China gene-edited baby experiment 'may have created unintended mutations' | Hacker News Reader

China gene-edited baby experiment 'may have created unintended mutations'

theguardian.com

117 pointspseudolus136 comments

It seems like a dead certainty that gene editing creates unintended mutations, since to do otherwise would require the technique to be 100% controllable and verifiable, and it is neither. So the only question is whether those unintended mutations are harmful or not, either to the immediate generation or subsequent ones. Because there is so much uncertainty around that question, these kinds of experiments are ethically, and in many cases, legally, prohibited.

Random harmful mutations have happened all day every day as long as life has existed. We are basically designed for dealing with it. But worst case, we can eliminate harmful mutations from being passed on to subsequent generations through screening. I wouldn't worry about the long term problems of that, it's fairly easy to solve.

What I would worry about is:

a) Short term suffering from failed experiments.

b) Reduced genetic diversity as everyone scrambles to get "the best" genes.

> we can eliminate harmful mutations from being passed on to subsequent generations through screening.

And the truly bad mutations should self-correct before passing to subsequent generations.

> And the truly bad mutations should self-correct before passing to subsequent generations.

That's an awfully euphemistic way to say "The kids'll die before they grow up."

I didn't want to say, "Survival of the fittest."

We live in a world where kids die before they grow up. Gene editing technologies will almost surely reduce the number of children who die before they grow up and lead to higher quality of life for everyone else.

I'm not necessarily for gene editing. I think it is probably a long-term certainty and a net good, but it makes me uneasy because it is one of the maybe-this-one-ends-humanity style technologies. That being said, the suffering that a gene edited baby and its parents go through is meaningful - we learn from it, we improve. At the moment if a baby is born with random congenital problems there is similar suffering and it is completely pointless; we don't really learn anything or change anything.

When both paths lead through suffering, anyone who knowingly chooses the path of greater long term suffering is a monster. Even if they want to claim they are acting for some sort of moral reason. We can't get hung up if a few children die when dealing with technologies of this consequence. There are just more important issues to work through.

Why would it end humanity? It may cause greater suffering than any war in history but it is not a serious threat to humanity.

Might create something better. It depends what we define as human and how quickly the technology develops.

> But worst case, we can eliminate harmful mutations from being passed on to subsequent generations through screening

Are you suggesting that we should prohibit these babies from reproducing when they reach adulthood? If not, how do you suggest we prevent harmful mutations from being passed on with "screening"?

Adults only pass on half of their genes during reproduction. I imagine at least in the case of in vitro fertilization there's a fair amount you can do to make sure the harmful genes aren't the ones passed along, so long as the parent doesn't have two copies of an autosomal dominant harmful mutation.

I wouldn't be surprised if more advanced methods exist either; as a carrier for a rare genetic disease maybe I should figure this out.

You can't argue with the "but what if" line of reasoning because there's always another hypothetical that could lead to the destruction of humanity or, at the very least, one more mutant baby than anticipated. And that's the problem here: these arguments boil down to "too dangerous", but that's not a characteristic amenable to empirically grounded, reasoned debate.

We can only have a scientifically constructive discussion within the context of a concrete, particularized therapy--disease, editing vector, gene, etc. Even then it's difficult, but at least you can reach a point at which you can agree to disagree on an actual, concrete scientific question. Everything else is philosophy and politics.

I think what people are trying to justify is an a priori assumption that gene editing (or germline editing if they're a little less cautious) is special and distinct. But I don't think you can scientifically justify that distinction from a harm avoidance perspective. Just because the technique is medically and scientifically distinguishable doesn't mean it's analytically distinguishable. And of course one of the principal drivers of these therapies, at least initially, is stopping the types of mutations that are feared but which already exist in nature.

