GENE EDITING: HOW CAN YOU ASK ‘WHETHER’ IF YOU DON’T KNOW ‘HOW’

Abstract

Though questions about whether gene editing should be done at all have dominated ethical discussion, a literature about how it can be done ethically has been growing. Work on responsible translational pathways for human germline gene editing has been criticized for focusing on the wrong questions. But questions about responsible translational pathways – questions about how gene editing could be done ethically – are in an important sense prior to questions about whether it is desirable and permissible. Asking ‘whether’ questions about gene editing requires a model of what responsible clinical use of gene editing would look like.

‘WHETHER’ AND ‘HOW’ QUESTIONS ABOUT GENE EDITING

The recent report from the joint US National Academy of Science/National Academy of Medicine/UK Royal Society International Commission on Human Germline Genome Editing (HHGE) is the latest entry in a developing literature on responsible translational pathways for germline gene editing.¹ Other commission reports, and parts of the academic literature, on gene editing have considered questions about translational pathways, but the HHGE report goes the furthest to date in considering the ins and outs of how gene editing could be implemented in clinical practice.² Up to this point, the majority of ethical discussion of gene editing has concerned itself with whether germline gene editing should ever be done. Debate has mostly unfolded along two axes: first, about the permissible goals of gene editing (whether it could be used to select traits for “enhancement”, or whether it should be restricted to “therapeutic” aims alone); and second, about whether gene editing would be consonant with moral commitments to autonomy, human dignity, and human rights.³

Less attention, on the other hand, has been paid to how – should it become technically feasible – gene editing could and should be done. Other “big statements” – from the US National Academies of Science, Engineering and Medicine, the UK Nuffeld Council, or the various statements calling for moratoria or intense examination of translational research on germline gene editing – have considered different issues involved with translational pathways for gene editing.⁴ But the HHGE report goes further in this direction – the aim of the report is to consider the technical issues for clinical implementation, and the myriad questions about the basic science, possible clinical applications, and clinical justifications for gene editing.⁵

Though the HHGE report bracketed questions about use of gene editing for enhancement and the like that have typically dominated the ethics of gene editing, the report touches on a few big ethical questions that are part the ethics of translational pathways for germline gene editing (most notably, it considers questions about clinical justification).⁶ Ethical debate about gene editing has mostly eschewed these sorts of issues involved with translational pathways, focusing instead on big picture questions about the downstream social impacts of gene editing, and whether germline gene editing should ever be done at all. This is different from other areas of biomedical ethics that engage with emerging technologies. For instance, on precision medicine and medical genetics, there is an enormous body of work on ground floor ethical issues such as what to do with incidental findings, protections for privacy, permissible uses of genetic information, communication of results and informed consent for research. There are still questions about whether genetics will ever be as useful for clinical application as the greatest cheerleaders of precision medicine claim.⁷ But there is not widespread doubt that there are significant questions not just about whether precision medicine is a worthwhile enterprise, but also how genetics could be applied in clinical settings ethically.

As the HHGE report shows, this neglect of ‘how’ questions for germline gene editing is beginning to change, as a literature on the ethics of taking gene editing into the clinic has begun to take shape.⁸ Interest has grown in charting, in the words of the Second International Summit on Human Germline Genome Editing’s Consensus Statement, a “rigorous, responsible translational pathway” for gene editing,⁹ an interested reflected in the HHGE report, which exhaustively details the current state of translational work on clinical application of germline gene editing and maps some of the necessary steps towards eventual clinical use.

SHOULD YOU ASK ‘HOW’ BEFORE YOU KNOW ‘WHETHER’?

This sort of work on charting a responsible translational pathway for gene editing has come in for serious and significant criticism.¹⁰ One argument advanced against this project is that it reverses the priority of the ‘whether’ and ‘how’ questions – asking how gene editing could ethically be done (that is, asking questions about responsible translational pathways) is not appropriate until we have some sort of consensus on whether it should be done in the first place. The central idea of this criticism is, as Françoise Baylis puts it, that

…the question about intent – is it ethical to proceed with human germline editing? – logically precedes the question about execution – how can we proceed ethically with human germline editing? Until the first question has been fully explored and authoritatively answered in the affirmative, the second question is moot.¹¹

Or in short: we shouldn’t bother with the ‘how’ until we have settled the ‘whether’.

