Gene Editing and Germ-line Intervention: The Need for Novel Responses to Novel Technologies
Authors: Courtney Addison, Samuel Taylor-Alexander
Journal: Molecular Therapy (2015)

The report by Liang and colleagues1Liang P Xu Y Zhang X Ding C Huang R Zhang Z et al.CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.Protein Cell. 2015; 6: 363-372Crossref PubMed Scopus (752) Google Scholar in April of this year describing gene editing in human embryos creates problems that stretch beyond the labs and clinics of expert geneticists. Flotte2Flotte TR Therapeutic germline alteration: has CRISPR/cas9 technology forced the question?.Hum Gene Ther. 2015; 26: 1-2PubMed Google Scholar writes that the experiment has “forced researchers, clinicians, and ethicists to face the issue of therapeutic germ-line alteration with renewed energy,” while Frederickson and Ylä-Herttuuala3Frederickson R Ylä-Herttuuala S Molecular Therapy special issue on gene editing technologies and applications.Mol Ther. 2015; 23: 1279Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar have acknowledged the “challenging ethical issues” raised by gene editing more generally. Although most commentators agree that public involvement in the debate ought to be encouraged,4Ellis K Terry SF Dangerous liaisons: connecting CRISPR/Cas9 to clinical science.Genet Test Mol Biomarkers. 2015; 19: 409-410Crossref PubMed Scopus (3) Google Scholar,5Friedmann T Jonlin EC King NMP Torbett BE Wivel NA Kaneda Y et al.ASGCT and JSGT joint position statement on human genomic editing.Mol Ther. 2015; 23: 1282Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,6Lanphier E Urnov F Haecker SE Werner M Smolenski J Don't edit the human germline.Nature. 2015; 519: 410-411Crossref PubMed Scopus (336) Google Scholar there have been few concrete recommendations of how this should be achieved. A noteworthy exception is Porteus and Dann,7Porteus MH Dann CT Genome editing of the germline: broadening the discussion.Mol Ther. 2015; 23: 980-982Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar who suggest using conferences and societies as mediators and/or venues for discussion. We contend that the response of the scientific community to the debate on gene editing could and should be optimized. Specifically, we identify two key issues: first, the potential marginalization of perspectives from outside the scientific community; and second, an overly linear model of ethical review and governance. If unresolved, these issues risk limiting regulatory and scientific developments in the field. They also present an opportunity for dialogue that can enhance the impact of gene editing on patients’ lives, render the field more responsive to the public's needs, and foster trust among stakeholders. Liang et al.1Liang P Xu Y Zhang X Ding C Huang R Zhang Z et al.CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.Protein Cell. 2015; 6: 363-372Crossref PubMed Scopus (752) Google Scholar used CRISPR/cas9 to edit the β-globin gene of 86 nonviable human embryos. In 26 cases the gene was cleaved successfully, but efficiency was low (52%) and was accompanied by substantial off-target effects and mosaicism. These and other detrimental effects or inefficiencies noted elsewhere (zygote viability, allelic variegation) effectively limit the human applicability of germ-line editing using current technology.7Porteus MH Dann CT Genome editing of the germline: broadening the discussion.Mol Ther. 2015; 23: 980-982Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The principal investigator of Liang and colleagues’ study, Junjiu Huang, concluded that the work was “too immature” to pursue clinically.8Cyranosky D Reardon S Embryo editing sparks epic debate.Nature. 2015; 520: 593-595Crossref PubMed Scopus (33) Google Scholar The paramount concern of most scientific parties is whether it is appropriate to target the human germ line with precise editing techniques. Recent commentaries, including a joint statement by the ASGCT and JSGCT,5 argue that germ-line alterations ought to be restricted to model organisms. Genome editing impinges upon ideas of relatedness and heritability,9Franklin S Roberts C Born and Made. Princeton University Press, Princeton, NJ2006Crossref Google Scholar as well as access to treatment and exposure to experimentation.10McGowan ML Fishman JR Lambrix MA Personal genomics and individual identities: motivations and moral imperatives of early users.New Genet Soc. 2010; 29: 261-290Crossref PubMed Scopus (109) Google Scholar DNA is culturally loaded, and editing it will have implications for concepts of life, “humanness,” and biology in general.11Nelkin D Lindee S The DNA Mystique. WH Freeman, New York1995Google Scholar,12Lock M Comprehending the body in the era of the epigenome.Curr Anthropol. 2015; 56: 151-177Crossref Scopus (114) Google Scholar More practically, the low cost of CRISPR raises questions about who has the right to use novel genetic technologies, and how. The study by Liang et al. appeared following Lanphier and colleagues’ suggestion of a moratorium on human germ-line editing,6Lanphier E Urnov F Haecker SE Werner M Smolenski J Don't edit the human germline.Nature. 2015; 519: 410-411Crossref PubMed Scopus (336) Google Scholar and Baltimore and colleagues’ call for a more open dialogue on the subject.13Baltimore D Berg P Botchan M Carroll D Alta Charo R Church G et al.A prudent path forward for genomic engineering and germline modification.Science. 