Don’t Fear the CRISPR

I’m honored to be here guest-blogging for the week. Thanks, Alex, for the warm welcome.

I want to start with a topic recently in the news, and that I’ve written about in both fiction and non-fiction.

In April, Chinese scientists announced that they’d used the CRISPR gene editing technique to modify non-viable human embryos. The experiment focused on modifying the gene that causes the quite serious hereditary blood disease Beta-thalassemia.

You can read the paper here. Carl Zimmer has an excellent write-up here. Tyler has blogged about it here. And Alex here.

Marginal Revolution aside, the response to this experiment has been largely negative. Science and Nature, the two most prestigious scientific journals in the world, reportedly rejected the paper on ethical grounds. Francis Collins, director of the NIH, announced that NIH will not fund any CRISPR experiments that involve human embryos.

NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.

This is a mistake, for several reasons.

  1. The technology isn’t as mature as reported. Most responses to it are over-reactions.
  2. Parents are likely to use genetic technologies in the best interests of their children.
  3. Using gene editing to create ‘superhumans’ will be tremendously harder, riskier, and less likely to be embraced by parents than using it to prevent disease.
  4. A ban on research funding or clinical application will only worsen safety, inequality, and other concerns expressed about the research.

Today I’ll talk about the maturity of the technology. Tomorrow I’ll be back to discuss the other points. (You can read that now in Part 2: Don’t Fear Genetically Engineered Babies.)

CRISPR Babies Aren’t Near

Despite the public reaction (and the very real progress with CRISPR in other domains) we are not near a world of CRISPR gene-edited children.

First, the technique was focused on very early stage embryos made up of just a few cells. Genetically engineering an embryo at that very early stage is the only realistic way to ensure that the genetic changes reach all or most cells in the body. That limits the possible parents to those willing to go through in-vitro fertilization (IVF). It takes an average of roughly 3 IVF cycles, with numerous hormone injections and a painful egg extraction at each cycle, to produce a live birth. In some cases, it takes as many as 6 cycles. Even after 6 cycles, perhaps a third of women going through IVF will not have become pregnant (see table 3, here). IVF itself is a non-trivial deterrent to genetically engineering children.

Second, the Chinese experiment resulted in more dead embryos than successfully gene edited embryos. Of 86 original embryos, only 71 survived the process. 54 of those were tested to see if the gene had successfully inserted. Press reports have mentioned that 28 of those 54 tested embryos showed signs of CRISPR/Cas9 activity.

Yet only 4 embryos showed the intended genetic change. And even those 4 showed the new gene in only some of their cells, becoming ‘mosaics’ of multiple different genomes.

From the paper:

~80% of the embryos remained viable 48 h after injection (Fig. 2A), in agreement with low toxicity of Cas9 injection in mouse embryos  […]

ssDNA-mediated editing occurred only in 4 embryos… and the edited embryos were mosaic, similar to findings in other model systems.

So the risk of destroying an embryo (~20%) was substantially higher than the likelihood of successfully inserting a gene into the embryo (~5%) and much higher than the chance of inserting the gene into all of the embryo’s cells (0%).

There were also off-target mutations. Doug Mortlock believes the off-target mutation rate was actually much lower than the scientists believed, but in general CRISPR has a significantly non-zero chance of inducing an unintended genetic change.

CRISPR is a remarkable breakthrough in gene editing, with applications to agriculture, gene therapy, pharmaceutical production, basic science, and more. But in many of those scenarios, error can be tolerated. Cells with off-target mutations can be weeded out to find the few perfectly edited ones. Getting one complete success out of tens, hundreds, or even thousands of modified cells can suffice, when that one cell can then be replicated to create a new cell line or seed line.

In human fertility, where embryos are created in single digit quantities rather than hundreds or thousands – and where we hope at least one of those embryos comes to term as a child – our tolerance for error is dramatically lower. The efficiency, survivability, and precision of CRISPR all need to rise substantially before many parents are likely to consider using it for an unborn embryo, even to prevent disease.

That is, indeed, the conclusion of the Chinese researchers, who wrote, “Our study underscores the challenges facing clinical applications of CRISPR/Cas9.”

More in part two of this post on the ethics of allowing genetic editing of the unborn, and why a ban in this area is counterproductive.

Comments

I work in synthetic biology, and with all due respect to Mr. Naam I think this analysis is terrible. The details of the Chinese experiment I don't want to touch on right now essentially because there are an awful lot of ongoing discussions right now about what it means, what the results really were, and how generalizable they are -- although that itself tells you that the tone of the analysis above is considerably premature.

