Editing the Book of Life

A new use for a still relatively new gene-editing technique is creating quite a stir. Through it, writes Melissa Healy of the Los Angeles Times, “scientists have rid human embryos of a mutation that causes an inherited form of heart disease often deadly to healthy young athletes and adults in their prime.”

The breakthrough here may be as much on the moral as on the technical front. “For the first time in the U.S.,” writes Amy Dockser Marcus in the Wall Street Journal, “researchers said they had edited viable human embryos to correct a disease-causing defect, avoiding problems that plagued previous efforts and stoking concerns that advances in the lab are outpacing public discussion about the ethics of gene editing.”

What’s all the fuss about? It looks like medical science is just developing one more weapon in its arsenal, in this case a gene-editing technique called CRISPR or Crispr-Cas9. The goal is a charitable one: to cure disease. That, in any case, is the argument put forward by those who would like to gain society’s acceptance of using heritable gene-editing on human subjects. In the well-respected journal Nature, where the CRISPR researchers first announced their breakthrough, the authors estimated that there are more than 10,000 diseases caused by a defect in a single gene, affecting millions of people around the world.

That’s a lot of good that could be done. What exactly are these public discussions of ethics, which usually means pretty obscure discussions among professional bioethicists, supposed to be about?

Up to this moment, American researchers have been very cautious about experimenting with human gene-editing when the resultant modification would be inherited. Indeed, the federal government prohibits the use of federal funds for research on human embryos. The Food and Drug Administration is prohibited from approving clinical trials of heritable genetic modifications. But the international team of authors who did the research in the present case followed a more permissive set of guidelines that were promulgated earlier this year by an international team put together by the National Academies of Sciences, Engineering and Medicine.

According to the Washington Post’s Joel Achenbach, the National Academies panel “urged caution in applying CRISPR to human germ-line editing but laid out conditions by which research should continue.” The panel “did not recommend an absolute prohibition of gene editing on the human ‘germline’ if such interventions can be proved safe.” Instead it took “a slightly more permissive, forward-thinking position, saying that, if and when such interventions are proved safe—which could be in the near future—and if numerous criteria are met to ensure that such gene editing is regulated and limited, it could potentially be used to treat rare, serious diseases.”

Achenbach quotes biologist Richard Hynes of MIT, a leader of the panel: “We say proceed with all due caution, but we don’t prohibit germline, after considerable discussion and debate.” Added the biologist: “We’re talking only about fixing diseases.”

Paraphrasing Hynes’ colleague on the panel, Alta Charo, a professor of law and bioethics at the University of Wisconsin, Achenbach also writes:

The list of criteria that would have to be met before going down that road is a long one . . . For example: The intervention would have to replace the defective, disease-causing gene with a gene already common in the human species. There would also have to be no simpler alternative for parents wishing to have a healthy child. And first and foremost, there needs to be more research to show that such modifications are safe and target well-understood genes.

“We are not even close to the amount of research that we need before you can move forward,” Charo was quoted as saying, in a news release called “Editing the Book of Life” on a CRISPR-related web site.

So here we are, only a few months later, moving forward on research that is not approved by federal regulation but that will open the door to yet more research, which will eventually be necessary to show that “interventions” of this sort are “safe.”

The safety of the intervention for sperm donors is relatively well understood; the safety for egg donors is considerably less obvious, but that is another story. The “safety” of the embryo is not even a question, really; at this experimental stage there was no plan to implant it, and it was presumably destroyed.

But of course the National Academies panel’s concerns about safety are really about showing that the genetic modification is safe for the individual being modified. About that, we presently know nothing. So far as I know, there is only one way to establish safety in this sense: Eventually, somebody will have to let a genetically modified embryo grow up into an adult human being whose life and health can be observed with the goal of finding out whether the experiment was a success or not.

Indeed, multiple such test subjects and follow-up studies will likely be required, replicating the early days of in vitro fertilization. Those experiments will be, in the spirit of the National Academies guidelines, hedged about with all kinds of things that sound like safeguards but are really the boxes that researchers will need to check to pass muster for ethics panels and regulators. After all is said and done, the “first and foremost” criterion for continuing down the road of more research is: more research. In the end, to establish that this gene-editing is safe, researchers will have to act as if they already know it is safe. That kind of willingness to perform experimentation on human subjects is the second step in these stories pointing to our genetic future.

Once you get to step two, step three is easy. Shoukhrat Mitalipov of Oregon Health & Science University, one of the lead CRISPR researchers, told Achenbach of the Post “that he is conscious of the need for a larger ethical and legal discussion about genetic modification of humans but that his team’s work is justified because it involves ‘correcting’ genes rather than changing them.” Mitalipov said: “Really we didn’t edit anything. Neither did we modify anything. Our program is toward correcting mutant genes.”

