Why human embryo editing is not a 'slippery slope'

The genetic modification of human embryos by a team of Chinese scientists has inevitably, and rightly, provoked controversy. The work, which could potentially lead to the cure of genetic disorders such as haemophilia, anaemia and some cancers but also raises the prospect of “designer babies”, was reported last week in the little-known journal Protein and Cell, after apparently being rejected by the leading journals Nature and Science on ethical grounds.

Those decisions could give the impression that the work is ethically dubious, and some certainly feel that way. What the researchers actually did was to acquire embryos by consent from IVF donors, and use a gene-editing technology called CRISPR/Cas9 to alter a gene associated with a fatal form of the blood disorder thalassaemia. The embryos studied were “non-viable”: because they had been fertilized, by chance, by more than one sperm, they had an extra chromosome, which means that they lacked the capacity to develop into full-term human fetuses.

CRISPR/Cas9 is already transforming genetic modification. It uses enzymes (Cas9) that have evolved in bacteria to combat viral infection, which enable the very precise and selective cutting and pasting of fragments of DNA. In principle it is possible to cleanly excise a faulty gene from a chromosome and replace it with a properly functioning one. The method has been shown to work pretty well in some animal embryos and human adult cells (included stem cells), but it wasn’t known if it could edit genes efficiently in human embryos.

If it does, one can imagine IVF embryos that have inherited genetic diseases being modified to correct the defect before being re-implanted and developing into healthy babies. But that would only look desirable if the technique didn’t introduce complications and flaws of its own. The Chinese team, based at the Sun Yatsen University in Guangzhou, found that in fact CRISPR/Cas9 is a decidedly imperfect editing tool for human embryos. Only a small proportion of the single-celled embryos that developed to the eight-cell stage had their faulty gene “repaired”, and several had unintended mutations in other parts of their genomes. In other words, the researchers said, CRISPR/Cas9 is still a long way from being ready for clinical use. Their argument, defensible if not unanswerable, is that if you’re going to study this technique for human gene therapy then it is better to know these things than not.

Most scientists in the field anticipated that this would be the case anyway. But it had never been checked out before, because of concerns about the ethics of such a dramatic and deep-rooted intervention in human genetics.

There’s every reason to take such concerns seriously. The “slippery slope” argument trotted out every time an advance of this kind comes along—it was used again for the debate over mitochondrial replacement (the speciously termed “three-parent babies”)—is not, however, among them. Philosophically and legally that objection carries no force: there has never been a fundamental reason why a technology permitted in one instance will inevitably be permitted in every other, and illegal abuses do not undermine the principle of legal regulation. But even setting aside the central issue of safety for such interventions, the power of a method that enables arbitrary gene-swapping in humans warrants very careful scrutiny and reflection. In particular, alterations produced by CRISPR at the embryonic stage would enter the germline: they would be inherited by the offspring of a person born from the embryo. In contrast, other gene therapies under investigation work only on “somatic” cells—body cells, not eggs or sperm. It’s seldom acknowledged, though, that this argument cuts both ways. If gene surgery could be conducted without complications further down the line—a huge and difficult thing to establish, without doubt—then who would not prefer that a potentially genetic disorder be eliminated not only in themselves but in their offspring too?

Some scientists had called for a moratorium on using CRISPR on human embryos even before the Chinese work was published. “At this early stage” one group wrote in Nature in March, “scientists should agree not to modify the DNA of human reproductive cells.” They argued that using CRISPR in human embryos would offer no therapeutic benefit over existing methods that modify genes only in somatic cells, or which involve genetic screening of IVF embryos before implantation. Today, they said, around 40 countries ban or discourage such research, and 15 of 22 nations in Western Europe prohibit any kind of germline modification.

But if there is no germline to speak of because the embryos aren’t viable, is there any reason not to establish whether the method would even work in principle? That, at least, seems to be the position of the Chinese team. The authors of the Nature commentary, however, worry that such a step could provoke a public outcry that would undermine efforts to use the technique on somatic cells to treat serious diseases. In other words, even if there is strictly speaking nothing wrong with such studies, people might think that there is. Pragmatically speaking this could be true, which is why it’s a valid concern. But that doesn’t make it any less dangerous a precedent.

All the same, the caution of the top journals is not easy to understand, unless they are concerned to avoid seeming to confer an imprimatur on any future applications of CRISPR to humans. The Chinese group broke no rules; they followed standard guidelines for human embryo research. If the journals feel that they haven’t yet had time to think through the implications of the research, that seems fair enough. But we could certainly do with more clarity of purpose and principle than what Science magazine seems to have offered; its comments to Nature’s reporters —“We believe strongly that the potential of genome editing must be viewed in terms of social mores and that the path forward must be developed through a consensus-building process”—are the kind of vague, inoffensive corporate waffle we’re more used to hearing from politicians. I think Science is saying that genetic modification of human embryos has ethical dimensions and they don’t know what to think about them yet. Well OK, but that doesn’t exactly advance the debate.

The impression given so far is that science doesn’t have a framework for discussing the issues this work raises. This is odd, to say the least, given that everyone saw it coming. If you accept that it is permissible to experiment on human embryos at all, in particular on those produced during IVF treatment that have turned out to be non-viable and for which consent is given, then it is not easy to formulate a logical objection to the Chinese study: it gathers potential useful information without putting any individuals, born or unborn, at risk. And if one accepts that such work should be banned at present in viable embryos, then the research is not opening up any floodgates.

I do expect the journals to emerge eventually with a set of policies on this kind of research, but I hope they won’t seek refuge in virtuously worded flimflam. The danger with this kind of research is not that it will take us into a Brave New World but that it will develop in a vacuum left by a reluctance to engage with anything controversial. In the United States, IVF itself was seen as too hot a potato in its early days, so that recommendations from ethical advisory boards were simply ignored by governments, effectively paralysingSci research in the public sector while creating a poorly regulated, laissez-faire private sector. There was similar prevarication in the UK for many years, but it was ultimately resolved with the Human Fertilisation and Embryology Act of 1990 that established transparent procedures and led to a generally progressive research climate in which science could flourish because the rules were clear.

As it stands, the statement released on 29th April by Francis Collins, director of the US National Institutes of Health, does little to resolve any ethical dilemmas. It reaffirmed the NIH’s ban on such work on human embryos, referring without further comment to the Dickey-Wicker amendment that “prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed”, as if to say “Look, we couldn’t fund this stuff even if we wanted to”. But the Dickey-Wicker amendment, especially in so far as it applies to non-viable embryos, is incoherent philosophically, morally and indeed theologically, and is a truly flimsy wall to hide behind.

What this discussion needs is an open expression of goals, motivations, concerns and values. What it seems to have got so far, from official channels at least, is nervous evasion. That’s not going to help us find a wise path ahead.