A genome editing year: developments since the Nuffield report

What we said

Genome editing denotes the use of any one of a number of related biological techniques, such as the CRISPR-Cas9 system, deliberately to modify a functional sequence of DNA in a living cell. Doing this in a human embryo, or human sperm or eggs, or their precursors, can result in the modified sequence being replicated in the cells of a resulting child. Without further intervention, it could potentially be passed on to that child’s biological descendants. Some people call this ‘germ line’ genome editing.

Our Nuffield report has received much scholarly attention since its publication. Notably, it received a perceptive and sustained engagement from Chris Gyngell, Hilary Bowman-Smart and Julian Savulescu in the Journal of Medical Ethics, to which others — including myself and former Nuffield Council member Anneke Lucassen (with Rachel Horton) — have responded. The continuation of this discussion is welcome and it helps to challenge and deepen our understanding of the conceptual issues. More practically, the report became almost instantly a standard reference point for broader debates, taking a prominent place among the very few sustained engagements with the issue of human heritable genome editing (the others being the US National Academies’ report – see my previous post – and, more recently, that of the Deutscher Ethikrat – see below).

In our report we concluded that genomeediting in human reproduction could be permissible in certain circumstances(although those circumstances do not obtain anywhere at present). For this to be the case, though, there wouldneed to be a great deal more research and, importantly, a ‘broad societal debate’leading to the development of governance arrangements informed, we thought, bytwo principles: to protect the welfare of the future person and to preventsocial injustice.

What He said

The debate was given an unwelcome boost by the claims made by a Chinese researcher, He Jiankui, in November 2018 that treatments he had provided had resulted in the birth of two genome edited babies. This claim, which was reported on the eve of the ‘second international summit on genome editing’ in Hong Kong (organised by three science academies), ignited a media firestorm that is still smouldering eight months later.

The reason that He Jiankui’s intervention is so significant is not that it fulfils the promise of genome editing treatment but that it betrays it by apparently blundering around in the genome (using an targeted but error-prone DNA repair pathway to disable a gene with plural functions), and does so not because it addresses an unmet need (since there are reliable ways for HIV infected fathers to have non-infected children) but apparently just because he could. Critics have seized on subsequent papers that suggest how insufficient is knowledge about the CCR5 gene to edit it with confidence. One of these showed, from experiments inhibiting the CCR5 receptor in mice and observation of stroke recovery in people with a natural CCR5Δ32 mutation, that the variant appears to have (positive) effects on memory and cognition. Another study, which linked genetic variant with mortality data, showed that that the CCR5 mutation may be associated with higher mortality rates (in a Western cohort aged between 41 and 76). The CCR5 gene has, as a consequence of all this, become emblematic in the debate about genome editing in at least two respects. The first is that it demonstrates how much may still be unknown about the function of most gene variants in the context of a whole genome and in a whole living organism. The second is that it suggests that the value placed on different risks and outcomes may depend significantly on circumstances, since it may be that in certain communities, in which the prevalence of HIV infection is high and access to treatment is difficult, and despite its effect on mortality, having a CCR5Δ32 variant may significantly increase someone’s chances of getting to 41, let alone 76.

Clearly, He should not have done what he did: it is uncontroversial that genome editing, particularly using the knock-out technique He used, was too risky to have been introduced to the clinic and it appears that He was told this repeatedly. But nevertheless, he did it. Nor should he have done it in the way he did it: there were many apparent failings in his clinical conduct, from the recruitment of patients through the seeking of consent to the circumstances of treatment, reporting and follow up (although these are admittedly secondary considerations). But nevertheless, he did. And he told the world about it, as I described in a previous post from the auditorium in Hong Kong. On behalf of the six continents represented, the Chair of the conference organising committee, David Baltimore, duly pronounced the anathema.

What Xi said

The response in He Jiankui’s home country, China, was somewhat less peremptory. It seems that He had been regarded as a rising star, favoured by the Chinese Government. He had apparently received research funding from the Chinese government (via the Ministry of Science and Technology, the regional Shenzhen Science and Technology Innovation Commission, and He’s university, the Southern University of Science and Technology) although it is not clear how much they knew about his intentions. Following He’s announcement at the summit on 28 November, the regional authority, Guangdong provincial health commission, launched an inquiry (also involving the science ministry and the National Health Commission). This found that He had raised funding for the treatments on his own, without official endorsement and also that He had forged a consent form and violated scientific ethics and Chinese regulations. The circumstances are difficult to verify, however. Interestingly, the story has been found to be one of most heavily censored in 2018 on the dominant Chinese social media platform WeChat, according to researchers at the University of Hong Kong.

In March 2019, the Chinese health ministry drafted new regulations that would require scientists to get approval before editing human embryos and would impose penalties on those who break the rules. Remarkably, in January the Chinese leader, Xi Jinping, intervened, calling for legislation on genome editing. An amendment was quickly inserted into the revision of the civil code, the overarching instrument of civil law in China. The amendment would mean that clinicians would be liable for genetic interventions that endanger health or violate ethical norms (which is not the same as an explicit ban) and is likely to be adopted in 2020. The status and the fate of He Jiankui is, however, still uncertain.