Yes, we need to have that ethical discussion—one of many that scientists and engineers have learned, as if by rote, to say that we need to have. But here’s the beauty of it: we really don’t! Because really we haven’t done anything! We edited without editing, we modified without modifying. We took out a mutation—you know, like those rampaging mutants you see on television or in the movies? Surely you don’t need an ethics panel to tell you it’s okay to take out those suckers. Charo adds, “no matter what anybody says, this is not the dawn of the era of the designer baby.” The medical and ethical professionals just have to “educate” people to understand what is “really” going on. Designing your baby not to have a genetic illness it might otherwise have is not designing your baby. Not bringing a “defective child” into the world is just being a “responsible parent.” It is refusing to play the “genetic lottery.”

If we want to know where on a slippery slope we really stand with this latest triumph of CRISPR genetic editing, it is best to turn to the late, great Richard John Neuhaus. Wrote Father Neuhaus:

If a certain measure is proposed, and if there is theoretical license for doing it, and if it is technically doable, and it is in the felt interest of those who are in control of the technique, why should we think it will not be done?

The measure proposed is the elimination of single-gene diseases. The theoretical license for doing it is the charitable concern for human health and well-being, for comfortable self-preservation. The technique required is apparently doable, the major reservation being a charitable concern for human health and well being, that is, safety. That concern is not extended to the embryos that are subject to experimentation, only to the born human beings who are their telos. So when these two charitable impulses clash, the latter will triumph over the former in the name of “curiosity-driven research” or “You can’t stop science” or “If we don’t do it, they will.”

In sum, it will certainly be very much in the interest of those who control the technique to act as if it were safe in order to establish that it is safe.

So let us not kid ourselves. All bland assurances about debates, regulations, and safety aside, this research program is a done deal, as are the therapeutic applications that will follow if it looks like the research is panning out. And then, with all we have learned from it, we will move on to more complex genetic diseases. And then we will move on to addressing stigmatizing physical conditions.

Over time, our view of what is a serious deficit of human health, appearance, or ability will grow more and more refined as our powers to redesign our genomes increase. The same three-step argument will play out again and again: We just want to cure disease, we just want to do the research that will make sure the cure is safe, none of this is really any big deal if you look at it from the right angle. Bit by bit human beings will become designer products, and the Designers will hold sway with all the attendant problems of such an elite pointed out long since by thinkers as otherwise diverse as C.S. Lewis, Aldous Huxley, and Bertrand Russell.

That is, unless we all upload our brains into robots first.

Reader Discussion

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on August 07, 2017 at 11:33:28 am

"It is refusing to play the “genetic lottery" - which is to say, it is not refusing to play God.

As the essay infers - that ship has already sailed the safety of its harbor...

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Paul Binotto
on August 07, 2017 at 16:31:15 pm

"In sum, it will certainly be very much in the interest of those who control the technique to act as if it were safe in order to establish that it is safe."

I'm not sure who you think is -- or ought to be -- in control of the technique. For the technique you discuss, I believe it is the prospective parents who are in a position of full control. Anyone thinking of using it on their offspring should certainly educate themselves on the benefits and risks, and think through the ethics of the decision. I know parents who, for religious reasons, withhold all modern medical treatment from their children -- who would not set a bone, let alone a broken gene.

I am much more comfortable using technology. I know some of the specific spelling errors that I am carrying in my DNA and those that my wife is carrying in hers, and I know exactly what their combined effect has been on our children. I look forward to the day when my grandchildren can be spared the suffering caused by avoidable genetic errors.

If you don't want that for your children, I respect your right to have a different point of view. But your suggestion of some kind of dystopia, ruled by a Designer elite, is neither realistic nor a helpful contribution to what should be a serious debate. If you are advocating some specific public policy regarding genetic medicine, please say what it is and why you think it would be desirable.

Full disclosure: I served from 1987 - 1992 on NIH's Recombinant-DNA Advisory Committee.

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Brian Mannix
on August 07, 2017 at 17:55:26 pm

I concur. Especially if we are looking at single spelling or syntax errors.
to go beyond that, at least at this stage, is to flirt with disaster.
We know so,little about this *code*, even today finding that what we characterized as "junk" DNA actually has usage and that the odds of this particular combination of spelling and syntax occuring by chance are on the order of 1 - 10 to the 40,000+power.

Proceed with caution - but if we can correct - let us correct.

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Image of gabe
on August 07, 2017 at 18:45:53 pm

This topic raises a number of challenging questions.

1. Do we have anything to fear from “invasive species” genes—that is, a novel gene that proves wildly adaptive and thus hard to control, even if people would prefer not to have it?

