None of the stuff that you suggested has worked for any animal. I’m not saying it’s impossible, but it is far harder to achiever compared to the stuff that HAS been demonstrated on mice.
I am PhD in Bio, have an extensive experience with stem cells and gene editing. The idea of human/animal cognitive enhancement is great, but the delivery of gene therapy to adult brains is doomed: first, it’s technically challenging if not impossible, second, if we want to achieve a true revolution in cognition, we need to target brain development not already developed brain!
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 want to see a 10xEinstein ;)
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
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.
Of course, attempting to engineer human babies right away is illegal and irresponsible. One would need to start with animals. I propose starting with rats, which are a great model of cognitive studies. Then move to dogs, for which training protocols are well-established, and therefore the cognition and trainability can be easily evaluated. Besides, enhanced dogs will have a commercial value (military, service dogs, etc.), generating cash which can be used for R&D. The IP generated for dogs could one day be applied to other species, including primates and eventually ourselves. While I agree that going for natural variations for human is the safest choice, I believe that to achieve a real cognitive revolution well beyond current human abilities, we might need to target general mechanisms of cognition, for example by engineering “super” versions of human brain master regulators, such as FOXP2, ARHGAP11B, etc.:
Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset | Science
A humanized version of Foxp2 affects ultrasonic vocalization in adult female and male mice—von Merten − 2021 - Genes, Brain and Behavior—Wiley Online Library
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.