The Consensus Study Report of the International Commission on the Clinical Use of Human Germline Genome Editing convened by the US National Academies of Medicine and Sciences and the UK’s Royal Society was published on 3 September.
Heritable human genome editing is a substantial report and stands as a worthy contribution to discussion of heritable human genome editing (HHGE) in the English-speaking world alongside the National Academies’ earlier (and broader) report, Human Genome Editing, science, ethics, and governance (2017) and our own Nuffield Council report, Genome editing and human reproduction: social and ethical issues (2018).
There are many good things about this report. It is clear, thoughtful and detailed. The Commission has bent itself earnestly to fulfilling the task given to it by the commissioning academies. The coverage of the current state of the science, the prospects for the use of HHGE in the clinic, and the presentation of its potential applications manages to be both thorough and readable. It strives constantly to keep its feet on the ground, both through repeated reference to the technical uncertainties that should still prevent clinical translation of current genome editing techniques and the need for continued research, including on embryo development and assisted conception (p.119ff., although this is a little thin on detail). There is also a helpful section on ‘How common are the circumstances for the [presumptive] initial clinical uses of heritable human genome editing?’(p.112ff). The recommendations for establishing an international scientific advisory committee and strengthening national regulatory procedures are well taken. It is interesting that the report gives space to developments in in vitro stem cell-derived gametes, and a translational pathway by which they may be enrolled in reproductive protocols along with genome editing. Acknowledging that its own area of competence is limited, the report makes a strong gesture towards the essential role of social and ethical considerations, and the importance of engaging with publics and those with specific interests (including often excluded voices). It also recognises the importance of historical and social contexts (p.149; Box 5-1).
The Commission’s task was to address ‘the scientific considerations that would be needed to inform broader societal decision-making’. It conceived this task as ‘considering technical, scientific, medical, and regulatory requirements, as well as those societal and ethical issues that are inextricably linked to these requirements, such as the significance of uncertainties related to outcomes, and potential benefits and harms to participants in clinical uses of HHGE.’(p.2) Indeed, the membership of the Commission includes ethicists and social scientists, who are not there merely as line judges to make a call when the discussion appears to stray beyond research and clinical governance. But one gets the sense that they didn’t quite persuade their scientific and clinical colleagues how much their joint endeavour was not only adjunct to social and ethical considerations but permeated and suffused by them at all points. As a result, the report sometimes protests too much that it is only concerned with technical questions, while tacitly – perhaps unconsciously – reinscribing value assumptions.
One instance of this is an equivocation in the central concept of responsibility. The report recognises that ‘Interest in using HHGE as an assisted reproductive technology – to assist at-risk couples to have a genetically-related child that does not inherit a serious genetic disease – is driven by the recognition that many couples have a strong preference to have children who are genetically related to both parents.’(p.95)* Whether this ‘strong preference’ constitutes a ‘compelling need’ requires consideration that ‘involves societal values, including ethical, cultural, legal and religious considerations… weighing both deep concerns (ranging from the appropriateness of altering human DNA, regarded by some as a fundamental aspect of humanity, to the ultimate societal impact of widespread and extensive manipulation of the human genome) and deep obligations to ensure that humankind can benefit from scientific knowledge and medical advances.’(p.95) These are explicitly ‘beyond the remit of this Commission.’ What is within the remit and, indeed, ‘at the heart of the Commission’s task’ is ‘defining responsible translational pathways for particular uses of HHGE, should a country judge the uses appropriate.’ This, it says, ‘involves scientific considerations, but it also entails societal and ethical considerations related to weighing potential benefits and harms, and uncertainties about them, in the clinical evaluation of a new medical technology.’(ibid)
‘Clinical evaluation of new medical technology’ sets the frame. Thus, when it comes to the ‘criteria for defining responsible translational pathways for initial uses of heritable human genome editing’ the report says: ‘In order to create the most favourable balance of potential harms and benefits, new interventions with substantial uncertainties ideally focus on diseases and prospective parents for whom there are no available alternatives, and on diseases or conditions for which mortality is high and/or morbidity is severe.’(p.97) In the first place, the alternatives, which exist, are pushed out of view by dropping qualifiers and accepting assumptions about the privilege of reproductive choice. In the second place, the seriousness of the condition is illegitimately imported by inscribing HHGE within a ‘medical model’ of therapeutic interventions. Reproductive choice becomes confused with the response to disease and disability (that is, there is a confusion between the presence or absence of people with disease and disability in a family or population, and the alleviation of disease and disability in existing individuals). The nature of the condition is relevant, but mainly insofar as it is connected with its tractability by HHGE – which is perhaps why monogenic conditions are the presumptive initial targets rather than polygenic disease or genotypes leading to more complex traits.