So it's simply a belief that you hold; full stop. It's a legitimate belief, and may even be strongly informed by science, but it's like believing in God or aliens or the utility of Mars colonization--we might as well just put labels on our foreheads so we know where the argument will end up without actually having to argue. Knowing the other person's starting point, and assuming the best versions of their likely arguments, most of us here can arrive at the other person's conclusions independently.

I think what people are trying to justify is an a priori assumption that gene editing (or germline editing if they're a little less cautious) is special and distinct.

Gene editing is special and distinct, in the sense that the genome is a complex and nonlinear system, where small errors can be amplified into large consequences, not only local, biological consequences but social as well. In cases where technology offers such potentially extreme leverage, it is scientifically justifiable to tread cautiously to avoid great harm.

The same debate occurred regarding innoculation nearly 250 years ago. In fact, it's still occurring. Moreover, we're still stumbling--just last week I think someone posted an article to HN regarding how the use of live polio (IIRC?) vaccines has led us to paint ourselves into a corner, perpetually unable to extinguish the last remaining reservoirs. So the original concerns about what we'd now characterize as "complex" and "nonlinear" have been validated. It was the conclusions that were drawn from those concerns that were invalid--in short, that it was too dangerous to be introduced and managed by humans. The benefits outweighed the harms, even though many of the parade of horribles exclaimed by the skeptics did in fact come to pass. Those horribles ended up being buffered and moderated, because that's how complex, nonlinear systems also tend to behave.

In Complexity Theory, one of the defining behaviors of "complexity", in addition to nonlinearity, is a tendency to return to a quasi-equilibrium state even though it can never reach, let alone stay, at an actual equilibrium. Absent the dual (dueling?) tendencies of spontaneous change and regression, you have by definition either chaos or stasis.

It was not the same debate, because innoculation doesn't have as much capacity for far-reaching consequences. With regard to the notion of relying on the stability of a complex system, they tend to return to a quasi-equilibrium state, not necessarily the state they were in before being 'kicked'. And rate of change matters. Gene editing has the capacity to vastly accelerate the rate of mutation---indeed, that's it's purpose. And even if the overall nature of the genomic system remained recognizably mathematically the same, our experience of it in this accelerated state might be quite different.

1) Inoculation resulted in known historical outbreaks that killed many people.

2) Vaccinations, not to mention treatments like antibiotics, have resulted in accelerated mutation of disease. It's a serious concern and a growing problem in ways both predicted and unpredicted.

And, yes, these have occurred together.

We can argue in circles all day, unless you can point out some novel effect, even hypothetical, that hasn't already been reported in the literature or debated to death. Arguing that it's "too dangerous" is fair. You just can't argue that reasonable people can't disagree on that score.

what is this thread about again? last I checked if I get vaccinated or take some antibiotics this won't result in my children also getting them, and with gene editing that's a very likely possibility. the impact is on a wholly different level. e.g. can somebody get a patent on genes inserted into an embryo? what if the person born from this embryo then passes the gene? there's been rulings about GMO crops about these questions.

"There are two types of screening that can be carried out as part of the IVF process. Preimplantation genetic test for aneuploidies (PGT-A) screens for any chromosomal abnormalities that may be present, while other preimplantation genetic tests (PGT) checks for specific conditions such as Down’s syndrome, Huntington’s disease and muscular dystrophy, among others. In fact PGT can now be used with IVF to test for nearly 400 rare genetic conditions, including cystic fibrosis and early-onset Alzheimer’s."

https://blog.ivf.com.au/embryo-screening

Many chromosomal abnormalities can be reliably detected at 10 weeks into a pregnancy, if not earlier. 10 weeks is well within the window at which many if not most women would be comfortable terminating. In California these tests are required to be covered by insurance for at-risk women (i.e. 38 and older, etc).

I imagine at some point these tests, as well as more precise ones, are likely to become standard procedure for all pregnancies, in California and everywhere else.

EDIT: I mean comfortable as in willing; not comfortable as in "whatevs".

