Human embryo editing - should we do it?
Two recent papers weigh the pros and cons but don't really emphasize the main barrier.
Last week Nature published a provocative think-piece by the eminent human geneticist Peter Visscher and his colleagues that works through the potential impact of human embryo editing on disease. They assume for the sake of argument that we can reliably edit individual embryo genomes in tens or hundreds places. Reliable here means that you edit all and only the target positions, so that there is little risk of off-target or incomplete editing. Assuming that capacity, Visscher and colleagues ran a model showing that you could substantially reduce the burden of common diseases among a hypothetical genome-edited population. Disease with polygenic risks, like type 2 diabetes, coronary artery disease, Alzheimer's disease, schizophrenia, and major depressive disorder could be prevented by editing in protective alleles.
They make the bold claim that “editing 40 variants could greatly reduce an individual’s lifetime risk of AD, SCZ, T2D and CAD to less than 0.2%”. The degree of risk reduction obviously depends on the base rate of disease, but the predicted reduction is impressive. For example, editing ~10 variants to protect against type 2 diabetes could reduce its prevalence among genome-edited people by 50 fold! The big point is that if such edits ever become feasible, we need to consider the potentially massive benefit to human health, at least among those whose genomes are edited.
What about the risks?
Anyone reading this surely is immediately thinking about a bunch of caveats, many of which Visscher and colleagues acknowledge and discuss. The model involves some important assumptions, and you could ask, how would this hold up across different environments? How much does genomic “background” matter — would these numbers hold for different populations across the world? What about pleiotropy — would editing a dozen variants to reduce your risk for major depressive disorder also increase your risk for some other condition in as yet unknown ways? And won’t routine genome editing basically bring on a dystopian Gattaca scenario in which those with the means to access editing for their kids dominate the world?
These are all good questions, and Visscher and colleagues discuss them. So do Shai Carmi, Henry Greely, and Kevin Mitchell, in a responding piece in the same journal issue. They are much less sanguine about the risks of genome editing than Vissher, et al. Their most compelling point is that even if you assume that embryo editing technology gets much better than it now is, the method would still impose unknown risks on the non-consenting future child. Mistakes and incomplete knowledge about the impact of particular alleles on development could have catastrophic effects on some children who had no say in the decision to submit their genomes to editing. We need to keep in mind that while idealizations may work for thought experiments, in practice no technology is ever mistake-free. A counterpoint would be that back in the 1960’s and 70’s, similar concerns were raised about in vitro fertilization (IVF). But IVF turned out to be an enormous benefit to millions of families, including mine, and it didn’t have a detrimental impact on the health of children born by the procedure. I recognize that the parallel to embryo editing is very imperfect, but we should keep that example in mind when we talk about unknown risks.
I have followed the individual work of Carmi, Greely, and Mitchell, and I have tremendous admiration for all three of them. Greely, for example, is the author of CRISPR People: The Science and Ethics of Editing Humans, and has clearly thought very carefully about the issues surrounding embryo editing. But I found this Nature perspective a bit frustrating, even a little hysterical too combative in its tone. They repeatedly accuse Vissher, et al of ignoring issues that are in fact discussed in their piece, though clearly not to the satisfaction of Carmi, Greely, and Mitchell. (Caveat: I don’t know what the editing process was, and perhaps an earlier draft of the Vissher piece, shared with those who wrote the response, didn’t address these topics.) Carmi, Greely, and Mitchell ask whether it’s responsible to even have this discussion, concluding their piece with the following sentence: “Is it wise to distract stakeholders, including the public, with a technology that is still a long way off at best, and might never actually be safe?”
The technology will get there but will we need it?
While I’m glad these three wrote an important response, I’m not so sure it’s unwise to discuss the possibilities of polygenic embryo editing. We should be wary of underestimating the technological advances in genome editing that will occur over the next generation. Vissher and his colleagues suggest a time frame of 30 years. 30 years ago, the technology to complete the human reference genome was still under development, and none of today’s major sequencing and gene editing technologies existed.
There are critical applications of gene editing technology other than modifying embryos, especially in basic research and gene therapy for people suffering from catastrophic disease. These applications, not embryo editing, are motivating hundreds of innovative projects to develop more reliable gene editing. This field is moving very fast, and an enormous number of potential technologies are quickly being explored. I think reliable, polygenic gene editing will get here sooner than we might guess. In parallel, the functional genomics field is currently putting in a big effort to expand our catalog of actionable genetic variants, and in 30 years I have no doubt at all that we will have enough causal variants on hand to implement the strategy proposed by Vissher, et al.
So I do think that, with the technologies moving as quickly as they are, it is important to start thinking about this issue now. But for me the biggest reasons to not go the route of polygenic embryo editing are ones that were hardly touched on in these two pieces:
First, while Vissher and colleagues showed that you can greatly reduce the incidence of disease among genome-edited people, there are easier ways to reduce many of these diseases now or in the near-term future. Drugs, in general, are the cheapest and easiest therapeutics. I recognize that’s not true for everything, but I propose that in 30 years, we will likely see substantial progress in drug treatments for all of the diseases discussed, including Alzheimer’s. Alongside that, gene therapy for already-born individuals is also likely to achieve major progress. The first FDA-approved gene therapy came out in 2018, and many, many more are in the pipeline. Not only will technology to treat disease advance, but we’ll also likely see major progress in preventative treatments. As some of my Washington University colleagues wrote back in 2012, “more than half of the cancer occurring today is preventable by applying knowledge that we already have.” By 2054, editing embryos to reduce disease may seem expensive and difficult compared to other the treatments and environmental interventions available.
And finally, the second barrier to a Gattaca society is the fact that if you are going to edit your embryo, you need to do IVF. Maybe someday we’ll edit embryos in utero, but that is a much more distant technology. It seems implausible that there will ever be enough people who voluntary conceive their children by IVF for embryo editing to have a big impact on human health or societal inequality. Sex is cheaper, easier, more spontaneous, and much more enjoyable, while at the same time, greater forces are driving inequality in society. Embryo editing will likely never be more than a niche factor.
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