2015; 348: 36-38Crossref PubMed Scopus (429) Google Scholar In the United States, the National Academies of the Sciences (NAS) and Medicine (NAM) have resolved to convene a discussion focused on the issues posed by gene-editing technologies, by means of an international summit and study committee.14Cicerone RJ Dzau VJ National Academy of Sciences and National Academy of Medicine announce initiative on human gene editing.News from the National Academies. 2015; (<http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=05182015> (18 May 2015))Google Scholar Their announcement references the 1975 Asilomar meeting that established frameworks for using recombinant DNA, and states that they will work “in keeping with these past efforts.” As other scholars15Hurlbut JB Jasanoff S Kim S Remembering the future: science, law, and the legacy of Asilomar.Dreamscapes of Modernity. University of Chicago Press, Chicago2015: 126-151Google Scholar,16Jasanoff S Designs on Nature. Princeton University Press, Princeton, NJ2005: 42-67Google Scholar have argued, however, Asilomar was a fait accompli for all but the select group who were invited. Setting up a separate expert forum to precede public consultation reproduces divides between the scientific community and diverse stakeholders. Thus, although successful in creating a governing framework, as an exercise in democracy it was less convincing. Porteus and Dann7Porteus MH Dann CT Genome editing of the germline: broadening the discussion.Mol Ther. 2015; 23: 980-982Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar also note that a single-meeting model like this would probably be insufficient to accommodate the necessary stakeholders today. We raise this point not to criticize previous efforts but to stimulate alternative responses that evolve and respond to the unique aspects of the problem and context in question. The current response to advances in gene-editing technology has two critical shortcomings that we discuss below, along with possible solutions. First, the structure of the debate risks marginalizing the perspectives of citizens and other key stakeholders. The committee nominated by the NAS and NAM comprises 14 members: 13 scientists and/or physicians, and 1 law/bioethics scholar.17National Academies of Sciences, Engineering, Medicine Advisory group for human gene editing initiative named.News from the National Academies. 2015Google Scholar The incorporation of diverse perspectives into biomedical and ethical decision making has been shown to result in greater trust in science in and after times of controversy.18Saha K Hurlbut JB Research ethics: treat donors as partners in biobank research.Nature. 2011; 478: 312-313Crossref PubMed Scopus (39) Google Scholar Scholars from other disciplines are also absent from these early discussions and could offer a more nuanced appreciation of the issues at stake so as to facilitate public involvement. Achieving this requires a genuinely engaged dialogue between scientists, scholars, physicians, and patient groups and other members of the public. We acknowledge concerns within the scientific community that such deliberations might be derailed by individuals with extreme viewpoints. A combination of randomized sampling, open public submissions, and judiciously chaired discussion can ensure a debate that is inclusive of alternative views, without being prohibitively broad. Patients and their families are the group most likely to first receive gene editing. They deserve a platform from which their needs and interests can be heard. This could take the form of focus groups, conducted by social scientists and sampled from existing registries of genetic disease carriers. People less immediately invested in genetic research also ought to be consulted because forays into the human genome theoretically implicate all of us. Randomly sampled questionnaires could be used to gauge public sentiment in a time-effective fashion. Funding should be allocated for these purposes. Investments made now will no doubt pay off over time in mistakes avoided, and will most likely be small compared with probable future investment in gene editing. A first step would be to invite a social science presence onto the NAS/NAM advisory committee, as has been done by the Nuffield Council on Bioethics working group in the United Kingdom.19Nuffield Council on Bioethics Genome editing working group announced. 2015Google Scholar Second, existing governance mechanisms try to preempt trouble and in doing so limit the iterative ethical reflection necessary for the sound development of novel scientific fields. The ELSI (Ethical, Legal and Social Implications) paradigm is a prime example of this. ELSI assumes that ethical issues are consequences rather than ongoing dilemmas.20López JJ Lunua J ELSIfication in Canada: legal modes of reasoning. Pitfalls in assessing high technology futures.Sci Cult. 2012; 21: 77-99Crossref Scopus (26) Google Scholar But attempts to establish a fixed governance model early on struggle to accommodate the inevitable iterative nature of research, from bench to bedside and back.21Williams R Compressed foresight and narrative bias: pitfalls in assessing high technology futures.Sci Cult. 2006; 15: 327-348Crossref Scopus (62) Google Scholar,22Laurie G Harmon SHE Cloatre E Pickersgill M Through the thicket and across the divide..Knowledge, Technology & Law. Routledge, New York2015: 121-136Google Scholar Furthermore, as Friedmann et al.5Friedmann T Jonlin EC King NMP Torbett BE Wivel NA Kaneda Y et al.ASGCT and JSGT joint position statement on human genomic editing.Mol Ther. 2015; 23: 1282Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar