development and survival (I’ve seen 90% efficiency in some experiments). For human, only 30% of naturally conceived embryos are born, and only 10% of IVF, so superseding nature for human will be even easier than for mice.
How epigenetically different are embryos produced with Sox2-17 compared to those produced through the normal IVF process?
In figure 4 we demonstrate that the mice are healthy, and can breed giving rise to healthy progeny, which is the highest bar for the quality of the cells. Again, our current IVF practice has only 10% success rate—the bar is pretty low. Also, the biggest advance of the paper is not creation of Sox2-17, but understanding the mechanism of naive pluripotency in mammals, which gives the unprecedented access to mammalian germline. Before, it was only accessible for mice and rats.
If this process or an improved one in the future were capable of inducing embryo-viable iPSC’s, would you be able to tell this was the case in humans with the current data available? If not, what data are you missing? I’m particularly wondering about whether you feel that there is sufficient data available regarding the epigenetic state of normal embryonic cells at the blastocyst stage.
This is just the first paper on the true nature of naive cells. Mouse is always first. The paper is unusual in the way that it contains 4 more species, including human. The next step would be to achieve tetraploid complementation for non-rodents, such as pigs, cows, sheep, dogs, monkeys, etc. If we could generate various animals and they are heathy and give normal progeny, then only we could think of humans. For humans, the first edits will address horrendous genetic diseases, rather than enhancements.
FYI, your iPSCs would give rise to your clones rather than children, which might only be okay for individuals with high value for society (eg. Einstain-like intelligence). I think it makes more sense to derive ESCs from IVF embryos, edit them in the dish, do QC, then use to create the embryos again—those will obviously be your children. Another option is to use iPSCs for in vitro gametogenesis (IVG), so basically your edited iPSCs are used to derive sperm/eggs. This rout will take longer to perfect, because so far very few mice have been born from IVG.
Do you know a study that has demonstrated enhancement of intelligence by editing adults? It would be a cool study, definitely worth to pursue, but there’s a big change it won’t work at all. I would bet on cell therapy for adults rather than gene therapy.
On the other hand, multiple studies have already shown enhanced intelligence for mice and monkeys by engineering the germline.
AGI will hopefully not kill all the humans. With such pessimism we can just give up and watch tv. If there are any humans in future it makes sense to enhance their intelligence and other talents. I did not suggest enhancing monkeys, I was just trying to say that if we want to achieve a chimp-to-human level transformation for human, we need to target the development.