I understand that these tests require withdrawing amniotic fluid to analise, and / or getting genetic material from the fetus itself. And my understanding is also that to get the amniotic fluid carries fairly moderate risks of infection etc for the fetus so these screenings aren't necessarily done because of the risks not to mention the costs involved.

I think there are some newer tests which only require maternal blood and can screen for some genetic conditions by filtering extra-cellular genetic material.

Correct. I should have been explicit about the technique I had in mind: https://en.wikipedia.org/wiki/Cell-free_fetal_DNA

AFAIU, if the non-invasive tests turn up positive doctors may recommend (and patients may prefer) amniocentesis for confirmation.

I just find it interesting that California would so quickly embrace such new technology. I think it became required about a year or so after the tests hit the market, even before they became widely known (obv still not widely known). But given the rising costs of healthcare, and the incredible amount of public money spent on developmentally disabled individuals[1], it makes alot of sense. For similar reasons, California has had for many years mandatory blood lead testing for all children living in pre-1978 housing. (I think in most states blood lead testing is only mandated through Federal Medicaid regulations, which require testing for child Medicaid recipients.) California's housing and population explosion coincided with peak consumption of leaded paint and leaded gasoline, so California has a uniquely acute lead problem.

[1] California has very generous educational programs for the disabled (generous relative to most states), partially as a result of state-based constitutional precedent. By generous I mean a ton of money is spent as a fraction of overall expenditures, relative to most (all?) other states. This is a smallish part of why in-classroom expenditures seem meager relative to other states. Many parents, OTOH, likely have lesser opinions about how generous the programs really are. But school-based speech and physical therapists, for example, can make a very decent living in California, even in the Bay Area. Better to work through a private contracting firm; working directly for the school districts tends to pay less, though benefits are better. I know at least one serial entrepreneur who started, built-up, and sold two school-based therapy contracting firms, and has already started a third.

Some genes have a (much) higher chance to be passed on than others.

I think that would make for a good book, exploring the society and problems which result from a genetically modified caste of people who are prevented from breeding with non-modified people. A modern-day Romeo and Juliet.

The film Gattaca explores some of these themes.

Great film. For those who haven’t yet seen it, I would highly recommended it

Well that could be a problem in Western countries, but we are speaking of China. Their political system and their culture - their people's intrinsic sense of right and wrong - will be fine with that.

> Are you suggesting that we should prohibit these babies from reproducing when they reach adulthood?

That's currently the only reasonable thing to do.

> Short term suffering from failed experiments.

By "short term" you mean "only until the kids die of their mutations"?

Well I was thinking more along the lines of disabilities, weakness and abnormalities, but I guess death too.

You guess harming a human baby to the point of death might be a problem?

The goal of gene therapies isn't to kill their patients but it wouldn't surprise me if introducing a lesser disease in exchange for curing a serious disease would be considered an acceptable outcome even if it means that people who have not been seriously ill will now suffer from the lesser disease more frequently.

But the problem with all of this aren't these strategic questions about eradicating disease and improving the human condition.

It's that all of this is happening within a frame of ignorance with regards to the insane, elusive complexity that is genetics.

Somehow the idea that changing genes at will can be predictable isn't dying off.

I wouldn't worry so much about reduced diversity. Once we're good enough at creating genetically manipulated babies we can recover any diversity we want in one generation.

We'll still need adults to raise this next generation. So, if we realize we swung the pendulum too far towards uniformity, it'll take 16+ years for the next "diverse" generation to mature and become self-sufficient.

Unfortunately, diseases typically run their course much faster than that meaning it would be possible for a disease to devastate a genetically homogenous population before they can raise the next generation and maintain population levels.

Will that be genuine or superficial? Will 'verifying the integrity of that DNA after these edits' become the new cryptomining? Here's a hard problem: 'integrity' and 'verfiy' and "good enough at creating" are ill-defined at best.

