An ASGCT Perspective on the National Academies Genome Editing Summit
Authors: Theodore Friedmann
Journal: Molecular Therapy (2016)

The armamentarium of modern genetics and gene therapy has recently expanded with the rapid development of the tools of “genome editing,” including zinc-finger nucleases, TALENs, and CRISPR/Cas9 techniques that allow exquisitely targeted sequence modifications. An alluring application of such technology is somatic cell genome editing for the prevention and therapy of genetic disease. Most scientific, ethics, and policy agencies support somatic cell applications of genome editing; the gene therapy community has understandably taken deep interest because we represent the major biomedical conduit through which the technology will eventually be translated to clinical application. But it takes little imagination to recognize that there are other more contentious potential applications of genome editing, especially those related to the potential for germ-line modification. The recent publication of an article from China reporting an attempt to edit the human hemoglobin locus using CRISPR/Cas9 in early-stage human embryos added urgency to these concerns.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: 363-372Google Scholar In response, the American Society for Gene and Cell Therapy (ASGCT) and the Japanese Society of Gene Therapy (JSGT) issued a joint position statement last year supporting rigorous basic and clinical research to perfect safe and effective clinical applications of genome editing at the somatic cell level.2Friedmann T Jonlin EC King NM Torbett BE Wivel NA Kaneda Y ASGCT and JSGT joint position statement on human genomic editing Mol Ther. 2015; 23: 1282Abstract Full Text Full Text PDF Scopus (41) Google Scholar However, the statement expressed concern that genome editing in human gametes, zygotes, and embryos carries serious scientific, ethical, and societal implications. The statement noted that there is no broad scientific and societal consensus about these issues and that the effects of inherited genomic modification cannot readily be evaluated scientifically or ethically over the long time course of a reproductive human application. The poorly understood long-term effects of inherited human genetic modification could encourage unwise and ill-prepared manipulation of human genetic evolution, lead toward the highly contentious and fraught area of human genetic enhancement of normal human traits, and provide tacit rationalization of an illusory neo-eugenics movement. The Societies therefore recommended that clinical genome editing applications with reproductive potential should be disallowed, at least until a scientific and international societal consensus was reached regarding research on these approaches. An important next step occurred with the holding of a public forum at the US National Academy of Sciences 1–3 December 2015, the International Summit on Human Gene Editing, chaired by David Baltimore and sponsored by the US National Academy of Sciences, the US Academy of Medicine, the Chinese Academy of Sciences, and the Royal Society of London. The goal of the summit was to discuss the scientific, ethical, and governance issues associated with human gene editing research in an open and inclusive forum, and to develop scientific and policy recommendations on the means to move forward. Participants in the meeting included many of the scientists responsible for discovering and developing genome editing technology, ethicists, policy makers from around the globe, historians, physicians, disease and disability interest groups, and both the lay and scientific press. The sessions included detailed presentation and discussions of the scientific background and basic research aspects of gene editing technologies; the application of gene editing technology and human germ-line modification; societal implications of emerging technologies; the potential for application to somatic cell therapy; comparison of national US and international governance, regulation and control policies; and potential dilemmas related to equity. ASGCT member and leading gene therapy physician–scientist Adrian Thrasher served on the planning committee for the summit, representing the British Royal Society. Thrasher moderated a very important session on somatic gene editing, at which several ASGCT members spoke, including Matthew Porteus and Fydor Urnov. They and many other presenters eloquently explained that basic and clinical research on the use of somatic gene editing to treat human disease was already progressing, involved no new ethical or regulatory concerns, and should not be confused with germ-line gene editing. Other speakers contended that germ-line genetic modification by genome editing of gametes, zygotes, or embryos would not fill a compelling clinical need that could not be more efficiently filled by the currently available technology of pre-implantation genetic diagnosis and even by the rapidly increasing effectiveness of somatic cell gene therapy. That leaves only those rare cases involving two potential parents who are both homozygous for