However, for one thing, the concerns about synthetic biology are _far_ beyond the Chinese experiment. The (CRISPR-driven) "gene-drive" experiments raise genuine difficult questions not so easily waved aside.

The four "rebuttals" above seem poorly thought out. Mr. namm tells us the reactions are hyperbolic because the technology is still developing -- but that's the time to consider it, no? He tells us that parents will act in the best interests of their children -- but parents and children perceive their childrens' interests quite differently, and many of the inequality concerns stem from that premise anyway. He pooh-poohs concerns about "superbabies" which are unmentioned in the NIH ban.

Look, damn near everyone who works on this stuff with any prestige has now signed on to a letter echoing the NIH concerns and urging further measures. And one guy who has never worked with it, is telling you there's nothing to be worried about. That should concern you.

That's B.S. and you know it or should know it, researcher or no. "Ethics" is a man-made doctrine that anybody can opine on, even Mr. Naam, or the ignorant ma'am next door. Ethics is not science, it is human driven. Victor Hugo once reported ("in L’Homme qui rit", *passage below ) that in times past infants would be made to grow in pots by their parents, so that they would be permanently stunted to look like a clay pot, then sold to freak shows (insert MR joke here). In the 17th and 18th century absolutist Europe period, young boys would be castrated to ensure their voices would not break, to enable them to sing falsettos better. In modern China prisoners are executed to harvest their organs. In southeast Asia where I live now parents name their kids after infamous personalities like Hitler and Stalin. And you want to quibble over CRISPR babies with blue eyes that their parents like? Ridiculous.

* V. Hugo: The comprachicos (child buyers) were strange and hideous nomads in the 17th century. They made children into sideshow freaks. To succeed in producing a freak one must get hold of him early; a dwarf must be started when he is small. They stunted growth, they mangled features. It was an art/science of inverted orthopedics. Where nature had put a straight glance, this art put a squint. Where nature had put harmony, they put deformity and imperfection.… In China, since time immemorial, they have achieved refinement in a special art and industry: the molding of living man. One takes a child two or three years old and puts them into a grotesquely shaped porcelain vase. It is without cover or bottom, so the head and feet protrude. In the daytime the vase is upright, at night it is laid down so the child can sleep. Thus the child slowly fills the contours of the vase with compressed flesh and twisted bones. This bottled development continues for several years. At a certain point, it becomes an irreparable monster. Then the vase is broken and one has a man in the shape of a pot.

Ray you are making your case weaker when quoting Victor Hugo you describe how layman discussions can veer off into imaginary fears and panics. Ofcourse in a free country everyone has to right to comment, but they would get attention only if the comment is meaningful. As our world becomes more technical, experts who can define the precise opportunities & dangers inherent in evolving technologies might be necessary. Laypersons might veer of into making imaginary, shallow and absurd comments on issues till the experts have described the implications of new technology in simple plain terms understandable by the layman. Cant we just say that in technical issues, domain experts are more rational than laymen? and state+experts must mediate?

@js - your point would be good if the laypeople could not grasp the technical issues. But here, as I said, the issues are not technical but moral. Simply put, if you had kids would you grow them in a pot and sell them to a circus? No? Would you mind if your neighbors did? Why or why not? Moral issues not technical. It's not rocket science, more like potted plants.

Negative. Anybody can opine on "ethics," sure. But my issue is that Mr. Naam has misrepresented or overstated some of the facts of the debate! Your example is a little terrible, and seems to favor my argument over yours: yes, one can imagine all kinds of possibilities, and expert opinion is helpful in understanding which ones are realistic. Mr. Naam has failed to provide that.

To the extent the ethical issues are blunted by difficulties making the technology work, it's likely that those issues are just deferred for awhile, not eliminated. Technology often improves.

"In modern China prisoners are executed to harvest their organs"

Rather, "Executed prisoners in China may have their organs harvested."

But in fact official policy (sorry, I read it but can't find the article, probably at chinadaily.com.cn) is now that organs are not to be harvested in order to prevent against the possibility that the corrupting influence of money could preferentially lead to a death penalty so that some corrupt officials could enjoy financial gains from the organ sale.

Worth noting that the Chinese experiment is only likely one of the first in a deluge of questionably ethical experiments. Mr. Naam's examples are in fact bogus when he cites the effectiveness of the Chinese study in only getting 4 embryos with the desired trait, in large part because the Chinese group's paper looks like it used an early generation of CRISPR without off-target reduction strategies like paired nickase activity that have become common (ethical problems aside, this makes the value of the research as a whole dubious, at best). Subsequent research is likely to correct this defect, meaning that the effectiveness of the technique is a helluva lot farther than Mr. Naam wants us to think.

