[wahern]

IIRC, when I studied biology in secondary school and as a freshman in college, it was believed that gametes were completely isolated and untouchable by viral infections. Turns out this is not true. But if you believe that gametes are incredibly fragile, I can see how it would be easy to believe this as otherwise you'd expect to see mutants everywhere.

I realize the stakes are higher for germline editing, but rationally speaking higher stakes alone don't change the calculus.

[ak217]

I don't follow. Gametes are isolated from many viral infections, but even assuming that a gamete undergoes viral mutagenesis, that's not evolutionarily novel (viruses follow relatively predictable insertion patterns, and transposons are basically degenerate/grounded viruses that are almost certain to generate mutation events in any given zygote, unlike viral mutagenesis). It's also outside our control, unlike germline editing, which is not random in completely novel ways.

It is precisely because the stakes are so much higher that the calculus changes. We have to be reasonably certain that we can safely edit germline by experimenting with somatic editing and germline in lab animals before we can do something as consequential as deploying it clinically.

[wahern]

Sure, they are more isolated. And in some ways they are more fragile. But my point is that they're not nearly as fragile as we believed. And more importantly a faulty premise--that they're extremely fragile--gave way to a faulty scientific conclusion--that gametes were impervious to common environmental stressors like the many infections that ravage our bodies.

We can't draw simple, categorical conclusions about gene editing, nor even germline editing in particular, because there are no simple, categorical distinctions. Suffice it to say, it's complex. Whenever we try to be reductivist about such things we end up drawing erroneous and even dangerous conclusions; e.g. gamete fragility -> viral imperviousness as solution to observed lack of harm -> underestimation of viral stressors and risks, and overestimation of gene editing risks.

Regarding stakes, what I had in mind was classic economic behavioral experiments where they show that a change in the magnitude of a bet changes choices in an irrational manner even though the expected payoff is exactly the same; even when you take into account marginal utility effects.

Yes, germline edits don't just effect one person, they theoretically could infect all of humanity. But so what? Remember when they were firing up the LHC and people were freaking out at the possible creation of blackholes. Given the error bars in known physics, there was a non-zero chance running the experiments could have destroyed the world.[1] Because nothing we could possibly learn would compensate for losing everything, does that mean we should never have turned it on? No. The calculus didn't change. That germline edits propagate doesn't mean our harm+benefit calculus changes; it's just that one of the risk factors in the equation changes from a 1 to something larger. Other factors, like confidence, may or may not need to be changed.

Regarding the argument that by intervening scientifically we're categorically more culpable than if we didn't do anything, that touches upon the is/ought and naturalistic fallacies. From a utilitarian perspective intervention vs non-intervention is irrelevant. I'm not a Utilitarian (capital U), but I don't see how we can have a constructive, scientific debate outside a utilitarian framework. Such lines of reasoning are more relevant to political and religious contexts.

[1] Well, maybe. Actually, perhaps many physicists would have said that the consensus science would have put the chance at 0. But the best argument was made by people pointing out that the Earth's atmosphere was constantly bombarded by particles far more energetic than what the LHC would create. Which is exactly analogous to germline editing. The fact is, the germline undergoes far more genetic stressors than we once believed. It must follow that it's more resilient than we believed, genetically, developmentally, and from an evolutionary perspective.

[ak217]

The concerns about the LHC were a hell of a lot more hypothetical than about germline editing, and that did change the calculus. We know that current genome editing techniques have off-target effects.

You're arguing from some abstract philosophical perspective, but the practical situation is much simpler. Nobody is drawing categorical conclusions and saying that we should never edit the germline, and at the same time the opinion that we should do germline editing right now is fringe. The tools, while much better than ten years ago, still suck. Outside a few well-characterized alleles in Mendelian diseases, nobody knows what to edit, what side effects edits will have or why. It's likely that in a few years we will know, given that we're quickly improving both the molecular techniques and the genome knowledge bases necessary to understand the consequences of the edits. But until then, it's dangerous and unethical to experiment on babies without their consent or pressing medical need, and scientists are right to freak out about it.

[wahern]

If you believe that germline gene editing is so risky and potentially costly as to be absolutely unwarranted, then you shouldn't support somatic gene therapy as there remains a very real and non-negligible risk of germline integration. Some vectors might be safer than others, but proving the impossibility of gene integration into the germline seems extremely costly and possibly unprovable. I mean, heck, there's at least one scientifically proven case of a virgin birth.[1] Where does that leave us?

