
China gene-edited baby experiment 'may have created unintended mutations' - pseudolus
https://www.theguardian.com/science/2019/dec/04/china-gene-edited-baby-experiment-may-have-created-unintended-mutations
======
vannevar
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.

~~~
im3w1l
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.

~~~
smallgovt
> 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"?

~~~
xvedejas
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.

~~~
wahern
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.

~~~
vannevar
_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.

~~~
wahern
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.

~~~
vannevar
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.

~~~
wahern
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.

~~~
baq
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.

------
buboard
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](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-...](https://web.archive.org/web/20181128061149/http://www.sustc-
genome.org.cn/source/pdf/Informed-consent-women-English.pdf)

Second informed consent;
[https://web.archive.org/web/20181128061153/http://www.sustc-...](https://web.archive.org/web/20181128061153/http://www.sustc-
genome.org.cn/source/pdf/Second-informed-consent-English.pdf)

Ethical approval:
[https://web.archive.org/web/20181128061204/http://www.sustc-...](https://web.archive.org/web/20181128061204/http://www.sustc-
genome.org.cn/source/pdf/HarmoniCare-Ethics-English.pdf)

Clinical registry:
[https://web.archive.org/web/20181128061216/http://www.sustc-...](https://web.archive.org/web/20181128061216/http://www.sustc-
genome.org.cn/source/pdf/CCR5-Clinical-Trial-Registry-
Chinese%20-%20English.pdf)

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](http://www.chictr.org.cn/showproj.aspx?proj=32758)

------
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.

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

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

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

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

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

~~~
ak217
The original point of yours that I find issue with was about "perhaps why most
scientists are less concerned", which is really bullshit because most
scientists in the field _are_ concerned about premature germline editing. And
the arguments you've arrived to in support of it rest on a bunch of false
equivalences.

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

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

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

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

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

------
wnmurphy
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.

~~~
anon73044
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.

~~~
mewpmewp2
Who coded that crap?!

~~~
raducu
Maybe it's Gods DRM.

~~~
trianglem
It’s God’s job security.

------
PhasmaFelis
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!"

------
RestlessMind
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

~~~
roenxi
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.

------
hamhand
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.

~~~
waste_monk
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).

------
tropo
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.

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

------
Hitton
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](https://www.nature.com/articles/d41586-019-03032-2)

------
ggggtez
>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.

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

------
jcims
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.

------
chrischen
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.

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

------
The_rationalist
Every human has 60000 mutations per day on average.

~~~
mkl
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.

------
signal_space
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

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

------
selimnairb
No shit.

------
throwaway1777
Not prohibited in China by ethics or legality.

~~~
lvturner
"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...](https://www.scmp.com/news/china/science/article/2182964/china-
confirms-gene-edited-babies-blames-scientist-he-jiankui)

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

~~~
toxicFork
Telekinesis, rapid regeneration, blue hair

~~~
anticensor
We would favor _painless_ rapid regeneration, though.

------
infinity0
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.

~~~
allovernow
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?