Naam also avoids what I think is one of the strongest arguments, which is that there is a great deal of therapeutic application possible in somatic cells, but that recklessly pushing forward with germline CRISPR research risks a backlash against all human cell CRISPR research as a whole. There's good reason for caution going forward.

The problem is that imposing a moratorium on testing with human embryos is essentially equivalent to killing the technology entierly, since without such experimentation the technology will NEVER develoip to the point where it is mature enough to be used in clinical practice. So the moratorium will never be lifted.

Now, I know that that is THE point - to kill the technology in the bud. But don't pretend that that isn't what it is. This isn't just about slowing things down or having an ethical debate. There is plenty of time to have an ethical debate while developing the technology further, since it is so far from being ready. If you halt research now, you never get to the point where there is a real decision to be made about whether to use it or not, because it will never be ready.

When one thinks it is unethical to do something, it is logical to oppose even developing the technology--particularly when developing the technology requires doing the thing that one opposes. Anyone who thinks it is wrong to genetically alter humans rightly oppose any research into this technique. Others might oppose it for reasons that are more contingent (e.g. the danger of certain results occurring), and perhaps they should allow the research and see what happens--but even then, it's a judgment call, based on one's view of the risks and potential benefits of the technology.

There are plenty of ways for human gene-editing to advance without directly working on human gene-editing, such as by experimenting in other mammals. "If you can't reliably do it on sheep, then probably now isn't the time to be trying on humans" isn't crazy.

I'm not pretending that there might not be a case never to work with human embryos, but your comment just isn't right, or conscious of the technology, and I don't think it's even slightly defensible. People can push the technology all kinds of ways and advance it substantially -- indeed as multiple commenters have pointed out, the technology available _for editing human embryos_ has changed enough since the work in that Chinese paper was begun, that is was a bit obsolete even as it came out. If one limits oneself to CRISPR then just in the past weeks new useful enzymes have been characterized and published, new techniques have been developed. Some of those techniques -- the "gene-drive" stuff I mentioned above -- are arguably much more significant, morally and technologically, than editing human embryos might be. I think your comment illustrates the problem and the great flaw in what Mr. Naam is saying: the technology -- how it works and is developed -- is very very poorly understood even by quite literate and capable people and so crazy ideas pop up as fact; the whole process needs to be slowed now while it can so this conversation can occur.

Isn't it a truism that all research is obsolete by the time it gets published?
The new techniques might be better, but we're not going to know how good they are (or not) if we don't allow them to be tested.
I'll grant that some progress can be made on animal testing, but ultimately people will need to test on human embryos to cure human diseases.

If you think the technology has beneficial applications then slowing it down is harming people. Consider that there are kids being born with Huntingon's genes all the time that delay is taking place.

My concern is that such a moratorium would create it's own inertia by stalling development of the technology in a way that would prevent us from answering questions about the risks, and thus make the ethical concerns harder to allay. I don't think you really answered that concern.

For those people who plan to kill it (the technology) entirely, waiting would certainly seem far preferable to going ahead right away. But there are also those who might be open to it but who think it is well worth taking time to think things through before barging straight ahead.

Two things, and I urge you to read part 2 tomorrow.

1. My piece above is specific only to the use of CRISPR to edit the human germline. There are many other things that CRISPR can be used for that I am not addressing here. CRISPR-driven gene drive gives me pause.

2. The letter you mention that leading scientists signed on to is substantially different from the NIH announcement. The letter calls for no clinical use of CRISPR to edit the genes of unborn children, until more research has been done to assure safety (and perhaps not even then). The NIH announcement cuts off funding for that very research. These things are not equivalent. They are, in fact, partially at odds.

A quote from the letter:
"the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever,for clinical testing. "

An ungated copy of it is here: http://longnow.org/revive/wp-content/uploads/2015/04/15Science.pdf

Mr. Naam, you are hanging on a very very fine distinction. If you added the word "viable" to the NIH statement you'd be talking about something that's really a clinical intervention and would need to go through some of the same safeguards.

I guess to clarify my point above for the nonscientists: Mr. Naam is exactly wrong: the NIH letter and the researchers' recommendations are functionally _identical._ That's because NIH funding is already prohibited -- and has long been -- for any research on viable human embryos (and even with nonviable fetal tissue you need a slew of permissions). All you _can_ do are clinical interventions. Fetuses are covered by human subjects protections, and you can do stem cell research explicitly because the stem cells are _not the same_ as a viable human embryo.

These are things the research community knows and the poster does not, and they are central to the debate!