It almost reminds me of ...me. "I don't need to study and get good at studying, I just need to get good at self-hypnosis and instruct my brain to absorb things faster and remember things better." Want to know how that turned out? It didn't.

That doesn't make any sense. Right now every single human is a gene designer and each of them is using a benchmark that is specific to their environment. There is no way you can replicate that without building a parallel society of gene designers.

I'd be more worried about subtle long-term mutations which won't have obviously observable effects at first but will severely disadvantage us in the long run. Or only become enabled in combination with some future mutations. If a gene increases chances of a disease by 5%, how soon do you identify that?

Once a gene is widespread enough, good luck preventing gene carriers from reproducing. Most people won't care enough to screen potential partners, or even worse, it could create social tension.

Also, why this is worse than a similar mutation in the wild, is because it will be coupled with "branded" genotype, which will be treated specially. People will potentially want to pursue certain genotype (with tall height, blue eyes etc), not caring about health implications, which I can almost guarantee won't be properly disclosed, even if known.

Just like dog breeding.

And you can judge how much people care about appearances by the success of plastic surgery business.

This isn't really it. It's not like this sort of thing would have been OK if editing was 10 or 100 times less likely to cause off target effects.

The way the whole thing happened was stupid. It was the wrong population of patients (healthy children), who had other options for avoiding HIV infection (antiretroviral suppression in parents, surrogacy, etc etc). And the fool decided this was the right population in which to employ highly experimental and underdeveloped gene technology? Any scientist with a modicum of integrity or common sense would never have done this. It's just bad science.

I don't agree that uncertainty is a valid objection in ethical discussions. That reasoning leads to circular denial: we can't study something because we don't know enough about it, and we don't know enough about it because we can't study it.

Rather, I would suggest that the ethical discussion focuses on intended and unintended side-effects of a specific direction of study, and whether the long-term effects can be aligned with healthy societal progress.

Personally, I think that pregestational gene editing doesn't have many secondary benefits, and that the technology, once available, will have a huge negative effect on society (both on the gene pool and on equality). So I would argue against this line of research should be prohibited based on that, not based on the limits of our knowledge.

No, uncertainty very much is a valid objection when you're manipulating the genome of a human being. Even from a purely utilitarian point of view you should at least be able to rule out the terrible consequences such an experiment could have.

Besides even if a particular experiment cannot be done because the outcome is uncertain and we can't have certainty without the experiment then that is circular but not circular reasoning. We cannot simply declare something to be ethical purely because declaring it unethical would not allow us to do something.

You essentially disregard one weak argument, and replace it with a worse one: "negative effect on society...both on the gene pool and on equality".

First you contradict your original dismissal, any negative effects on the gene pool most likely can be solved by more research.

Asserting a negative effect on equality is an equally damaging and incorrect opinion. A similar analogy here would be arguing vaccines should be avoided and prevented because not everyone has access to them, thereby having negative effects on equality

The articles don't really say much about the data. I think this is the same data from his talk in 2018. I read somewhere that one baby is a heterozygous CCR5+/- knockout and the other is a mosaic. His clinical plan was to test to infect the babies blood a few months after birth, probably someone has done that already. Pity that we have to play hide and seek with this study.

his talk where he probably presented the same data : https://www.youtube.com/watch?v=pcGALqX_YD8

Consent forms that he had published in his website at the time:

https://web.archive.org/web/20181128061149/http://www.sustc-...

Second informed consent; https://web.archive.org/web/20181128061153/http://www.sustc-...

Ethical approval: https://web.archive.org/web/20181128061204/http://www.sustc-...

Clinical registry: https://web.archive.org/web/20181128061216/http://www.sustc-...