For example, imagine some accidental gene manipulation would cause young men at puberty to suddenly become wildly aggressive and prone to rape people. Yes, society would hate this. Maybe even the young men themselves would hate it. But the very nature of the defect might cause the gene to be disproportionately likely to show up in each succeeding generation. If we also imagine that detection and correction is very expensive, and that many people develop moral qualms about engaging in the practice, perhaps we’d trigger some kind of avalanche.

The problem with this hypothetical is evolution: If such traits really were adaptive, it would seem likely that humans would already have such traits. And indeed, adolescent men can be quite aggressive, especially regarding sex. But the fact that most men do NOT exhibit such traits suggests that sociability and self-control are MORE adaptive traits, and that people with these traits manage to out-reproduce the hyper-aggressive types.

In short, arguably we don’t need to worry about the “invasive species” threat. Natural selection will still protect us.

2. On the other hand, what genetic duty does any individual have for the perpetuation of the species?

Ponder: Why are humans so prone to genetic “defects”? One thesis is that a certain level of genetic variance is adaptive for the species even if it may be hard on the individuals. When the population has a variety of genetic patterns, no one disease will be able to wipe us all out. But if individuals (or their parents) are given the power to limit the range of variation they will endure, and if large percentages of individuals opt for this limitation, then the herd will have a narrower genetic range—which may prove maladaptive when confronted with a new threat.

After all, Irish potatoes may have been optimized genetically for the circumstances that people could anticipate. But being so optimized, they exhibited limited genetic variability. When an unanticipated circumstance—potato blight—arose, the population was decimated. What seemed optimal under one circumstance proved to be suboptimal under another.

But that just applies to potatoes, right? Well, many people find living with sickle-cell disease to be sub-optimal. If people had the opportunity to avoid this condition, it seems likely that they’d pursue that option. But apparently sickle-cell disease is an adaptive trait if you live in environments with malaria. If humans opted to breed themselves clear of sickle-cell disease, and then encountered malaria for the first time (or for the first time in memory), what would be the outcome?

Well, maybe the outcome would be a massive die-off. And that would be sad.

Or would it? If every individual (or his parent) made the choice freely, should we care about the species? That is, should individuals be expected to sacrifice their welfare by enduring “bad” genes just for the benefit of society at large (basically, treating themselves as a genetic seed bank)? And if so, should society compensate them for the sacrifice?

(Full disclosure: I have no background in this stuff at all. As a cyborg, I don't even own blue jeans, let alone human genes.)

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Image of nobody.really
on August 07, 2017 at 19:04:16 pm

You make some good points, even in light of your full disclosure. While it is tempting, the notion that Pittsburghese could be "edited" out of the local gene-pool, you may be right; this same offending gene that propagated among the settlers that made the journey successfully across the Alleghenies to settle Pittsburgh in the west may actually contain the adaptive trait that saved us from having to endure the horrors of a Philly accent...

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Paul Binotto
on August 07, 2017 at 22:06:55 pm


Good questions / comments - as a cyborg, I think you should be more conerned about the proper lubricant you require. I may be able to help there.

On a serious note - quite right about the adaptive capability of sickle cell vs malaria.

Raises the more fundamental issue:

If we can not find a way to properly understand and manage a simple constitution, how in the world can we expect to manage something INFINITELY more complex such as the human DNA code. I read a while back that the likelihood of a simple 100 (or was it 40) element peptide chain occuring by chance is 1 in 10 to the 40,000th power. Heck, I wouldn't go to vegas with odds like that and some knucklehead wants to pull the "one-armed bandit" and gamble on "adaptive" change mechanisms.

Nope, let us cyborgs stick to simple lubricating fluids (beverages).

take care


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Image of gabe
on August 13, 2017 at 12:24:03 pm

On the question of parental control, allow me to note two kinds of problems. First, we have anti-vaxers, who (it seems to me anyway) exercise their control in ways that are ultimately irresponsible. I don't find it at all hard to imagine equally irresponsible choices employing genetic engineering, not just refusing to employ it. On the other hand, as I understand it it is very common these days for medical professionals to discourage very strongly parents from allowing a baby diagnosed with Downs Syndrome to come to term. Parental rights over against such professional judgments are looking increasingly fragile in many parts of the world.

Now I understand that these two issues point in opposite directions, but they are the Sylla and Charybdus between which our genetic policies and choices will have to maneuver. My judgment is that given commercial motives, insurance motives, professional motives and government motives, parental genetic choices will be made under circumstances where the actually available options will have already been defined for them by elite decision makers--because for the most part, that is already how things work today. If I am wrong, then responsible public policy making will have to concern itself with veering too far in the other direction. But forgive me if I think it is a perfectly serious contribution to public policy debates to point out the direction in which things already seem to be going, and suggesting the pitfalls thereof. The well worn mantra of "educated parents," particularly when it is acknowledged that this is more aspiration than reality, does not really settle the control issue.

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Charles Rubin

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