a genetic disorder and whose offspring would all be similarly affected. Admittedly, germ-line modification by genome editing might indeed offer a reproductive opportunity for such people, although those situations would be exceedingly rare. Another theme was the very disparate international philosophies, regulations, and funding of assisted reproductive technologies, which would be a component of any germ-line editing approach. Finally, there were extensive discussions on how or whether lines can be drawn between correction vs. “enhancement” of the germ line, how any such technologies could be applied equitably across the globe or even within technologically developed societies, and ways to reconcile germ-line editing with evolving concepts of disability. All slides and discussions from the general sessions of the summit can be viewed at http://www.nationalacademies.org/gene-editing/Gene-Edit-Summit/index.htm. Based on these presentations and discussions, the summit's planning committee formulated a series of recommendations for the development and human applications of genome editing.3The National Academies of Sciences, Engineering, and Medicine, 2015 On Human Gene Editing: International Summit Statement Press release <http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a> (3 December 2015)Google Scholar Next steps include review by the parent sponsoring societies and planned follow-up meetings to be sponsored by the National Academies. We summarize the central recommendations below. •Basic and preclinical research. Research on gene editing in both somatic tissues and human embryos or gametes was strongly supported, subject to appropriate legal and ethical oversight. The statement, however, warned: “If, in the process of research, early human embryos or germline cells undergo gene editing, the modified cells should not be used to establish a pregnancy.”•Clinical use: somatic. This section of the statement specifically stressed that valuable clinical applications in somatic cells are ongoing and should continue, singling out examples including treating sickle cell anemia or cancer via editing in blood cells. The statement indicated that research on the risks and benefits of somatic gene editing approaches should continue and that the existing regulatory framework developed for gene therapy is sufficient to encompass these approaches.•Clinical use: germ line. This section of the statement summarized the current scientific, practical, and ethical objections to human germ-line editing, including risks of passing on off-target effects, mosaicism, population risks from the introduction of genetic changes, considerations regarding implications for both the individual being treated and future generations, the impossibility of removing alterations once introduced, the possibilities that permanent genetic “enhancements” could exacerbate inequities or be used coercively, and the moral and ethical implications of purposefully altering human evolution. This central section of the statement concluded: “It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use.…However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.”•Future steps. The statement called for continued international discussion and cooperation to establish norms and harmonize potential acceptable uses of human germ-line editing, recommending that the sponsoring academies lead ongoing forums on these topics, continuing to bring together all nations and perspectives to address the evolving issues. The Genome Editing Summit has provided us with a prudent and cautious high bar that strives to protect legitimate and universally desired tools for amelioration of suffering while recognizing the deep ethical quandaries that accompany this new potential capability of shaping aspects of our human inheritance. Gratifyingly, these recommendations echo most of the recommendations proposed by the previous study of inherited genome modification carried out by the American Association for the Advancement of Science4Frankel MS Chapman AR Designing Our Descendants: The Promises and Perils of Genetic Modifications. Johns Hopkins Press, Baltimore, MD2003Google Scholar and the joint ASGCT/JSGT policy statement on the use of genome editing.2Friedmann T Jonlin EC King NM Torbett BE Wivel NA Kaneda Y ASGCT and JSGT joint position statement on human genomic editing Mol Ther. 2015; 23: 1282Abstract Full Text Full Text PDF Scopus (41) Google Scholar This is only the beginning of a long and complex process that will be influenced differently in different jurisdictions with disparate social, jurisprudential, and religious traditions. There will probably be no uniform final consensus, but the scientific and public discussion will point the way toward fruitful and beneficial uses of this powerful new technology. Interested parties and ASGCT members should plan to attend a special workshop on the topic of genome editing that will cover many of these issues and include presentations from leaders in the relevant scientific, ethical, and regulatory fields, to be held on 4 May 2016 as part of the 2016 ASGCT annual meeting in Washington, DC.