There is also some info including an excel file with the outcomes of the trial here: http://www.chictr.org.cn/showproj.aspx?proj=32758

Back in my genetics class in Uni, unitended mutations from gene editing struck me as a concern almost immediately. and its scary to think about. these unknown mutations could be benign, harmful, or even helpful, but if they entered the population through procreation... i mean i had an anxiety that the whole human genome could be damaged at a fundamental level.

the complexity of the biological machinery that occurs during gene transcription and replication and translation is maddening. yes, its sort of like a zipper in some ways, but remember that the geometry of a zipper is 2 dimensional, teeth and grooves. DNA is "zipped" by a protein that will fit with the geometry of hundreds or thousands of nucleotide pairs, and even that is a really basic way of putting it. and that natural system of transcription, translation, and protein synthesis at the core of DNA still makes mistakes.

You think index mismatch by 1 in an array can be a bit tricky, imagine how with DNA you have a long array, sort of, with millions of discrete parts that have start and end segments sort like how memory is managed in ram. CRISPR is in some ways, like trying to write perfect memory safe code in a non mem-managed language. crude metaphor but it was how i thought about it during university learning about both compsci and genetics.

If you want to play god, you have to take it all the way ie. be prepared to sterilize or kill your creations.

Or you know, set them free...

For the most part mutations like that simply reduce the reproductive viability of the offspring. We can't really poison the entire human genome worldwide without going to absolute extremes.

Could we engineer a human so irresistibly sexually desirable and voracious that they could spread their genetic material with a subtle recessive defect across the globe in the span of a generation so that it could take effect before people realized what was going on?

Dunno, but all kinds of things could happen with novel co-dependent alleles with devistating effects when the express. Imagine theres a cool gene edit in 100 years that lets you live to 200 easy and it becomes normal for most people to get it. But, it just so happens that thers an early gene edit that was available 20 years from now, less ethically created and expensive. but hundreds of thousands of people get that first life extender.

Then, turns out the better / safer one 70 years from now has a co-expression with the decendents of the people who got it 20 years from now that makes you infertile, senile, or whatever.

thats the danger. If these edits become available broadly, youre not only worrying about co-expressions of edit genes developed at the same time, but edit genes developed at any time in the past (oh and also the rest of the human genome, which we still dont understand fully, and is a base concern for any gene editing whatsoever)

> thats the danger. If these edits become available broadly, youre not only worrying about co-expressions of edit genes developed at the same time, but edit genes developed at any time in the past (oh and also the rest of the human genome, which we still dont understand fully, and is a base concern for any gene editing whatsoever)

<shrug> Then people who chose that mating pair will get weeded out. It sucks to be the individual victims of that, but that's not a big deal for the species.

In addition, biological systems almost always have variation. Even Ebola isn't 100% fatal. So, even if you have an interaction, some people will have another mutation that deactivates the interaction.

I'm now wondering what measures scientists use to prevent genes that reduce child mortality but also decrease life expectancy. It's unlikely that the company that designed your genes will stay in business for 70 years so that it can update its gene designs to fix this fatal flaw.

You don't need to. Read up on gene drive. Just need to engineer the next generation to only produce males.

> natural system of transcription, translation, and protein synthesis at the core of DNA still makes mistakes.

Exactly, which means the system is resilient, which means it's more forgiving of random mutations introduced by gene editing, which is perhaps why most scientists are less concerned than you think they ought to be.

Imagine if we took the same approach to surgery--overly worried that scar tissue of any kind at any point would completely disrupt the functioning of an organ. We'd be a hundred years or more behind where we are now. Scientists and doctors understand that the body is both much more complex than a simple machine, but also much more resilient.

Such criticism cuts both ways. Likewise for GMOs. Demanding perfection is unreasonable and unnecessary.

To play devil's advocate: Scar tissue doesn't get passed to offspring or propagated throughout the population though.

To play the angel's advocate (or whatever is the next-step reverse of devil's advocate): natural selection helps eliminate problematic genes in populations. A good chunk of harmful mutations will prevent people from procreating, either by killing them first, or making it unlikely for them to find a mate.

Not nearly as much in 2019's modern societies.