Yes, the lack of mention of the Dickey-Wicker amendment was. . . surprising.
https://embryo.asu.edu/pages/dickey-wicker-amendment-1996

Given that this web site is dedicated to the virtue of small, I'm not so sure there will be a warm reception here to CRISPR; sure, the technology may be small, but the consequences are LARGE. Cowen has been visiting China, where the people today (the leaders anyway) think large, the opposite of both the way America thinks today, which is small, and the approach to problem solving favored by Cowen, which is likewise small. Risk aversion on steroids. While the objection to CRISPR is framed in terms of ethics, the actual concern is risk, namely the risk of creating a mutant race. As a science fiction writer, Naam must think large, which may be natural for him given his background in the non-fiction world. I have a home in the low country, where oysters are consumed like popcorn. The first person who ate one must have been either highly risk tolerant or barking mad. I'm glad some people are willing to take risks, for they make a much better world. Well, maybe not always, but most (some?) of the time.

>actual concern is risk, namely the risk of creating a mutant race.

What's the downside?

No superpowers.

Mutant in a bad way? Why would parents want to make their children disabled?
If the technology carries a high risk of undesired mutations then people won't use it.

People need to think carefully about what the risks realistically are and not just imagine science-fiction scenarios.

What about concerns on weaponizing viruses with this technology - Can rouge states develop bio-weapons easily now ? Can it be controlled?

And what of the taupe states?

With a few hundred ferrets, you too can have your bio weapons research placed under the strictest of scrutiny - http://news.sciencemag.org/2011/11/scientists-brace-media-storm-around-controversial-flu-studies

The strange thing is how does one define rogue state? After all, only a couple of nations have active biowarfare (defensive only, as per treaty obligations) programs. The rest don't bother - it seems to be one of those odd ethical questions, where the majority of humans (including rulers, apparently) believe that causing a plague is an immorality that only the most evil can even contemplate. And those with biowarfare programs (defensive only, as per treaty obligations) cannot imagine that such people, even in positions of power, exist.

With gene drive, you can force bad genes to replicate beyond their fitness, potentially leading to population collapse. This isn't very useful against humans because even in 50 years you'd only have 2 generations to propagate the bad gene and by that time that target humans would be able to detect the attack and edit their genes back.

You could probably use this against animal populations you want to wipe out, though. Might be a great way to undo species invasion.

The technology isn’t as mature as reported. Most responses to it are over-reactions.

We should wait for the inevitable disaster before warning of the inevitable disaster?

Parents are likely to use genetic technologies in the best interests of their children.

As Sanjay points out, parents have different views to children. Suppose they could make their child much smarter but more likely to have a whole range of spinal cord problems resulting in death at 39? A lot of parents might accept that trade off. Would their children?

However the bigger objection is that this assumes parents and the scientists know what they are doing. We have been here before with thalidomide. You want to edit genes with no idea what all the effects will be? Go look at those thalidomide babies again. Parents acting in the best interests of the child.

Using gene editing to create ‘superhumans’ will be tremendously harder, riskier, and less likely to be embraced by parents than using it to prevent disease.

I am not sure. Disease will always be a niche market. Brighter children won't be

A ban on research funding or clinical application will only worsen safety, inequality, and other concerns expressed about the research.

If only this had come up in the debates with Lincoln! Banning slavery just means that it cannot be properly regulated and made safer and more equal.

Second, the Chinese experiment resulted in more dead embryos than successfully gene edited embryos.

Some people might see that as a bad thing in itself.

ISTM that the ethical issues center on several different points:

a. The *intentional* impact of editing on the edited children. Assume we someday (in the far future) know what we're doing with this technology and can safely and reliably edit unborn childrens' genomes to give them some advantages in life. Parents will choose (and doctors will offer) things that seem to them like improvements--smarter, taller, stronger, healthier, longer-lived. But you can imagine some conflicts there--parents might select for religiosity to keep their kids in the faith, or for a desire for children so they'll get grandkids while they're young enough to enjoy them. On the outside edge, you might get parents making really nasty decisions for their kids--making their kids shorter-lived to make them better athletes, say. You can also imagine cults or governments editing children to make them better servants for the cult or government.

This seems like an area where we might come to some common ethical standards, in terms of forbidding some kinds of tradeoffs or editing. (No shortening expected lifespan or lowering intelligence, say.)

b. The *unintentional* impact of editing on the edited kids. We won't start out knowing what we're doing, and may never get very high reliability for doing this. In that case, there may be a lot of collateral damage--you boost the kid's IQ a standard deviation, but at the risk of making him emotionally unstable. Or you make your child a foot taller and movie-star perfect in looks, but risk him also being sick all the time because a mistargeted bit of editing screwed up part of his adaptive immune system.

