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Comment by xr4ti | Hacker News Reader

Unrestricted gene editing in humans is probably a bad idea. (1) Evolution has been pretty effective to this point, (2) decreasing genetic variability will make humans as a species more susceptible to extinction from a single event, and (3) it will probably backfire as humans do not possess the foresight to know what the world will be in 1-3 generations and what traits might predispose their descendants to success.

Hell what we think of as genetic "diseases" give an evolutionary advantage under the right circumstances (ex. sickle cell anemia + malaria, cystic fibrosis + cholera).

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You misunderstand so many things.

1. There are many somatic applications of CRISPR that have no effect on the germline.

2. Even the germline applications don't necessarily "decrease genetic variability". Why would you think that?

3. Even considering off-target effects, the edits made to any particular genome are miniscule compared to its overall size, which I'm sure would astound you. There is no reason to believe these edits will make us less (or more) resistant to environmental exposures.

4. We are not talking making people more likely to contract cholera, which is easily controlled by sanitation. We're talking about preventing or curing debilitating illnesses that confer no benefit to the organism.

For 2, isn’t there risk that people will be influenced by association studies and seek out editing of single nucleotides thereby potentially removing ‘bad’ variants from the entire population? For example, say a gwas shows that a snp variant is associated with higher IQ. People rush to edit that nucleotide. But, they don’t understand that that snp variant may have had other beneficial effects ...

Likely, only the rich will be able to run out and get gene mods for some time.

Likely, the rich will set up charities that sponsor gene mods for the poor.

(Only a cynic would call it beta testing.)

Aren't we already doing beta-testing medicaments big scale in africa?

Given that genetic testing(+) has had twice the rate of performance-to-cost doublings as Moore’s Law since the Human Genome Project completed, “some time” may be 21 years from billionaires to subsistence farmers.

(+) yes I know that’s not the same as editing, but it’s the closest comparison I have for guestimating future improvements.

I imagine that (at least for the foreseeable future) genetic engineering will only be targeted to modifying SNPs (and other mutations) that unambiguously cause diseases.

I imagine that genetic engineering for intelligence has already happened on the downlow.

bloodlines

If we'd had the option to remove the gene that causes sickle-cell anaemia from the population, wouldn't we have taken it? Which would have meant we then didn't have the malaria-resistant population that now exists due to that same gene.

On the one hand, correct.

On the other, we’re currently exploring ways to wipe out malaria carrying mosquitoes.

On the third (genetically modified :P) hand, easy gene modification will probably lead to a similar patch-cycle as we already have for software.

On the fourth hand, thanks to the typical decade long testing cycle for medicines, the worst parts of this hypothetical future are likely to happen around the same time we get full-mind uploads.

I agree with points 1-3, but I would be remiss not to mention, that with respect to point 4, diseases like sickle cell anemia, which is hideously painful and fatal as a double inheritance (25% homozygous offspring in a heterozygous pairing, ss), but a wonderful defense against malaria in heterozygous offspring (Ss, 50% of said pairing). The remaining 25% homozygous wild-type (SS) are healthy, except when encountering malaria.

https://www.cdc.gov/malaria/about/biology/sickle_cell.html

I would think that a mendelian genetic disease like sickle cell might well be on our hit list for all the trouble it causes. Of course, it could be argued that mosquito nets and drugs (i.e. technology) are a better, less costly defense, than these inborn genetic mutations.

I think his point was, that in general, even the terrible mutations like sickle cell serve a purpose in ensuring the survival of our species in the face of diseases like malaria (which if it was much more potent, or our population much smaller and closer together, could wipe us out). From an "effectiveness of evolution" stand point generating those sorts of terrible diseases is a feature of the "algorithm".

We are smart enough to face the consequences of eliminating such things, of taking control of the selection function used by evolution. The question is if we are wise enough to understand that we must be prepared for the consequences, or even understand that there will be consequences.

>1. There are many somatic applications of CRISPR that have no effect on the germline.

Yes, but there are many that have.

>2. Even the germline applications don't necessarily "decrease genetic variability". Why would you think that?

Because he talked about "Unrestricted gene editing in humans" in general, and one of the goals would be designer humans and babies, which will decrease "genetic variability".

>3. Even considering off-target effects, the edits made to any particular genome are miniscule compared to its overall size, which I'm sure would astound you. There is no reason to believe these edits will make us less (or more) resistant to environmental exposures.