Less now, for sure, but you're overlooking a major category.

Many of the really bad mutations are embryonic-lethal, which is why a surprisingly high proportion of pregnancies "don't take" or end in miscarriage.

Yes, and many more cause carrier mutations that won't surface until the next generation, or late-onset metabolic or neural disorders that will cripple the individual later in life, or increase mutational load resulting in much higher chance of cancer. The fact that some mutations are benign and others fatal really doesn't change the issue that we don't yet know how to safely edit the human germline.

Totally agreed--I think this was a horrific and stupid thing to do.

I just wanted to push back a bit on the idea that medicine is badly "breaking" evolution by keeping people alive.

>A good chunk of harmful mutations will prevent people from procreating, either by killing them first, or making it unlikely for them to find a mate.

well, what about a recessive allele that doesnt cause problems in the first generation but does in subsequent? What about co-dependent deadly / devastating gene expressions between newly added genes that pop up after 2 people with these co-active genes expressing like a hundred years from now? look, given what i studied and why, i would never say we should forever abstain from gene editing technology. BUT, we have to hold those who conduct genetic modification experiments to the absolute highest ethical and engineering standards. It is akin to the level of power given by atomic science, maybe even more. one can be sure that the powers of a God would include the power of the atom and the power of the gene near the top of the list.

There's a huge difference between somatic and germline editing. Surgery is like somatic editing. It's elective, based on medical need, and its effects are confined to one individual. Germline editing is more like forcing an entire population to undergo surgery that is claimed to enhance their bodies.

Nobody is particularly concerned about somatic editing where a medical need exists. Everybody is rightly freaking out about germline editing because it's non-elective for the babies, its consequences are permanent and can be severe, and we aren't good enough at it yet (not even the somatic variety) to claim anything about its safety.

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.

Is what you describe the basis of Human Endogenous Retroviruses?

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.

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.

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.

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.

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

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.

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.

I agree it is resilient, but that resilience has been tested by a slow, small increment evolution over millions of years. And even given that, genetic disorders with novel expressions exist that confound modern science. if we start making very fast changes, the resilience of the genetic system shouldn't be expected to hold up against a far faster change rate. And more to my point about the complexity of it all, there are huge regions of our genome that we thought were "unrelated" to human phenotypes (physical expression of genetic code) until very recently when we discovered some of this "junk" DNA actually is critical for certain types of RNA transcription / repair.

GMOs are a different issue. My underlying concern about the influx of new genes introduce to the wild quickly being potentially dangerous aside, the genetic modification have mostly been to make plants resilient to various herbicides/fungicides/pesticides to allow large scale monoculture farming. That's one solution, but not the only. And we have seen invasive forms of GMO crops spread out of containment, thus entering the wild population, and we wont know the consequence of that for a long time, if any.

takeaway being, its probably worth being conservative about even moderate scale genetic manipulation of any species we rely on, and especially our own genome. Not saying dont do any genetic modification, just that it really has to be air tight, you might say NASA level standards of engineering. Now, you tell me if you think Monsanto's engineering standards are at NASA level, or that the Chinese Governments ethical standards are without problems.

The human body, incredibly robust and frustratingly fragile at the same time.

>Exactly, which means the system is resilient, which means it's more forgiving of random mutations introduced by gene editing, which is perhaps why most scientists are less concerned than you think they ought to be.

The argument should go the other way. Because these DNA mistakes are predictable our genes have designed safeguards against them. If you now randomly introduce a "mistake" that is beyond the capability of the system then it won't help you.

From conversations with a biochemist, I gained an appreciation for the complexity of genetics. It’s like a computer reading byte code to boot, except the computer makes the hardware that executes the code. That’s the simplest layer of it. I only know a scratch On the surface of how interconnected it all is. If you have an error in a gene that will likely cause an incorrectly generated protein. Proteins and protein synthesis must be relatively resilient to this kind of common error. If that system isn’t resilient then other systems prevent the error from propagating. These solutions must exist or else life wouldn’t work. And this is all in a single cell. Cells coexisting is such a strange thing.