point out, this early ethical assessment is simply not possible for germ-line gene editing, the effects of which may not arise for decades after application. The challenge is thus to develop a model that can produce early-stage hypotheses of ethical issues that might arise but that can also respond to the field as it evolves. This is an issue of both timing and scope. The brunt of ethical evaluation is concentrated before a trial begins, and it is conceptualized narrowly, in terms of risk, benefit, serious adverse events, and other familiar (reified, some might argue) terms. The challenge, as Williams21Williams R Compressed foresight and narrative bias: pitfalls in assessing high technology futures.Sci Cult. 2006; 15: 327-348Crossref Scopus (62) Google Scholar notes, is to avoid reductive and functionalist interpretations while addressing “the serendipity of innovation processes and their outcomes.” One way of doing so is to build long-lasting partnerships between the natural and social sciences, so that ethical evaluation is not just conducted at the beginning of projects and reported on later, but is woven throughout research processes. This will require a commitment from researchers to engage with alternative scholarly methods and theories, and that commitment in turn will require institutional support, as mentioned above. This move may also enrich the ways we speak about ethics. There is an entire area, for example, of anthropological ethics, which empirically examines how ethics manifest in people's routine conduct and interactions. Oversight of new technologies tends to be time-consuming, costly, and bureaucratic.22Laurie G Harmon SHE Cloatre E Pickersgill M Through the thicket and across the divide..Knowledge, Technology & Law. Routledge, New York2015: 121-136Google Scholar The National Institutes of Health Recombinant DNA Advisory Committee has recently had its remit over gene therapy restricted—not for the first time—to reduce overlap with other regulatory bodies.23Federoff HJ Wagner JE The evolution of gene transfer, gene therapy, and the RAC: IOM recommendations to the NIH director.Mol Ther. 2014; 22: 685-686Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Similarly, the United Kingdom's ethics procedure was restructured in 2012 to streamline protocol assessments.24National Health Service Health Research Authority New arrangements for the Gene Therapy Advisory Committee (GTAC).NHS HRA News. 2012Google Scholar Such changes may work for gene therapy, which has been under way for some time now, but they will probably not suffice for more precise, developing techniques. Effective strategies must be implemented that both foster development of gene-editing technologies and ensure their rigorous oversight. We contend that investing in the above-mentioned deliberations both before and as gene editing advances, will pay off in more effective governance of subsequent research; it may well save time, money, and mishap in the long run. Perhaps more importantly, it would make the innovation process more democratic and acceptable to all. Useful insights may also be gleaned by looking outside of the biosciences, or to parallel conversations. Camporesi, for example, looks to environmental justice to suggest that liability in cases of gene doping should fall to the sponsor.25Camporesi S From Bench to Bedside to Track and Field. University of California Medical Humanities Press, San Francisco, CA2014: 111-128Google Scholar She thus presents an alternative model of accountability that could make gene transfer in the sporting world more amenable to control. Increasing the range of voices contributing to gene-editing debates expands the intellectual resources available to all and better equips us to navigate future challenges. To summarize, we encourage the following steps. First, social scientists ought to be invited to contribute to the NAS/NAM international summit in December. Second, before then a discussion needs to begin about how to position patients and the broader public as formative contributors to this and subsequent debates; we have suggested that mixed methods with geographically dispersed consultation should be the first stage of this. Third, mechanisms should be put in place to facilitate ongoing iterative debate between diverse parties, to ensure that regulation develops concomitantly with changes in the field. We urge people to think widely and resourcefully here; a collaborative, interdisciplinary online space dedicated to tracking the field's development may be useful, as might a series of biannual review meetings with a changing host of contributors. What we hope to elicit from this commentary is a critical, creative engagement with both the problem at hand and the response to that problem. Advances in science and technology deserve and demand discussions that are as innovative as the advances themselves. Such a model will not be established overnight, and certainly not in the space of this Commentary, but it should be established before the summits and committees convene. C.A. is a member of the Consortium for Designer Organisms, which is funded by the University of Copenhagen's Excellence Programme for Interdisciplinary Research. S.T.-A is funded by Wellcome Trust Senior Investigator Award No: WT103360MA, “Confronting the Liminal Spaces of Health Research Regulation”, PI: Graeme Laurie. The authors thank Sylvia Camporesi (Kings College London) for thoughtful feedback on an earlier version of this manuscript. The authors have no conflicts of interest to declare.