[deusofnull]

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.

[wahern]

> 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.

[ak217]

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.

[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.

[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.

[deusofnull]

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.

[pythonaut_16]

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

[TeMPOraL]

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.

[deusofnull]

>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.

[sudosysgen]

Not nearly as much in 2019's modern societies.

[mattkrause]

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.

[ak217]

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.

[imtringued]

>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.

[VectorLock]

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

[jandrese]

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?

[deusofnull]

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)

[imtringued]

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.

[bsder]

> 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.

[omegaworks]

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

[willis936]

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.

[markdown]

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

[holler]

Or you know, set them free...