Tiny changes can have huge effects, especially when one doesn't fully understand what they're changing and second order effects of their meddling.

Heck, it's 2018 and we can't cure common cold or obesity, and we don't know tons of stuff about the human body, metabolism etc and how it works.

>4. We are not talking making people more likely to contract cholera, which is easily controlled by sanitation. We're talking about preventing or curing debilitating illnesses that confer no benefit to the organism.

Who is this "we" who is talking it? There's no doubt tons of state actors will be interested in making people more likely to contract all kinds of things (or be resistant to them, as long as they can spread it to the others) -- that is, weaponize the thing.

This sounds too much like the old "man playing God" trope: we don't know, therefore we should continue to revel in our ignorance instead of taking any risks. To hell with that, if I can give my children genes that prevent debilitating diseases and low intelligence and if the risks are manageable, I will take that. That possibility is decades away, but it's a worthy goal to pursue.

This is not about "designer babies" in the eye color or physical appearance sense - who knows what will be the beauty norm 50 years from now. It's about ridding humanity of what we know is deadly and, on a personal level, preventing my own bad genes getting passed on. I have a bad back, an insatiable appetite and high cholesterol, I'm balding and have a slight heart deformity. Should I pass those traits along just for the hope that someday some bald distant sibling will have immunity from a future plague? I don't think I'm really responsible for that, it's the task of future generations to keep the baldness genes in a bank or database and use it at that time if they find them useful.

The reduced genetic diversity is moot - people of all ethic groups have today a chance to reproduce instead of being wiped out like for most part of human history. We are in an explosion of genetic diversity, even very dangerous traits are being preserved in the gene pool due to the advances of medicine that made them survivable. When genetic editing will be so widespread as to threaten the genetic diversity of the human species, we will be living in a Star Trek egalitarian paradise, it's very presumptuous to think we have any foresight into such a future.

>This sounds too much like the old "man playing God" trope

Which was never much discredited in the first place.

I see: we aren't having a scientific debate, we have a political disagreement about the place of science in society.

> Decades away

Worth mentioning that Iceland has virtually eliminated Down's Syndrome from the population with genetic screening of pregnant women.

Almost all Icelandic women choose to terminate the pregnancy, if the test comes back positive for Down's Syndrome.

7 minute mini documentary:

https://youtu.be/S-X97xxw5aI

Not to counter your point, but I was referring to gene editing before implantation and inserting/replacing various traits that maximize the health of the offspring - that is still experimental. Genetic testing and selective abortion has similar end goals but is not a direct application of the ideea.

Evolution is nothing more than dumb luck trial and error. There has to be a better way. I remember a quote from Gattaca "I not only think we will tamper with Mother Nature. I think Mother wants us to."

It would be folly to think that we know how to improve the Human genome. I don't think we understand enough of how the genome works. We certainly can't predict how genetic changes will affect an organism. But I'd like to think that someday we will get there

I'd like to think someday AI will help us make those technical decisions, even though we won't fully understand them because the human brain simply can't process the multi-dimensional complexity that a computer theoretically handles no problem. That leaves a lot of room for fear-mongering, but one man's utopia is another man's dystopia, I suppose.

As long as humans benefit, I say it's a worthwhile goal to at least explore. If that leads to the extinction of the human race through genetic defect or similar existential tragedy stemming from this, then maybe we just weren't cut out for this gig and should go the way of the dodo. Maybe on another planet, a higher intelligence will figure out how to peacefully coexist with an intelligence of their own creation/modification. Maybe this is just all an inevitable aspect of the evolutionary algorithm at work; who are we to think we can avoid it?

I've seen a number of articles that there is suspicion that AI (ie., ML'd coefficients in a set of matrices) just reinforces already held prejudices in certain cases which do not actually jive with the facts. How are we to know the AI won't make decisions based on current prejudices that end up also dooming mankind in the future?

And those are definitely valid concerns. And if those 'bugs' aren't preventable or fixed, I guess the question then becomes: whose irrationality kills everyone first, human's or machine's? Perhaps the situation is inevitable, just part of the Great Filter that decides which intelligence-type survives the birthing process into post-evolution. If machines don't threaten our very survival, something (or someone) else will.

Perhaps prejudices may be unavoidable in any intelligence, since we build stereotypes as predictive models and ML makes similar abstractions and assumptions which influence perception and predictions. Tangentially related, when TBI patients whose emotional centers are impaired, so is their ability to make decisions [1]. Building a decision-making network without an emotional center may be impossible, since the two seem to be naturally correlated. It's probable an AI won't ever truly be 'emotional,' at least not in the near term.