Yet this is precisely what the HHGE report does. The most vivid example is the position on clinical justification staked out in the report, codified in Recommendations 4 and 5.¹² The HHGE report lays out specific general criteria (while also noting that no general criteria can be sufficient, as there will be particular differences that are relevant for assessing justification – this is stated in Recommendation 3) for any clinical use of gene editing to be justifiable, addressing issues such as clinical need, safety and efficacy standards, and acceptable genetic targets and outcomes. The HHGE report confines justifiable uses to those that target pathogenic genotypes, where germline gene editing is either the only or the best available therapeutic option, and where the outcome is to replace the pathogenic genotype with a non-pathogenic and common allele – to uses of gene editing for correction of pathogenic genotypes, in other words.¹³ The HHGE report recommendations on clinical justification assume that there could be a justifiable therapeutic use for gene editing, an assumption some argue depends on implicit value commitments about what does and does not count as a medical need, commitments that should be interrogated before we consider issues about clinical justification at all.¹⁴

There is something to these criticisms, as they are born from a very real worry that the world may be moving too fast towards clinical use of gene editing. But this is, however, precisely backwards. With gene editing, the ‘how’ question is prior to the ‘whether’ question. In order to ask whether gene editing should ever be done, we have to have some idea how gene editing could be ethically done. Until very recently, possible clinical use of gene editing has been completely speculative, and largely based on dystopian science fiction scenarios about runaway human enhancement and social control through biomedical technologies. We need a model of how gene editing could be done ethically that is based in scientific possibility and the context of reproductive medicine in order to responsibly consider, with a reasonable model of future clinical possibility, whether we should do it. In short, with germline gene editing, in order to ask ‘whether’, we first must have some idea ‘how’.

HOW CAN YOU ASK ‘WHETHER’ WITHOUT SOME IDEA ‘HOW’

Two reasons can be given in favor of reversing the priority of the ‘whether’ and ‘how’ questions. First, without a model of responsible clinical use of gene editing, any deliberation over whether it is permissible or desirable will inevitably rest on undischarged assumptions about future clinical applications. Any ethical clinical use of gene editing will need to answer questions about what conditions would be justifiable targets of gene editing-based interventions, who would be eligible, what criteria would determine whether gene editing is a better intervention than alternatives, and many others. Without some idea how a proposed application of gene editing would answer these questions, there is no real way to consider whether that application would be permissible or desirable, as permissibility and desirability depend heavily on how any proposed application answers these kinds of questions.

Consider concerns that widespread use of gene editing will create a kind of arms race, introducing new and more demanding norms of health that spur prospective parents to opt for more expensive (and so, less accessible) applications of gene editing to have “healthy” children.¹⁵ As Jodi Halpern and David Paolo state, “…parents may feel pressure to ensure that their children have ‘normal’ genetic profiles, as well as not have ‘serious’ or ‘preventable’ genetic diseases.”.¹⁶ This worry is predicated on assumptions about clinical justification for gene editing, specifically on what will count as an acceptable target for intervention. For example, one statement on potential use of germline gene editing, from the Quebec regional government’s Commission de l’éthique en science et en technologie, calls for restricting any future use of gene editing to “very serious, high penetrance diseases, where there are no other reproductive or therapeutic options available.”¹⁷ In Recommendations 4 and 5, the HHGE report adopts a very similar position on clinical justification, and presents a six-fold categorization schema for clinical justification that classifies the kinds of editing that could give rise to these worries about a genetic arms race to Category E, which the report argues should not be permitted at this time (and, really, for the foreseeable future, owing to numerous technical and ethical considerations).¹⁸ On this conception of clinical justification, the population eligible for gene editing would be extremely limited, and the targets of any interventions would arguably already be widely recognized and accepted pathogenic genotypes (such as the mutation in the HEXA gene that causes infantile Tay Sachs). It would be hard to imagine such a restricted use of gene editing giving rise to widespread anxiety among prospective parents about ensuring their children have a “normal” genetic profile. But other proposed applications of gene editing are more expansive and may well have these societal effects.¹⁹

In short, this worry, which influences whether we think gene editing is desirable or permissible at all, rests on hidden and undischarged assumptions about how gene editing would be done, specifically on questions about clinical justification –what conditions, which targets, under what circumstances and for which therapeutic goals, we would consider use of gene editing justifiable. How seriously we should take such worries is connected to answers we give to these questions. We cannot ignore these ‘how’ questions, as the ‘whether’ question depends on assumptions – acknowledged or not – about the ‘how’.

IF THERE IS NO ‘HOW’, THERE IS NO POINT IN ASKING ‘WHETHER’

Second, if it is not possible to ethically do gene editing, then it doesn’t really matter whether we think we should move forward with it. We could envision all sorts of applications for germline gene editing – if these violate ground floor requirements of research ethics and clinical ethics in reproductive medicine, then it shouldn’t be done no matter how wonderful the outcomes of these applications could be, full stop. If we do not know if gene editing can be done ethically, then it is a moot point whether it is desirable or will lead to dystopian social outcomes – it simply cannot be done.