Of course, things are not so simple, and the distinction between a ‘compelling need’ and ‘strong preference’ can be subject to indefinite interrogation. Meanwhile, the interests of those who carry genetic disease traits in their families may have a special claim on our compassion, though it must be balanced by concern for future generations and the implications for wider society. The important thing to recognise is that the potential benefits and harms of HHGE are distributed among different people (and, silently, beyond those whose interests are recognised in the therapeutic model). This is why, in the UK, for example, we have what is called ‘ethical regulation’ under the HFEA rather than merely consumer protection. What this shows is how little the considerations relevant to HHGE are about medicine and how much they are about biotechnology and public health.
Rewind. There is a sense in which the report is a regrouping following He Jiankui’s announcement of the birth of genome-edited twins, which caught the research community off guard in November 2018. It became inevitable when David Baltimore drew the distinction between responsible and irresponsible research and the organising committee of the second ‘international summit’ set its sights on defining a responsible pathway towards the kind of ends that Dr He had pursued irresponsibly (see my post from that summit, What He said). The pathway is a powerful organising metaphor for technology. The pathway drives traffic to its destination. If you have not asked for a pathway, or if you don’t want a pathway, being presented with fully drawn-up plans for a pathway may seem a little presumptuous. Forgetting that everything that can be said about HHGE is implicitly bracketed by technical uncertainty about the technique’s viability has consequences, however, which include materialising the procedures it describes. This is not so much a ‘limitation’ (as it is described in the report) as an impasse that prevents HHGE getting off the ground in the first place. Reading the report, however, it is easy to forget this. Certainly, the technique is not ready now, but it will be. The effect is not merely rhetorical but strategic. By treating HHGE for monogenic diseases as a virtual fait accompli, it is left to individual states to determine whether they want to follow the pathway or forswear it. The role for international debate has been moved on to applications of HHGE ‘that go beyond the translational pathway defined’ in the report (p.170).
Subsidiarity, naturally, is a problem where rules are weak or absent, compliance arbitrary, and enforcement ineffective. While the Commission recognises that ‘not all countries necessarily have the scientific expertise and regulatory and societal engagement mechanisms to meet the requirements’ its recommendation is rather laconic: ‘any country in which the clinical use of heritable human genome editing (HHGE) is being considered should have mechanisms and competent regulatory bodies’. This seems somewhat jejune since the places where it is not being considered are most likely to be the unwitting resorts. We know, for example, that He Jiankui already had ambitions to expand his service under more accommodating regimes than those of China. The template had already been established by the US clinicians who resorted to Mexico to perform mitochondrial donation. This is why, in our Joint statement on the ethics of heritable human genome editing with the Comité Consultatif National d’Éthique pour les sciences de la vie et de la santé (French National Advisory Committee on Ethics in life sciences and health) and the Deutscher Ethikrat (German Ethics Council) we called on ‘all jurisdictions to bring heritable genome editing unambiguously within the control of relevant public authorities and to make its abuse subject to appropriate sanction.’
Though mistaken in both his assessments, Dr He’s ambition to use HHGE in a way that seemed to him to be both technically feasible and socially endorsed may nevertheless be explained, if not excused, as a reasoned approach to biotechnology innovation. The desire for genetic relatedness seems particularly strong in individualistic societies and in those that have either pronatalist or strong population control policies. The values associated with reproductive rights, the industry that exists to support them, and the implications of social attitudes to genetic relatedness and disability, which vary across cultures, are the heart of the broader discussion. These are issues that the new Global Observatory on Genome Editing expects to take up when it begins work with three meetings organised from Berlin later this week.
*Strictly speaking, this should be ‘… who are direct genetic descendants of both parents’: intra-familial gamete donation can preserve close genetic connections in cases of infertility.
Thanks for another great article. I am currently commencing my doctoral studies at UCL within the department of Science, Technology, Engineering and Public Policy. My thesis topic is on conducting primary research to better understand key stakeholder opinions around the topic of hGGe within the UK. Look forward to reading more of these blogs.