So, in the end, it's reasonable to assume that the AI of the future that can crunch these complex problems won't tell people the answers, they will merely provide possible solutions with varying likelihood of success depending on goals and constraints. In the end, we will have to decide our own fate, and my point is maybe we don't have control over deciding our fate either way--such is the nature of fate.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032808/

I agree with you that purposeful gene editing ought to be better than random evolution at the individual level.

However, grand parent raises a good point about reduced diversity, which is bad at the species level. There is really no way to guard against this because:

1. Even though diversity is good at the species level to safeguard against future disaster, everyone will race to have the same set of (currently) desirable traits. Framed another way, since human genetic diversity is a public goods, few people will help maintain it at the cost of their own benefit

2. While we could theoretically understand the genome in full, I'd argue it's impossible to foresee all the potential disasters that can wipe out a genetically homogeneous humankind.

hasnt diversity already been reduced by transportation? didnt it prove to be a bad things for american indians?

The opposite is true - transportation has increased diversity. The American Indians suffered due to a lack of exposure to diseases (smallpox) common in Europe due to their relative isolation

Erm ... that's also a way to put it. Another way to put it, they would not have suffered if not for rapid transportation.

But genetic diversity did increased - through mating.

a lack of diversity is only really bad in a changing world. however humans have made the world far more stable than before, and as we move our civilization into space, we'll find likely more stability (in the long run)

The potential disasters can be man-made as well. Therefore, even though we're increasingly better at taming the vagaries of nature, we're increasingly at the mercy of our fellow men.

> humans have made the world far more stable than before

You must be kidding. Humans have changed their environment almost beyond recognition. We may already have broken ourselves, look at birth rates in the most industrialized countries.

"as we move our civilization into space"

That is pretty optimistic

We can't even make it on Earth without horribly fumbling it, how would moving out to dead rocks help?

This is how we play for time, this is the whimpering with which we fade out. Looking straight at the iceberg, saying "it'll probably transform to cotton candy if we hit it fast enough". The drunk captain and the armed guards letting no sane person near the bridge is how you know everything is fine.

Exactly, just look what happened with dog breeding and how many breeds now suffer from significant genetic defects due to trying to breed desired traits.

The defects are largely a result of the limited capabilities of the breeding process (cross animals with a trait, hope that not too much other stuff comes along for the ride).

A fun angle: genetic engineering will eventually enable us to correct many of the problems in purebred animals. They are often good targets for even a limited genetic engineering capability (where the pure bred population has a high frequency of a single defective gene).

Some of the problems with dog breeding are due to the inefficiency of he breeding process, but others are simply the direct biomechanical consequences of the desired traits; for example the neotenous compressed faces of many lapdog breeds have consequences for mastication, respiration, and orbit shape that can't really be addressed without relaxing our selection for that particular look or accepting other tradeoffs.

I find the argument about reduced diversity to be way too optimistic (or pessimistic ?) about people’s will and might to change their genes.

To draw a parralel, esthetic chirurgy is wildly available at relatively reduced risks, and it’s not like every bloke and their dog goes to have a face lift, even if it’s understood that a better appearance would have benefits.

Or even thinking about the core group of people who refuse to vaccinate. There’s just no way a medical practice is applied to the totality of a population, even by law.

  it’s not like every bloke and their dog goes
  to have a face lift

Right, but society has a conflicted history with beauty - some parts of our culture like and reward beauty, other parts curse the vain and superficial - and especially with people making uncommon efforts to improve their looks.

Not so with being born charismatic, tall, smart, healthy and with a full head of hair.

> everyone will race to have the same set of (currently) desirable traits

I think it is not the case. Just on Earth you need different traits due to different climates and life conditions. Once we start really colonizing our solar system what makes humans better on some rock will be different for another or just for space: weaker heart, better bone density, some myopia could be useful to limit the currently known effects of 0G.

There is some indications that organisms have ways of controlling evolution to some extent. Certainly, organisms have ways of increasing or decreasing how many mutations they accrue depending on environmental signals.

I agree with most of what you say. We know of no "better way". Nature is infinitely more intelligent. If Nature wanted us to not know or do something, we would not have been able to. Our ability to edit genes is a result of Nature's willingness to let us experiment. We still have very little understanding of what genes are or how Nature edits them for evolutionary purposes.