This is a good reason to have restrictions on the technology early on, and it might make the whole line of technology really hard to live with.

c. The impact on society. If we have effective versions of this technology one day (whether it's based on CRISPR or something else), it will have an impact on the kids whose parents didn't or couldn't use it.

(i) Competition: If there were a technology that would boost your kids' IQ two standard deviations that cost you $100k out-of-pocket to use, my guess is that a generation later, pretty much the *entire* entering class at MIT, Harvard, Stanford, Yale, Caltech, etc., would be kids who had that boost. (The parents who could afford $100k and cared enough to do so would probably start with an average IQ that was higher than the general population--I imagine this technology giving you kids whose mean IQ is around 145.) A few years later, the entire elite layer of science, technology, business, and government are these kids. People who refuse to use the technology or can't afford it are shut out of the top levels of successful life.

That potentially leads to a spiral of competition, where eventually parents are pushed toward accepting all the modifications that boost (say) IQ or height, even when they have nasty tradeoffs, because only the smartest kids will truly be on top. (Think about what happens with performance enhancing drugs in sports.)

(ii) Side-effects: Even if the modifications are well-understood, there will probably be some side-effects, which may not be deadly or anything, but may still have an impact. Suppose the IQ-boosting modifications tend to also make you more easily bored. You might end up with an entire elite of people with the same flaws--all these super smart Gauss-level intellects, but none with the patience to withstand any boredom, so some ideas and fields will remain very hard for them to investigate, because they require a long period dealing with boring details to get anywhere in.

(iii) Disappearing social subgroups: If parents can make sure their kids will be straight, have little taste for alcohol or drugs, and be born hearing and seeing perfectly, they'll almost certainly do that in overwhelming numbers. There are cultures of people living now who would see their culture disappear, because there are almost no new gay kids born, or almost no new kids born deaf from birth, or whatever. I don't know that this requires any response, but it certainly is an impact and some people will feel it profoundly.

Balanced against all that, there are several huge benefits for society: a bigger pool of smart, healthy people who presumably will have long lives full of inventing new stuff and making things work better. If you're summing up the plusses and minuses, this is the place where the biggest plusses come in. I'm not sure what US society looks like with a Feynmann or Von Neumann being born every month, but it might be a kind-of nice place to live in, even if you were a prole.

d. The impact on fetuses/embryos/human cells. If the editing technology requires killing a lot of embryos, that raises ethical issues for some people, and not for others. It's not too easy for me to see the moral difference between sex-selection by getting a dozen embryos and dumping the female ones down the drain, and aborting the female ones when the ultrasound shows they're girls. I suspect this is an area where it's very hard to get to consensus (even harder than the other points).

What am I missing?

It's highly unlikely that being gay is *genetic*.
There are many things that occur developmentally between conception and adulthood that have all sorts of influences on personality, including in-utero influences.
Unless you are a hard-code- biological determinist, there are still going to be social sub-groups.

albatross May 18, 2015 at 10:41 am

a. The *intentional* impact of editing on the edited children. Assume we someday (in the far future) know what we’re doing with this technology and can safely and reliably edit unborn childrens’ genomes to give them some advantages in life. Parents will choose (and doctors will offer) things that seem to them like improvements–smarter, taller, stronger, healthier, longer-lived.

Well already you are assuming technological advances not in evidence. It is not safe as yet. We don't know what we are doing. However it is unlikely that there is any low hanging fruit here except for a number of diseases and the like. Humans are a product of compromises with evolution. If you push people to be taller, it is likely to have an impact somewhere else we don't know about yet. It is an advantage to be taller, more handsome and so on. So why aren't we? There must be a trade off somewhere.

A good example of this is the claim that Ashkenazi populations have been breeding for intelligence. OK, this is dubious as all hell, but there is a small literature on it. Jews may do well on IQ tests, but they also tend to have a lot of genetic diseases associated with brain and spinal chord tissue. It looks like breeding for one results in the other.

On the outside edge, you might get parents making really nasty decisions for their kids–making their kids shorter-lived to make them better athletes, say.

Sure. I have no doubt many parents would be happy to trade off a chance at the NBA or the NFL for a few decades of their child's life.

You can also imagine cults or governments editing children to make them better servants for the cult or government.

We have already identified genes for a propensity to violence. I don't doubt that governments will be breeding us to be more docile soon enough.

This seems like an area where we might come to some common ethical standards, in terms of forbidding some kinds of tradeoffs or editing. (No shortening expected lifespan or lowering intelligence, say.)