Isn't it the case that each gene does not have a single function? This seems like we're tampering with a many-variable equation for each gene we modify. It's like modifying a function when you're not aware that that function has potentially many side effects, which are necessary.

Actually, that's exactly what it is. Genes are the most tightly coupled code in existence (literally!), and we've barely scratched the surface in seeing what changes we could make and where to make them without bringing the whole thing crashing down.

Who coded that crap?!

Maybe it's Gods DRM.

It’s God’s job security.

The figurative equivalent of a million monkeys pressing random keys in an IDE for hundreds of millions of years until it compiles. Rinse and repeat.

It's a bit like climate change, there are so many dependent/independent variables, most of them we're not even aware of, that there is no way to make accurate predictions.

I don't think anything is closer to a literal pandora's box than gene editing. I have no trouble seeing it going on the same path as asbestos or lead in car fuel: It'll feel almost like magic for a few decades, and by the time we understand how bad we fucked up it'll be too late to fix it properly.

It's unsettling how many pleasant euphemisms I'm seeing that amount to "any kids who get really fucked up by gene editing will die before they reproduce, so it's fine!"

China demonstrates that it is willing to cross moral boundaries (CRISPR, IP theft) and sacrifice the present to improve the future (Massive infrastructure paving over individual properties).

Western world shows exactly opposite trends - absolute refusal to make any sort of sacrifices (see: reaction to Carbon taxes, minority property owners blocking major infrastructure projects), prioritizing status quo at the cost of hurting future generations (see: Prop 13 in CA, highly cumbersome firing process in France), risk aversion (see: reaction to Nuclear energy proposals)

If China was not facing adverse population pyramid coupled with hostility to immigration, it would have had an easy way to global supremacy. Though Western world is trying very hard to erase that advantage by both producing fewer babies and raising barriers for immigration.

* albeit for a small marginal minority, never for the elites

IP theft isn't a moral boundary; it is a legal one. Pro- and Anti- IP positions are not moral positions. I can't claim moral superiority to you because I think copyright should be a year longer or shorter. Enforcing IP law that retards the lifestyle of 20% of the worlds population is arguably the immoral position.

China is anything but future over present. Massive infrastructures are a result of stimulating the economy for short term stats over long term economic sustainability. Same with terrible pollution and countless political and security measures that hurt future prospects, detention camps being one of them.

I'm not sure what's immoral about IP 'theft'

The shocking and disturbing thing about it is the ignorance the general public showed toward it. "Super baby", "supermen army", people just assume that this much touted CRISPR is precise, that human actually know more than a tiny bit of the human genome. All in this current wave of technological optimism.

It doesn't have to be precise (at this stage). Two things about China:

1) They have a massive population. ~1.386 Billion people. Large enough to conceal large populations (100's of thousands of people) without drawing attention to cities, supply chain movements, etc.

2) There are no problems with using unethical or illegal actions to advance the CCP's agenda. See: parting out fully conscious and unanesthatized prisoners for organ transplants, etc.

I have no doubt that they will (if they aren't already doing it) devising experimental gene-edits and applying it to batches of hundreds or thousands of babies, and seeing what happens as they grow up. They wouldn't even need to hide them from the general population, with the whole pervasive surveillance / facial recognition / etc. thing they've got going on they could release the children into the general population and track them across their entire lives covertly.

I'm not saying that we'll end up with a supersoldier scenario or anything like that, but this could lead to a medical advantage over the west that could have tremendous implications economically and to security (the possibility of blackmailing someone into spying in exchange for medical treatement).

Identical twins have hundreds of differences across the entire genome. None of those are carefully planned.

Prior to that, during generation of sperm and egg, many other unintended mutations occur. Each chromosome typically breaks and misjoins (crossing haphazardly with the matched one) about 3 times.