I return to my original point: Demanding perfection [and omniscience] is unreasonable and unnecessary. All of these other concerns are typical of any medical procedure: you attempt as best you can to integrate known risks as well as unknowns (known unknowns and unknown unknowns) into a cost and you compare it to the benefit, and if the benefit outweighs the cost then go for it. For germline editing in particular the costs will likely outweigh the potential benefits in most cases for some time, but we still need to make that determination regularly, honestly, and in context (actual proposed cases), without our fingers on the scale.

Issues like consent are ancillary. And they exist regardless of gene therapy. People don't consent to be born. Or consent to be "identified" through family members choosing to publish their genetic information. Social engineering experiments have lead to holocausts, even when they began innocently; if you go back far enough in the causal chain, they're all innocent and completely unintended. These problems, high-stakes consequences, and paradoxes already exist; we already struggle with them. Gene therapy, not even germline therapy, create fundamentally de novo issues. That's the real hubris, the delusion that we're not already playing with fire.

At the end of the day what the Chinese researcher did was reprehensible, but mostly for very particular reasons. I'd wager big money that a significant plurality of medical scientists, if not a majority, are today already prepared to approve germline editing given a good candidate therapy--patient, vector, payload, etc. As for medical ethicists, as scholars they tend to splinter into radical advocates or skeptics because that's how you get tenure and attention; and unlike doctors they don't get fired (or "disappeared") when they're wrong.

[1] "Oral conception. Impregnation via the proximal gastrointestinal tract in a patient with an aplastic distal vagina. Case report", http://img2.timg.co.il/CommunaFiles/21227065.pdf

[ak217]

The original point of yours that I find issue with was about "perhaps why most scientists are less concerned", which is really bullshit because most scientists in the field are concerned about premature germline editing. And the arguments you've arrived to in support of it rest on a bunch of false equivalences.

[wahern]

I never said not concerned, I said less concerned relative to the apparent concern in the comment I was replying to. Any error would be in the relative level of concern.

I know of their concerns. A friend of mine just got his Ph.D and has a very interesting story about how he answered a query by one of the CRISPR patent holders (then a student in his program) regarding techniques for delivering an intact sequence to the mammalian nucleus.[1] Prior to graduate school my friend spent several years working at the Craig Venter institute studying rhinovirus (while his wife completed her post-graduate work at NIH), and the technique he utilized at the institute and recommended "coincidentally" ended up being the one used. Which gives credence to the whole argument that the CRISPR "discovery" was basically combining together two already well-established methods for gene editing in an obvious way.

Also, he was the safety directory in his lab, both at school and at the institute. Because of the nature of the work, he would obviously be well aware of the risks involved with any sort of gene therapy. I don't know whether he would approve of germline therapy, but I'm pretty sure he'd agree that any blanket ban with the pretense of saving humanity would be naive as it's quite likely already happening to some extent under the radar, both deliberately and unintentionally. But that's a different sort of argument and doesn't contradict what yours, as far as I understand it.

I just took your argument as being excessively alarmist, and my point boils down to that scientists tend to be less alarmist because they're already inured to these things. They know how the sausage is made, and it's never pretty. They see the enormous holes in knowledge that you can drive fleets of buses through. But they also understand that nature is far more forgiving than popular science journalism would have you believe. "Holy sh+t, I didn't expect that'd work as well as it did" is, I think, not an uncommon experience; likewise for "holy sh+t, that didn't go as I expected", for that matter.

[1] Or something to that effect. Don't quote me because (a) I'm recalling from memory, (b) he gave me the dumbed down version, and (c) a Harvard e-mail system migration meant that he lost all his previous correspondence so he's likewise recalling his discussion from memory.

[coolguy132435]

Is what you describe the basis of Human Endogenous Retroviruses?

[wahern]

I've assumed so, but I'm not a scientist by trade and never looked deeply into it. I just know that over the years I've crossed paths with several papers that showed infection of gametes (usually sperm) by common viruses and often gave them a cursory look. These papers always catch my attention because what I was taught in school never made sense to me. I mean, I know gametes are in some ways more fragile than most cells, and they are clearly isolated to an extent (for obvious reasons), but the imperviousness I was taught seemed unlikely and unsupportable. And because of that I've always been especially skeptical of arguments premised, directly or indirectly, on the extreme mutagenic fragility of gametes and germlines.