Again you assume we know what the hell we are doing. And we don't. But on what basis are we going to make such agreement? I doubt we can all agree on anything and anyway, people will just go off shore.

b. The *unintentional* impact of editing on the edited kids. We won’t start out knowing what we’re doing, and may never get very high reliability for doing this. In that case, there may be a lot of collateral damage

There is bound to be some. Which I think is a good reason not to start down that path.

(i) Competition: If there were a technology that would boost your kids’ IQ two standard deviations that cost you $100k out-of-pocket to use, my guess is that a generation later, pretty much the *entire* entering class at MIT, Harvard, Stanford, Yale, Caltech, etc., would be kids who had that boost.

Indeed. Although perhaps Legacies ....

Balanced against all that, there are several huge benefits for society: a bigger pool of smart, healthy people who presumably will have long lives full of inventing new stuff and making things work better.

Why do you think they are more likely to make things work better or even invent new things? They could be smarter and yet not driven. We don't really know what drives people to invent things. Steve Jobs would be hard to pick as an innovator on the basis of his smarts alone.

I’m not sure what US society looks like with a Feynmann or Von Neumann being born every month, but it might be a kind-of nice place to live in, even if you were a prole.

If Sheldon Cooper was in charge, I expect proles would be gassed.

I suspect this is an area where it’s very hard to get to consensus (even harder than the other points).

Yep. There's the problem. The technology exists and no one will have to will to resist it. No matter what horrors it inflicts.

I think religiosity is mostly a matter of upbringing, a sort of cult-like brainwashing within a family and faith community. Perhaps there are some genes involved in making some people more or less predisposed to fundamentalism, for example, after they have a good chance to think it all through.

Also, I think most people would find it demeaning to their understanding of their source of truth and guidance in the world to have to genetically predispose their children to believe in it.

However the bigger objection is that this assumes parents and the scientists know what they are doing. We have been here before with thalidomide. You want to edit genes with no idea what all the effects will be? Go look at those thalidomide babies again. Parents acting in the best interests of the child.

Thalidomide is irrelevant and wrong an example: it was a brand new drug with unknown effects. In contrast, the proposals for engineering are always based on the existing natural common variatiants which is analyzed by the GWASes - if tweaking Klotho to be homozygous led to horrible thalidomide babies, well, we'd already know that because then 10% or whatever of babies would be thalidomide babies!

This sort of engineering is no more likely to lead to babies with horrible birth defects than, well, regular old sexual reproduction and for the same reasons. (Less likely, actually, for the simple reason that the implanted embryo will have been checked for - at the very least - gross chromosomal abnormalities, and if CRISPR is being used, probably the whole genome will be checked as well.)

This is Dolly all over again - the early prototypes have problems, people leap on the reports as an excuse to panic and spread FUD, and when the later lambs start coming out fine and healthy with no problems, somehow *that* news never seems to get out to all the people who are so very anxious about our brave new world...

Also, Thalidomide wasn't exactly the end of life on earth or the beginning of a mutant race of super-humans.
In the larger sceme of things, it was was blip. What if we halted all drug research and testing on the grounds that we just don't know if it will cause birth defects in pregnant women? Surely that isn't the lesson we should be learning from Thalydomide.

gwern May 18, 2015 at 11:01 am

Thalidomide is irrelevant and wrong an example: it was a brand new drug with unknown effects. In contrast, the proposals for engineering are always based on the existing natural common variatiants

So far these people are using a shotgun approach. They are sticking genes in wherever they will go. If you re-arrange the order of the DNA strand, you are not simply adding function. They interact with others nearby. You may turn off something you didn't mean to or turn on something you would not like.

It is exactly like thalidomide. We are messing with things that are too complicated and that we do not properly understand yet.

This is Dolly all over again – the early prototypes have problems, people leap on the reports as an excuse to panic and spread FUD, and when the later lambs start coming out fine and healthy with no problems, somehow *that* news never seems to get out to all the people who are so very anxious about our brave new world…

Dolly had a shortened life. She suffered from arthritis. It may be that her problems were not caused by cloning, but we don't know that either. We know that IVF produces problems but that is because we do enough of them to have a reasonable sample size. We do not for cloning as yet.

We are operating in the dark and it is absurd to pretend otherwise.

We might be able to delay it, but in the long run, there is no stopping human gene editing. It's kind of like nuclear profileration.

While this may well be true (or it may not!), I will point out that there's not a lot of support for handing out H bombs to El Salvador and Zambia.

It doesn't take a lot of people to create an arms race.

Nuclear weapons are a completely different case--as far as anyone who's telling will say, developing nukes requires expensive, hard-to-hide infrastructure. Also, your developing nukes threatens lots of other countries, who thus care a lot about detecting and deterring any nuclear program you might have.

