I’m a layman, but the “Hulk Sperm” method seems the most plausible EC-bypass method to me, and EC-bypass generally seems a more plausible route than EC-making. After reading the paper, it seems like any of the routes to EC-making seem either speculative, or very prone to failure (while also being hard to verify as a failure).
an issue with spermatogonial transplant into testicles is that GV (e.g. edited) spermatogonia are likely to be stressed and imperfectly maintained, and therefore are likely to be outcompeted by normal spermatogonia and die out
If the problem is a concern with competitiveness after re-transplantation, is there a way to create an environment where the stressed spermatogonia has either reduced competition, or is more competitive relative to its unedited counterparts?
Off the top of my head this might look like locally “sterilizing” just the spermatogonia tissue after a biopsy somehow, without damaging the machinery that leads to functional spermatozoon development and paternal imprinting. I’m not sure if this sort of targeted wiping is possible though, but at least with two testicles, the option of sterilizing one from spermatogonia tissue wouldn’t necessarily lead to complete sterilization. Or even if our only option here was complete spermatogonia sterilization, sperm preservation is relatively easy, so it still might be tolerable.
Alternatively, rather than just editing in a fluorescent reporter, you might also edit in a gene that makes the edited sperm more competitive in an environment that can be artificially induced in vivo. With just a fluorescent reporter, such a change arising naturally would naturally lead to the sperm being outcompeted and dying out (or if it as a completely neutral adaptation maybe not?), but if we induce conditions that are more favorable to spermatogonia with a specific tolerance induced by an inserted gene, they may have enough of a competitive advantage to persist in meaningful numbers. Off the top of my head I would consider higher temperature tolerance (with higher temperatures induced with a willy-warmer or something), or perhaps resistance to a chemical that’s normally harmful to spermatozoon? No idea what this could be though.
Also, would a fluorescent reporter gene edited into spermatogonia and present in spermatozoon persist into the zygote, and therefore into all the descended cells of the eventual mature organism? I think it would be hilarious and incredibly fitting if a side effect of making supermen is that they literally glow.
“Hulk Sperm” method seems the most plausible EC-bypass method to me, and EC-bypass generally seems a more plausible route than EC-making
I partly agree, though with qualifications. One thing to note is that SSC methods are strictly haploid, hence half the power of diploid methods. Another thing to note is that SSC methods, especially ones that require iteration (editing), are not trivial in terms of EC; you have to maintain imprints, probably, as well as maintaining the general stem cell niche (i.e. ability to proliferate and ability to differentiate into spermatocytes).
I find e.g. sperm chromosome to have a comparable chance of working soon, though it has its own somewhat separate challenges.
Here “plausible” means “plausible really soon, like in a couple years”. The more robust way, that will quite likely work eventually, is more natural gametogenesis / EC-making (IVO and IVS). These have far more investment from scientists, so in particular it’s somewhat more clear what it would take and how to accelerate it, though far from fully clear. But yes, they do seem harder.
Yes, sterilization is possible; they sterilize mouse testes before retransplanting exogenous SSCs.
Sterilizing one testis is an interesting suggestion I hadn’t thought of, thanks. It does seem like a big cost, but presumably much less than half the cost of sterilizing both. It’s still a cost because you’re decreasing your fertility, and because IDK if there are sterilization methods that aren’t more generally toxic (e.g. oncogenic or something).
locally “sterilizing” just the spermatogonia tissue after a biopsy somehow, without damaging the machinery that leads to functional spermatozoon development and paternal imprinting. I’m not sure if this sort of targeted wiping is possible though,
Yeah, IDK either, interesting question. I would very weakly guess that native SSCs can colonize the whole testis but IDK.
you might also edit in a gene that makes the edited sperm more competitive in an environment that can be artificially induced in vivo
Yeah, this is a good idea that I’ve heard in the abstract. I don’t know about implementation details. I think I get pretty nervous whenever we’re talking about some unnatural modification, i.e. some modification that isn’t already present in natural humans. The case for safety seems significantly harder to make. If we do adult somatic gene therapies that are not just modifying to a common allele, and it’s fine, that could be some evidence that it’s fine. But SSCs in particular are stem cells, so a priori they are cancer risks, I would think. Like “how can I make this cell proliferate more than natural, and outcompete its natural healthy counterparts” is kinda like asking “how can I make some cancer”.
would a fluorescent reporter gene edited into spermatogonia and present in spermatozoon persist into the zygote, and therefore into all the descended cells of the eventual mature organism?