What they said

What are now often referred to as ‘the Events in China’ have increasingly divided responses elsewhere in the world. These responses have polarised around, on one hand, attempts by the global scientific elite to reclaim the right to govern the Republic of Science and to define a responsible pathway for translation, and, on the other, the wish to explore the finding a broad and inclusive (and international) consensus before proceeding (if that should indeed be the outcome). Which side you take broadly depends whether you think that the issues are primarily to do with clinical safety and reproductive liberty (you’re with the pioneers) or with human dignity and social justice (you’re with the cosmopolitans). Though the US National Academies have been a driving force in international debates (taking a lead in organising the two international summits in 2015 and 2018), this fault line has also fractured the US scientific establishment, dividing influential researchers, even those working in the same institutions. The latest initiative of the US National Academies, with the UK’s Royal Society, is to set up an International Commission on Clinical Use of Heritable Human Genome Editing, of which Nuffield Council member, Andy Greenfield, is a member.

What seems clear is that the Events in China have both reset the initial conditions for the debate and raised the stakes. This has led to undisguised frustration on the part of many researchers, particularly in the US. Having had their credibility impeached by the witch hunt that followed He’s trail through a number of US universities, the exoneration of the supporting cast has left unanswered questions about the probity of scientific self-regulation as a whole, on which the ‘responsible pathway’ approach relies. Their frustrations are no doubt compounded by a recent confirmation of the legal mechanism prohibiting clinical trials of reproductive genome editing in the US. This prohibition is the effect of a rider to an appropriations bill that prevents the Food and Drug Administration (FDA) using its allotted funds to review applications for clinical trials ‘in which a human embryo is intentionally created or modified to include a heritable genetic modification.’ Given that the FDA has asserted regulatory competence over this field, no trials may go ahead without its authorisation. In May, a House of Representatives appropriations subcommittee approved a draft FDA spending bill without the customary rider, which has been in place since 2016. It was probably the intention for this to spark a debate about whether a more nuanced rider might permit mitochondrial donation (see previous post) or even licensed trials of reproductive genome editing. In the event, the language of the original rider was restored in the House without it reaching the Republican Senate.

In Europe, the spiritual home of cosmopolitanism, the running has mainly been made by the major international human rights institutions: UNESCO (which called, in effect, for a moratorium in 2015 but has been relatively silent since then), the Council of Europe Bioethics Committee, which is reviewing Article 13 of its Convention on Human Rights and Biomedicine (known as the Oviedo Convention and the only binding international law that prohibits deliberate heritable genetic modifications, albeit without any expectation of revision at the present time), and the World Health Organization (WHO), which has set up an expert advisory committee on developing global standards for governance and oversight of human genome editing, with a slightly more diverse membership (both disciplinarily and geographically) than the US committee. The initial meeting of the WHO committee (at which I presented the findings of the Nuffield report) yielded a concrete recommendation to establish an international registry of relevant research. For completeness I should also note further stand-alone initiatives such as now incorporated Association for Responsible Research and Innovation in Genome Editing (ARRIGE) and the anticipated Global Observatory on genome editing, which have yet to exert a clear pull.

Into the mix should also be added statements and initiatives of advisory committees, learned societies, professional organisations and national ethics committees from Andorra to the Vatican. These include, notably, the recent report of the German Ethics Council, the Deutscher Ethikrat, in May 2019. This is the latest of the substantial engagements with the issue of heritable genetic modifications and it is hard to underestimate the significance of its conclusion that genome editing is not contrary to human dignity, thereby breaking open the seals that were set on European discussions about human genetic modification in 1997 with the passing of the Oviedo Convention. (As I have argued elsewhere, this Convention represented a prudential rather than a moral consensus, and one whose time may be running out. The preparatory discussions show clearly that the agreement to prohibit genetic modification was a temporizing step, given the intolerable risks associated with the techniques then in view. On the other hand, the moral consensus that did emerge, which was broadly against ‘eugenic’ practices, was not a consensus against all human genetic modification; it was just that, given the absence of a safe technique, the need to distinguish acceptable from unacceptable modifications did not need to be addressed at that time.)

Sting in the tail

There is a sting at the end of this unresolved tale of controversy and competition: publicity has recently been given to a Russian researcher who has declared his intention to edit the genomes of human embryos to be transferred to HIV positive women. Again, the CCR5 gene is the target. This provoked ARRIGE, the Genome Writers Guild and the Japanese Society for Genome Editing to produce a common statement addressed to everyone and no one, calling for ‘the urgent implementation of a more comprehensive framework for the international regulation of human gene editing activities in embryos’. The latest intervention promises an added frisson of competition between the old superpowers alongside the emergence of the new. It will undoubtedly inflame the research community, although whether in dismay or frustration will be hard to tell.