One area in which this issue is most acute is in determining standards of safety and efficacy for moving gene editing into human subjects research. As has been well-documented, there is significant danger of off-target effects and genetic mosaicism involved with use of the most promising technique for germline gene editing – CRISPR – on germline cells, and most experiments have shown that, though editing of targeted stretches of DNA via CRISPR-associated nucleases is possible, the rate of off-target effects is unacceptably high.²⁰ This remains a stubbornly persistent problem, even as translational work has advanced on other fronts. As the recent controversy over the role of homology directed repair in knitting double-strand breaks in developing embryos has shown, this is (maybe) not just a matter of overcoming some technical hurdles, but rather of getting a more complete understanding of the mechanisms of DNA repair in embryogenesis.²¹

There is an analogy here with the situation facing translational research on somatic gene editing during the 1990’s and early 2000’s. Initial attempts to move somatic gene editing into the clinic were disastrous. In the wake of these failures, more work and resources were devoted to understanding the basic biology involved in somatic gene editing, which greatly improved understanding of the underlying cellular mechanisms.²² Fundamental ethical commitments regarding safety of research subjects, which were treated cavalierly in early somatic gene editing research, required a return to the drawing board, and the resulting improvement in prospects for somatic gene editing as a consequence of this are plain for all to see. For somatic gene editing, ‘whether’ and ‘how’ questions were and continue to be tackled together, and the result has not only been technical improvements that have led, ultimately, to the introduction of safe and effective somatic gene editing interventions for clinical use, but also significant reflection on acceptable targets and goals for gene therapies.

The current situation for germline gene editing resembles that for somatic gene editing in the late 1990’s, in that much more work needs to be done to understand the biology, and to get germline gene editing to meet technical benchmarks for accuracy. Only if that happens can germline gene editing be considered safe and effective enough to consider human subjects research. This is not just a technical issue; it also involves significant ethical questions, about risk, construction of trials, follow-up of research subjects (potentially for multiple generations), and others.²³ Gene editing may never actually meet these technical requirements, and even if it does, it may be the case that human subjects research can never be conducted ethically. If so, then it is a moot point whether gene editing is desirable or permissible: it simply can’t be done. This is not an unfamiliar situation – there are many things that may be technically possible and may have some medical benefit (such as human cloning via somatic cell nuclear transfer) that we do not believe are ethically permissible at this time, and so – regardless of said potential benefits – we do not do.

Work on ethical questions about what levels of accuracy are appropriate, what levels of risk can be metabolized given the possible clinical benefits of gene editing, and what applications would be appropriate given these levels of risk is, then, in one sense prior to questions about whether we should do gene editing at all. If we don’t know that it can meet these ground floor ethical requirements, then it doesn’t really matter whether we do or do not want to do it – it just can’t be (ethically) done. Questions about safety, efficacy, and risk are necessary preparatory work for asking more substantive ethical and philosophical questions about gene editing.

CONCLUSIONS

Part of the motivation for the criticism of pursuing ‘how’ questions most likely resides in the worry that if we have mapped out a responsible translational pathway for gene editing, then the ‘whether’ questions will get pushed to the side.²⁴ This should not happen, under any circumstances. The bioethical consensus – that public engagement, discussion, and an inclusive democratic process to sort through the many issues involved is a requirement for proceeding with gene editing – is at this point overwhelming. What this worry shows is that there is a significant question in the ethics of gene editing that is neither of the ‘whether’ or ‘how’ variety – the question, rather, is: can we continue with research and continue to consider the myriad ethical issues involving gene editing without closing off possibilities to say “Stop!” to any future clinical use of the technology? This is a significant issue in its own right that deserves serious attention. It is also, for what it’s worth, a significant and serious question about emerging technologies generally. Given the importance from all angles of issues involving AI, blockchain, gene therapy, and other emerging technologies to broader social, economic, and political currents in our world today, it has a good claim to be one of the more significant philosophical questions of our time.

One way to approach this issue is to consider what the results of prioritizing ‘whether’ or ‘how’ questions about gene editing would be, and how these results could aid in any decision-making about whether to proceed with translation of gene editing into the clinic. The now infamous He Jiankui case gives us some reason to think that charting responsible translational pathways for gene editing is necessary to retain the option to stop translation altogether. As this case showed, a blanket moratorium was clearly insufficient to prevent a patently unethical use of gene editing.²⁵ The result of a serious public debate about whether gene editing is permissible or desirable, based only on undischarged assumptions about what could happen if translation moved forward, would only either end in another blanket moratorium or a clearing of normative and conceptual space to consider the many unanswered questions about the requirements for permissible gene editing. The result of the alternative process charted here – consider what a responsible translational pathway would look like, then take this as a model to ask whether it should be done at all – presents more specific guidelines (in the form of answers to significant ethical questions about responsible use of gene editing) that can be used to shape regulation and international ethical frameworks.

Whether these frameworks would be effective at severely restricting or stopping altogether unethical use of gene editing remains to be seen; there are some reasons in favor of such an approach, given the success of analogous regulatory regimes and ethical frameworks in areas such as stem cell biology.²⁶ Given that a blanket moratorium has already proven to be ineffective, it is time to pursue alternatives. Translation of gene editing into the clinic should not proceed under any circumstances unless there is extensive, inclusive, and transparent public discussion about whether it is permissible and desirable (a model for this may be the UK’s experience with mitochondrial replacement therapy, which went through such a public consultation process before it was approved for clinical use).²⁷ But in order to consider whether to proceed, we need to have some idea what responsible translation of gene editing into the clinic would look like. Only with some model of a responsible translational pathway and ethical clinical use of germline gene editing can we know what we are arguing about in the first place.