The idea is that you put the reporter near a gene whose protein is only present in sperm—e.g. a meiosis-specific protein (which I have heard do exist). So the child wouldn’t glow. But their gametes, and their descendants’s gametes (with 50% probability, etc.) would glow.
I’m a layman, but the “Hulk Sperm” method seems the most plausible EC-bypass method to me, and EC-bypass generally seems a more plausible route than EC-making. After reading the paper, it seems like any of the routes to EC-making seem either speculative, or very prone to failure (while also being hard to verify as a failure).
If the problem is a concern with competitiveness after re-transplantation, is there a way to create an environment where the stressed spermatogonia has either reduced competition, or is more competitive relative to its unedited counterparts?
Off the top of my head this might look like locally “sterilizing” just the spermatogonia tissue after a biopsy somehow, without damaging the machinery that leads to functional spermatozoon development and paternal imprinting. I’m not sure if this sort of targeted wiping is possible though, but at least with two testicles, the option of sterilizing one from spermatogonia tissue wouldn’t necessarily lead to complete sterilization. Or even if our only option here was complete spermatogonia sterilization, sperm preservation is relatively easy, so it still might be tolerable.
Alternatively, rather than just editing in a fluorescent reporter, you might also edit in a gene that makes the edited sperm more competitive in an environment that can be artificially induced in vivo. With just a fluorescent reporter, such a change arising naturally would naturally lead to the sperm being outcompeted and dying out (or if it as a completely neutral adaptation maybe not?), but if we induce conditions that are more favorable to spermatogonia with a specific tolerance induced by an inserted gene, they may have enough of a competitive advantage to persist in meaningful numbers. Off the top of my head I would consider higher temperature tolerance (with higher temperatures induced with a willy-warmer or something), or perhaps resistance to a chemical that’s normally harmful to spermatozoon? No idea what this could be though.
Also, would a fluorescent reporter gene edited into spermatogonia and present in spermatozoon persist into the zygote, and therefore into all the descended cells of the eventual mature organism? I think it would be hilarious and incredibly fitting if a side effect of making supermen is that they literally glow.
I partly agree, though with qualifications. One thing to note is that SSC methods are strictly haploid, hence half the power of diploid methods. Another thing to note is that SSC methods, especially ones that require iteration (editing), are not trivial in terms of EC; you have to maintain imprints, probably, as well as maintaining the general stem cell niche (i.e. ability to proliferate and ability to differentiate into spermatocytes).
I find e.g. sperm chromosome to have a comparable chance of working soon, though it has its own somewhat separate challenges.
Here “plausible” means “plausible really soon, like in a couple years”. The more robust way, that will quite likely work eventually, is more natural gametogenesis / EC-making (IVO and IVS). These have far more investment from scientists, so in particular it’s somewhat more clear what it would take and how to accelerate it, though far from fully clear. But yes, they do seem harder.
Yes, sterilization is possible; they sterilize mouse testes before retransplanting exogenous SSCs.
Sterilizing one testis is an interesting suggestion I hadn’t thought of, thanks. It does seem like a big cost, but presumably much less than half the cost of sterilizing both. It’s still a cost because you’re decreasing your fertility, and because IDK if there are sterilization methods that aren’t more generally toxic (e.g. oncogenic or something).
Yeah, IDK either, interesting question. I would very weakly guess that native SSCs can colonize the whole testis but IDK.
Yeah, this is a good idea that I’ve heard in the abstract. I don’t know about implementation details. I think I get pretty nervous whenever we’re talking about some unnatural modification, i.e. some modification that isn’t already present in natural humans. The case for safety seems significantly harder to make. If we do adult somatic gene therapies that are not just modifying to a common allele, and it’s fine, that could be some evidence that it’s fine. But SSCs in particular are stem cells, so a priori they are cancer risks, I would think. Like “how can I make this cell proliferate more than natural, and outcompete its natural healthy counterparts” is kinda like asking “how can I make some cancer”.
The idea is that you put the reporter near a gene whose protein is only present in sperm—e.g. a meiosis-specific protein (which I have heard do exist). So the child wouldn’t glow. But their gametes, and their descendants’s gametes (with 50% probability, etc.) would glow.