By contrast, here we're talking about something that mainly raises ethical issues about human experimentation, at least in its early stages. (The big social implications don't start to matter until you've got really widespread adoption of the technology.) So nobody's going to be spending anything like the resources to detect and deter it. And, detection will be way harder, because this will look a hell of a lot like someone running fertility clinics and genetic counseling clinics and also having some good bio labs nearby.

OK, but that gives away the entire game. The _point_ is to delay it. There is a feeling among researchers that the general public is stumbling backward into this stuff without a good sense of its applications and consequences and we need time to decide on an appropriate regulatory framework and safeguards.

Since the 1990s, I've been proposing that we ought to pay serious attention to natural human biodiversity to help us decide whether to introduce artificial human biodiversity.

The general reaction, however, is to prefer not think about it.

That just might be because whether in the Virginia of the 1920s, or the Germany of the 1930s and 40s, your ideas have already been put into practice.

There is a reason that the hosts of this web site find you respectable - after all, it is only a matter of rebranding and remarketing to return those halycon days, where Americans were enthusiastic supporters of eugenics laws. Though back then, they didn't need to use weasel words like 'human biodiversity' - which is just another example or rebranding and remarketing, after all, for those who feel the need to use PR in public discussions of their beliefs.

'On March 20, 1924 the Virginia General Assembly passed two laws that had arisen out of contemporary concerns about eugenics and race: SB 219, titled "The Racial Integrity Act[1]" and SB 281, "An ACT to provide for the sexual sterilization of inmates of State institutions in certain cases", henceforth referred to as "The Sterilization Act". The Racial Integrity Act of 1924 was one of a series of laws designed to prevent inter racial relationships.

The Racial Integrity Act required that a racial description of every person be recorded at birth and divided society into only two classifications: white and colored (essentially all other, which included numerous American Indians). It defined race by the "one-drop rule", defining as "colored" persons with any African or Native American ancestry. It also expanded the scope of Virginia's ban on interracial marriage (anti-miscegenation law) by criminalizing all marriages between white persons and non-white persons. In 1967 the law was overturned by the United States Supreme Court in its ruling on Loving v. Virginia.

The Sterilization Act provided for compulsory sterilization of persons deemed to be "feebleminded," including the "insane, idiotic, imbecile, or epileptic."[2]

These two laws were Virginia's implementation of Harry Laughlin's "Model Eugenical Sterilization Law",[3] published two years earlier in 1922. The Sterilization Act was upheld by the U.S. Supreme Court in the case Buck v. Bell 274 U.S. 200 (1927). This had appealed the order for compulsory sterilization of Carrie Buck, who was an inmate in the Virginia State Colony for Epileptics and Feebleminded, and her daughter and mother.

Together these laws implemented the practice of "scientific eugenics" in Virginia.' http://en.wikipedia.org/wiki/Racial_Integrity_Act_of_1924

It is likely that in free market China, in the absence of regulation they are going to rapidly mess around, suffer casualties and if they draw the right lessons probably rapidly evolve safer technology to make superkids (not just blue eyes) - more healthy, more smart and more beautiful. And ofcourse free market will win. Not just because it is more rational or because of the invisible hand. But because of the hiding hand - because the actor does not know the risks beforehand! So is more daring, over time learns to minimise risks and then proceeds to tap the rewards.....

Whatever ethical proscriptions we come up with is likely somewhat beside the point. As with drone delivery research, the restrictions on research outside the US and a few other places are far less stringent than we might want. That means that whatever happens here, progress is likely to continue.

And yes, CRISPR isn't perfect, but it is indicative of the explosive progress in genetic engineering. We mapped the first human genome less than 15 years ago, for $3B. Now it costs, $1k and is still crashing. Don't focus on this point in time. Focus on the trajectory and get ready...

That's just the cost for the puzzle. The completed picture, however, involves various social determinants and therefore is to some extent unknowable.

if you support crispr, you should be glad the NIH is prohibiting it for now with easily reversed administrative policies. the alternative is for scientists to support it and fearmongering lobbyists/politicians to make it a target

This. Government is not the only source of funding. If the technology is really promising, private money will fund research. This way, researchers can work in peace without worrying about political debates.

Most people try to conceal the things about themselves that you proudly announce to the world. Nice to know you think I'm at the bottom of your hierarchy.

FYI, there is a factual error in this piece. Nature and Science did not reject the paper on ethical grounds, ethical grounds were ostensibly one motivating factor in rejecting the paper. The paper itself was also of poor quality.

Can I offer a resolution? Allow gene editing, but only after the singularity comes to pass. If, after uploading your brain, you want to edit the genes for your next incarnation, by all means enjoy!