One thing that I know is that ethics have no meaning in Nature's eyes.

Nature is not a fucking intelligent being.

Just tell it like you mean it and replace Nature with God in your message.

Even if it is intelligent with a purpose, it would have made us with all our capacities. An important one being able to make tools and soon alter voluntarily our genes. Humans are not some superior or inferior beings outside of Nature. They're part of it as are all they produce.

I think it’s more accurate to say “nature is not a singular intentional personality”.

Evolution is a form of intelligence, just utterly unlike us. Azathoth rather than Yahweh, as Eliezer Yudkowsky puts it.

Found the easily triggered neck beard. He never said anything about God.

If evolution is so horrible, and we are so brilliant, why can't we outdo or even reproduce to any degree the biological organisms it has created?

Do you mean why don't we have gray or green goo? The thing that outreproduce and outsurvive biological organisms. Maybe because engineers optimize for other things usually.

We can. In multiple different senses.

Synthetic biology covers literal reproduction of organisms: https://en.m.wikipedia.org/wiki/Synthetic_biology

“Outdo” has multiple meanings, but pure engineering has made us go faster, fly higher, and survive worse cold, than anything purely evolved.

And if you mean purely organic items, not engineered, then you still need to explain the sense of “outdo”, because GM foods outdo non-GM foods in many ways we care about (e.g. bacterial rennet replacing cow stomach in cheese making, outdoing it by cost-efficiency and coincidentally making more cheeses suitable for vegetarians).

I accidentally bought some Vegetarian cheese last week and it is not suitable for anyone

Are you sure you mean vegetarian and not vegan? Vegetarian cheese is pretty much the default in UK supermarkets these days, and almost nobody even knows that things like Parmesan are non-vegetarian.

Vegan cheese, on the other hand… oh dear.

I try it sometimes; vegan cheddar-alike tastes like vanilla ice cream that refuses to melt, but vegan feta-alike sort-of works.

> vegan cheddar-alike tastes like vanilla ice cream that refuses to melt

That sounds really nice. I might have to try some.

All our genetic engineering tweaks existing organisms. We cannot make life in the lab.

Except for the lab-built bacterial chromosomes (1), the lab-built entire viral units (2), and the lab-built xenobases (3).

(1) http://www.jcvi.org/cms/research/projects/minimal-cell/overv...

(2) https://en.m.wikipedia.org/wiki/Synthetic_virology

(3) https://en.m.wikipedia.org/wiki/Xeno_nucleic_acid

Edit: just to add, I wouldn’t accept “we have not done it from scratch yet” as a valid argument that we cannot do better than natural selection, any more than I would accept ”$person has not yet fabricated a CPU” as an argument that $person can’t code better than at least one professional CPU designer.

CPUs weren't evolved.

Irrelevant. I thought that would’ve been clear from me using the comparison as an example of a bad argument.

Also, not even correct, assuming I have been correctly informed that simulated evolution is used for some optimisations of e.g. precise physical transistor placement.

We are in the infancy of genetic manipulation. A working understanding of CRISPR only developed in the past few years. There were some significant hurdles to getting to that point.

In the coming decades, we shall be programming genes like we program computers. We'll model organisms, formulate changes, simulate the formulated changes, then create the genetic "programs" (really, life forms) using some kind of biological gene expresser.

Right now we're in something akin to the vacuum tube era of computing where you need to be a government or a large corporation to do more than just tinker. As with computers, those barriers to entry will not remain in place for very long.

This assumes life works like a program.

I'm not saying that we're going to be writing genetic Perl scripts. I'm saying that the basics of looking at genetically-based organisms as a type of programming/engineering is inevitable.

You may not have an "if" statement, but you have genetic segments than can cause the synthesis of a protein when present. You may not have goto statements, but you have stop codons that end the processing of the creation of a protein.

Read up on the genetic engineering solutions already being created regarding how payloads are created in bacteria, how they're delivered to target cells, how the payloads are activated, etc. These are step-by-step processes with conditional behaviors, loop-like replication of processes, spawning of processes, subroutine-like embedded processes, etc.

Genetic programming will be similar to computer programming in ways. It will be different in ways. But the arc of progression of how we start off with huge barriers to entry and little understanding to where we eventually manipulate genetics cheaply and trivially are inevitable.

The question is how do you test it?

Do you really think we can transfer the usual edit, compile, run, rinse and repeat workflow to genetic engineering?

