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or more than a year, 22 of the world’s leading geneticists, bioethicists, physicians, and legal scholars have been wrestling with thorny questions posed by the revolutionary advances in scientists’ ability to edit the human genome.

On Tuesday the experts, convened by the National Academy of Sciences and the National Academy of Medicine, released their report. One of the most noteworthy conclusions: The supposed agreement that it’s unethical to tinker with the genomes of human eggs, sperm, and early embryos — so-called “germline” editing? Not so much.

Are “designer babies” nigh? What about CRISPR therapies? And what does the report leave out? Here’s your cheat sheet:

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We’re glad that’s settled:

Should using CRISPR-Cas9 and its cousins to alter DNA be called gene editing or genome editing? The Academies report chooses the latter. It’s more accurate than “gene editing” — which the Academies’ 2015 international summit used in its title — because what’s edited could be strings of DNA that do not code for proteins (the usual definition of a gene). Instead, the new editing tools can delete or alter strings of DNA that regulate gene expression, turning actual genes on or off. “Genome” editing also captures one of the powers of CRISPR: to alter multiple regions of the genome, not just a single gene, at once.

Haven’t we heard this before?

Yes, on questions concerning lab research as well as clinical applications, the report is very much in line with the statement issued after the 2015 summit. It concludes that “basic laboratory research in human genome editing is already manageable under existing ethical norms and regulatory frameworks at the local, state, and federal levels.” Similarly, using genome editing to treat or cure patients is also well-trod ground: The United States (and much of the developed world) already has guidelines for gene therapy, and those will do just fine when it comes to CRISPR’ing people, the report concludes.

But what about germline editing?

The report is also in line with the summit statement on editing the human germline — that is, sperm, eggs, or early embryos, with the result that any changes affect not only one individual but, potentially, that individual’s descendants in perpetuity. Countless words have been written about how that would create generations of genetic have’s and have-not’s, how it would turn children into commodities for which parents could select options, and how it is an affront to human dignity. The Academies committee didn’t buy that. “Germline genome-editing research trials might be permitted, but only following much more research,” it argues, though “only for compelling reasons and under strict oversight,” and after “resolving questions about germline editing’s safety and efficacy” and reaching “societal consensus” about it.

Biochemist Jennifer Doudna of the University of California, Berkeley, a pioneer in the development of CRISPR-Cas9 who was instrumental in getting scientists to grapple with its ethical ramifications, told STAT that she was “impressed with [the report’s] depth of analysis and insightful guidance,” saying it “provides a clear and balanced roadmap for research applications of human germline editing.”

Bioethicist George Annas of Boston University, who reviewed the report at the behest of the Academies, told STAT that its cautionary warnings on germline editing were “modest.” That reflects, he suggested, its “use of an ethical framework that relies entirely on a benefit/risk calculation in which while both are highly speculative, [but] the benefits seem to taken as more likely than the risks,” at least if there is regulatory oversight.

So we’re good to go?

In practical terms, it would be impossible to conduct germline editing in the US: A 2016 law forbids the Food and Drug Administration from reviewing “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.” But the report takes an “if it can be done, it will be done” position. It suggests that medical tourism means that germline editing “will be impossible to control completely if the technical capabilities exist in more permissive jurisdictions.”

That doesn’t sit well with some ethicists. Annas, for one, argues that “the fact that something could be done even if outlawed is hardly a [reason] not to outlaw it if you think it should not be done.”

The report also concludes that clinical trials using heritable germline editing should be permitted only if there are no “reasonable alternatives,” if it prevents “a serious disease or condition,” if it edits genes known to cause the disease or condition, if the edit produces a version of the gene that some people already have (like a healthy hemoglobin gene rather than a sickled one) rather than versions never seen in nature, and other restrictions. As the committee acknowledges, however, “reasonable alternatives” and “serious disease or condition” are vague terms. Its bottom line: “Heritable germline genome editing trials must be approached with caution, but caution does not mean they must be prohibited.” It remains to be seen how that debate will go, but as Doudna pointed out, “Although it has been relatively easy to reach consensus about research applications of editing the human germline so far, I expect it will be more difficult to decide about clinical applications.”

Any glaring omissions in the report?

It would have been nice to get a recommendation on what safety standard should be applied to CRISPR’ing human cells for therapy. A big concern is that CRISPR isn’t perfect, and if the DNA sequence it’s supposed to edit is similar to a part of the genome that it’s supposed to leave alone, the similarity might cause “off-target effects” — that is, inadvertent editing. How do you know if that happened? There are algorithms that indicate how likely a target is to have a near doppelgänger, but even the scientists who created the algorithms warn that they’re imperfect.

Should researchers be required to sequence the genomes of any edited cells they’re preparing to put into patients (to cure, say, sickle cell disease or cancer) to be sure that the intended edits and only the intended edits were made? How many off-target edits are too many? The report doesn’t say, explaining only that “no single standard for somatic genome-editing efficiency or specificity — and no single acceptable off-target rate — can be defined at this time.”

Are there any lines in the sand?

The committee isn’t wild about genetic enhancement, which means using genome editing to give people traits “beyond levels considered typical of adequate health.” Examples include lowering cholesterol below the range considered adequate, bulking up muscles in people with no known disorder to make them super-strong, and editing genes that are active in the brain to improve memory. The committee says genome editing for enhancement “should not proceed at this time.” But it is dismissive of the more apocalyptic arguments against genome editing for enhancement, saying it “is very unlikely to be the most profound source of inequality” in any society.

Could enhancement happen anyway? 

Three words: stem cell clinics. Many of those enterprises get away with using patients’ own adult stem cells (in fat, for instance) to treat diseases and repair joints. They’re able to do so because although the FDA has jurisdiction over the use of manipulated cells, cells taken from and returned to a patient aren’t similarly regulated. The committee thinks it would be a good idea to clarify this ASAP, so regulators can “halt the marketing of therapies that use human genome-editing products that have not” been approved. To which a cynic would say, that’s not worked so well with stem cell clinics.

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  • These people… they jump around with glee like children who have just discovered their father’s loaded hand-gun. Of course they’re going to do it!

  • I’m grateful that this article acknowledges that there might be red lines at all. If it can be done it will be done is what I see from just a passing view of history. We already have fetuses aborted if they are the wrong sex or have disabilities like down syndrome. Why wouldn’t we use these therapies for enhancement? If the basis for restrictions is a risk benefit analysis, what will stop any assault on human dignity? Humans are incredibly adept at rationalizing the worst behavior. Embryos in human development are unique individuals never to be repeated. We use them for research? There’s alot that is left out of these discussions that is troubling. Our abilities have way outstripped our sensibilities and ethics. This is one former embryo who hopes we can wake up to our limitations and be willing to discover the red lines rather than rationalize or deny the need for them.

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