Limitations are a good idea because they allow perfecting the techniques on lesser organisms and our knowledge about its effects before pursuing them on humans fraught with ethical concerns and unknown effects.

For better or worse, it does not matter what the governing medical authorities of G7 countries want nor does it matter what the current success rate is.
With a significant demand, a reasonably permissive developing or near-developed country, and a level of affordability that facilitates the risk, this will proceed. First through parents, then government agencies, then corporations insistent on the best people (whether they 'ordered' such people or not)(or other order). The only more compelling technology that would cause us to otherwise act in such a risk-tolerant way would be a solution to ageing. Such flavours of 'non-immediate casualty ethics' is for the complacent, the risk-adverse, and the non-experienced-emotionally-rigid - often flowing and reforming with time and comfort. I myself would do the medical tourism if I was at such a stage as could reasonably expect a child with 40 extra IQ points (or genetic equivalent potential) and a modified life-expectancy of greater than 95 years. Now that near-developed countries who feel little affect of sanctions or international pressures on abstract medical-philosophical ideas (likely culturally influenced), yet still appreciate reasonable medical testing standards, such as China, Russia, and India, are emerging - this type of technology can only proceed with, at best, mild 'official' resistance. Influxes of G7 medical tourism money, can do nothing but lighten this challenge.

It will be interesting to see - as cultural tolerances polarize across increasingly-economically similar areas (prudish G7 vs irresponsible southeast-Asia+Russia) how our world will diversify and what industries will locate and thrive in which locations - especially when the interest in maintaining a solid socio-politoco-cultural norm across the world is not enforced by military means.

Let's add this to the mix - 'Every year, thousands of students from across the world compete to build biological systems from pre-existing parts in a competition organized by the International Genetically Engineered Machine (iGEM) Foundation. Last November, to spark discussion on security and health risks raised by synthetic biology, FBI Special Agent Edward You presented an example: the production of opiates from sugar by yeast (Saccharomyces cerevisiae) that has been genetically modified.

You's hypothetical scenario is becoming a reality. One week after the iGEM competition, two developers of opiate-producing yeast strains approached us, specialists in biotechnology policy. They had results in advance of publication, and requested advice on how they might maximize the benefits of their research while mitigating the risks. Now, published papers by these researchers — John Dueber at the University of California, Berkeley, and his colleagues1, and Vincent Martin of Concordia University in Montreal, Canada, and his colleagues2 — describe all but one step of an engineered yeast pathway that converts glucose to morphine (see 'Brewing bad'). Meanwhile, researchers at the University of Calgary have put in place the final piece.' http://www.nature.com/news/drugs-regulate-home-brew-opiates-1.17563

Interesting, but much less problematic from a bioethics perspective. Most people feel a lot more strongly about doing things to sentient life that permanently alter their nature.

Furthermore it's actually quite hard to make even small batches of complex molecules of the type you are talking about even if you have the bugs to do it, particularly if you are working with tertiary metabolites like opiates. It requires substantially more expertise than a meth lab, for instance, to perform the necessary engineering, and even with the strain pre-produced it isn't a cookbook recipe you're working with like most of the routes from pseudoephedrine to methamphetamine. Neither are the organisms likely to be robust enough to work without a fully sterile environment due to their metabolically impaired nature (as is commonly the case with industrial biotechnology), so it's not nearly as robust as beer yeast and even less so than botulism toxin Clostridia (moreover, without reading the paper, it seems likely that such a culture would also have to be aerobic, which introduces still more technical complexity). So, methamphetamine or beer brewing this is not.

Also worth noting is that with drugs or even botox the problem can be said to be, on a rough level, directly proportional to the quantity of the dangerous substance produced. Contrast this with the possibility of truly dangerous threats like the possibility of terrorists copying researchers that managed to identify, isolate, and insert the traits of the Spanish flu that made it exceptionally virulent and deadly - since the threat is a pathogen that self-reproduces, the level of technical sophistication required does not serve as an effective barrier, as the production process need only produce a small quantity exactly once for it to be a massive threat.

CRISPR at this point seems to me an interesting novelty. I am more concerned about the enhancement we are already doing with IVF.

That being said, I am surprised and glad to see Mr. Naam sticking closely to known science.

The author engages in not mathiness, but something related
gene editing by parents will be in childrens best interest
Really ?
We don't know enough to create superhumans
maybe not, but we could make soldiers with low levels of remorse or fear or pain

in other words, these are the authors opinions; there is no way to evaluate them, but, recalling Thinking Fast and Slow, we note that pundits are wrong more often then by chance (ie pundits do worse then a random coin toss)

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