This experiment is really mild by comparison.

This will end with China and other countries not interested in moralistic faffing about full of actual superhumans, won't it?

This seems like as good opportunity as any other to remind that the previously published study that those gene-edited babies will have shorter life expectancy, that was used to bash He Jiankui previously was retracted [0]. It almost looks like some scientists are envious of him and scramble to find something to use against him. There are risks to many medical procedures and only time will show if these are more or less serious.

That said, I don't think that attempting to grant immunity to disease you might never encounter and is possible to be well treated (if not cured) nowadays was a right reason for first human gene edit. If it fixed a single gene disorder which would allow some parents to have their own healthy biological child, it would be certainly more palatable.

[0]: https://www.nature.com/articles/d41586-019-03032-2

>While the team targeted the right gene, they [created] novel edits whose effects are not clear.

Welp. If it's not the right gene, you can bet it's probably just going to cause cancer or something.

It is the right gene; it's allegedly not the right allele.

Is there any evidence that the gene edits were actually targeted at HIV immunity? Seemed like an odd selection, I always figured it was a cover story.

Even if the technique were perfect, there are unintended consequences to letting people pick things.

You can think of the one child policy as a precursor experiment to letting people select genetic attributes (gender in that case). People selected the trait that they thought was “better” (male). The unintended consequence wasn’t that it turned out men are not good, but that too many men instead of woman was bad for the population in general.

Are there any guarantees we are not going to repeat mistakes from dog breeding?

Every human has 60000 mutations per day on average.

Those are in individual cells, and almost certainly all different, so they have little overall effect. This is something that (if it works correctly) affects every cell, in the same way. That's very different.

the thing with ethical germline edits is that it implies recording all future progress of the edit.

ie continued gene level surveillance for all progeny

We let people breed with anyone they want to, and look at the reject rate on that.

No shit.

Not prohibited in China by ethics or legality.

"A team of investigators told the official Xinhua news agency on Monday that a preliminary investigation had concluded that He had “organised a project team that included foreign staff, which intentionally avoided surveillance and used technology of uncertain safety and effectiveness to perform human embryo gene-editing activity with the purpose of reproduction, which is officially banned in the country”."

https://www.scmp.com/news/china/science/article/2182964/chin...

The article doesn't explain what the unintended mutations might be..?

it would be really really hard to figure that out at this point, most likely. again, like the article says, they cant investigate the embryo too fully without "destroying it". Same sorta goes for a kid. But if the unintended mutations manifest in a bad expression, you might be able to start researching in situ in labs with cell cultures with and without the gene present / expressing.

Telekinesis, rapid regeneration, blue hair

We would favor painless rapid regeneration, though.

They CRISPR'd to cut out the correct spot, but instead of filling the gap with Delta32, which is known to help with HIV immunity, they replaced it with... random data it sounds like.

In other words, it sounds like every cell might have gotten it's own randomly selected garbage data... They seem to say only a single cell they measured got the correct mutation.

this file apparently lists the variants in the embryos

http://www.chictr.org.cn/Ajax/Download.aspx?type=downloadfil...

some are marked as benign, some likely pathogenic

Unintended mutations happen all the time naturally. Some are beneficial, and some are harmful. This just speeds up the process a bit. Life has natural processes to error-correct, otherwise it would not have survived for millions of years.

Sure, but too many unintended mutations in too short of a time period and you end up with things like cancer or fatal congenital diseases. Gene editing with CRISPR is potentially increasing the mutation rate by orders of magnitude. Where is the line?

Ahhh, the good ol' "fires burn houses down all the time" defense of playing with gas indoors.

> * This just speeds up the process a bit.*

You can't make an omelet without killing a few kids.

By that same logic we shouldn’t care about radiation exposure.

We’re just speeding up the process a bit.

Reply on news.ycombinator.com