From the perspective of the majority it's an acceptable tradeoff to sacrifice a few thousand humans for the benefit of billions. It could even cause less suffering than natural selection.

I still wouldn't want to be one of those pre release versions...

Probably a lot of animals will be used at first.

Then, human tissue samples can be grown and kept to test results on actual human DNA.

As time goes by, computers will model more and more of the problem space.

I still wouldn't want to be one of those pre release versions

The particular applications will vary, but we're already doing human trials using gene therapy. This is our "Hello World" phase happening now.

https://www.cnn.com/2017/12/14/health/hemophilia-trial-uk-cu...

Nature invented higher intelligence because of how it could outperform instinct. Gene editing is the improvement to evolution by random variation. Just don’t expect a free lunch.

Considering we are reinventing that same process with black boxes of statiscal correlation engines - there’s a lot to be said about trial and error at scale and over massive time scales.

Not to mention this all occurs with co-evolving systems and predators/prey dynamics.

>>Evolution has been pretty effective to this point

Survivorship bias, pure and simple. In terms of evolutionary timescales, the success of humans is an anomaly, if not an outright accident. The overwhelming majority of all species that have ever existed has gone extinct.

Gene editing has the potential to not leave things up to chance, moving forward.

Not leave things up to chance?! Is the universe not inherently probabilistic? I'm guessing you mean make things a little more deterministic than they are now in terms of human evolution? Maybe, but I think its important to ask whether or not we already exist in some sort of thermodynamic equilibrium with the rest of the universe (on an evolutionary spacetime scale).

I also think it's not totally accurate to say that most species have gone extinct vs have evolved into something else.

It's equally risky not to do it.

Human genetic engineering is a completely new technology. It could be massively disruptive or a dud. But if it is disruptive, then people who are conservative and late to get on board will be left behind.

If you're risk adverse, that's probably why it concerns you. Are you afraid it works, or afraid it doesn't?

It is usually better to be the inventor of a new weapon than to sit back and let all your enemies do it instead.

When testing a new weapon, it is important to make sure it doesn’t explode in your face.

I’m not too worried about genetically modified humans, but I think there is a risk someone will make a synthetic “perfect plague” combining high transmission before it’s symptomatic with high lethality — think “breath transmitted HIV”.

1. https://en.m.wikipedia.org/wiki/Synthetic_virology

Or genetic engineering works, like gambles sometimes do, and societies that embrace it totally leave more conservative, risk adverse cultures in the dust.

Once we get proficient at gene editing, why would reduced diversity be a problem? Diversity is then no longer stored in DNA molecules in different people, it's stored in computers. Getting a new genotype out in the wild could be as simple as downloading a file from the Internet.

Indeed, why would reduced diversity be a problem if we're moving towards engineering the optimal human?

The existence of sickle cell and cystic fibrosis means we have a moral obligation to use it, and prevent these horrible diseases.

We have ethical justification to use genetic manipulation to enhance lives. By not doing so you're sentencing people to a life of suffering.

CF yes, if I correctly understand that it evolved to help us deal with cholera — which we have now pretty much solved.

Sickle cell would be immortal to fix prior to fixing malaria, because the gene that causes sickle cell when you have two copies also makes malaria much less dangerous with one copy.

I think you underestimate how adaptable humanity is, and how much desire it has to survive. If it turns out that there are huge negative effects a few generations down the line, I really doubt that humanity (which is naive on an individual level, but largely wise in aggregate, at least when it comes to survival of the species as a whole) won't correct course.

> "(1) Evolution has been pretty effective to this point"

to this point. Yet it doesn't look like it will be effective from this point onwards, considering that the traits that will likely be useful to the next era of humanity are not the same traits natural selection chooses.

Given that more educated, career-focused humans have less kids than the less educated.[1] I find it somewhat welcome that we can turn natural selection around, towards those traits we need more to move forward as a species.

[1]: https://en.wikipedia.org/wiki/Fertility_and_intelligence

> Unrestricted gene editing in humans is probably a bad idea

Isn't this what the point of testing is for? To find out if it is "probably a bad idea"?

> genetic "diseases" give an evolutionary advantage

Touting the amazing evolutionary benefits of CF isn't really helping your case. Sure you (maybe) can't get cholera but you will likely die by 40!

> Touting the amazing evolutionary benefits of CF isn't really helping your case. Sure you (maybe) can't get cholera but you will likely die by 40!

Only if an antibiotic resistant cholera epidemic doesn't wipe you out first! (;

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