WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing Background Paper Governance 1 Human Genome Editing Dr Emmanuelle Tuerlings This background paper was commissioned by the World Health Organization to serve as a background document for the first meeting of the Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing (18-19 March 2019). This background paper aims at providing an overview of the governance issues around human genome editing and is not intended to offer any policy conclusions or recommendations. The author would like to thank the Committee’s members for their inputs on the background paper as well as Dr Piers Millett for his comments on an earlier version of this paper. 1 Table of contents 1. INTRODUCTION 3 2. HUMAN GENOME EDITING AND APPLICATIONS 5 Definition of genome editing 5 Applications in human somatic and germline cells 6 Basic research using genome editing in human somatic cells and germline cells 6 Genome editing clinical applications using somatic cells 8 Genome editing clinical application using human germline cells 8 3. KEY ISSUES ASSOCIATED WITH HUMAN GENOME EDITING 10 Technical issues of genome editing 10 Ethical, social and governance issues 11 Ethical considerations 11 Governance considerations 13 Human enhancement and eugenics 17 Security implications 17 4. POLICY OPTIONS AND STAKEHOLDERS 18 Background 18 Existing oversight regimes applying to somatic and human germline cells 20 Regulation of research on germline cells and human embryos using genome editing 20 Regulation of research and applications on somatic cells using genome editing 22 Genome editing applications on human germline cells 23 Proposed additional policies on genome editing 25 Review of existing regulations and development of standards for safety and efficacy for genome editing 26 Moratorium 27 Public engagement and ongoing public dialogue 28 Development of principles and specific regulatory mechanisms for governing human genome editing 31 REFERENCES 32 2 1. Introduction In recent years, rapid advances have taken place in the science and technology of genome editing. While technologies for manipulating DNA have been developed since the early 1970s with the breakthrough of recombinant DNA, making “site-specific modifications in the genome of cells and organisms remained elusive” (Doudna JA, Charpentier E, 2014) and most of the methods did not achieve “a high degree of fit, precision or specificity” (Reich J et al., 2015). Genome editing technologies, or “gene scissors”, and particularly the discovery of CRISPR-Cas91, are new methods that have accelerated progress in this area. They offer important opportunities to improve the understanding of human disease and health and have also opened new avenues for research and applications in plants and animals, raising the interests of the biotechnological and private sectors. Their specificity, rapidity, simplicity and relatively low cost compared to other genetic engineering techniques have greatly contributed to their success and their integration into everyday laboratory practices. However, the use of genome editing in human applications has raised profound concerns, in particular because of the potential of genome editing to modify the human germline and thereby transferring genome edits to future generations with unpredictable consequences. In April 2015, the publication of a study (Liang P et al., 2015) carrying out changes in the human genome of non-viable human embryos using CRISPR-Cas9 highlighted considerable safety, ethical, social and legal concerns (Cyranoski D, Reardon S, 2015). Subsequent experiments using a variety of genome editing methods in early human embryos have revealed their potential both for basic discovery and as a way to avoid genetic disease, but these have also highlighted problems that need to be solved before any clinical application should proceed. Moreover, in November 2018, a Chinese scientist announced the birth of twin girls whose genome had been edited, using CRISPR-Cas9, to disable a gene called CCR5 that encodes a protein, which is used by HIV to enter cells (Cyranoski D, Ledford H, 2018). Going several steps further and leaving a pure research context to one involving an application, these controversial experiments provoked international condemnation (Second International Summit on Human Genome editing, 2018; Cyranoski D, Ledford H, 2018; Collins FS, 2018b; ECEPAS, 2018; ARRIGE, 2018; CBE, 2019). The advent of genome editing has challenged researchers, scientific communities, ethicists, policymakers and the public to think about the appropriateness of existing oversight and ethical frameworks to govern genome editing and triggered debates about the ethical, legal and wider societal implications of genome editing technology. In addition, there is concern that the science and innovation of genome editing is moving ahead of public understanding and policy (Nuffield Council on Bioethics, 2016). This background paper focuses on the governance issues associated with human genome editing.2 Section 2 briefly defines the concept of genome editing and describes its different methods. The section then reviews current and potential applications of genome editing in somatic and in germline cells. Section 3 subsequently reviews some of the key ethical, social and governance issues associated with the use of genome editing in somatic and germline cells as well as in basic research and clinical applications. Section 4 examines the existing governance mechanisms and proposed policy options suggested so far by different stakeholders, including the scientific communities, bioethicists and policymakers. The potential of genome editing and its associated benefits and concerns has prompted the holding of national and international debates, for example the two International Summits on Genome Editing of 2015 and 2018, and has led national academies, scientific and international organizations, scientists and bioethicist to express their views through the publications of reports, statements and policy papers. The literature review of this background paper is based on these different sources. 1 The CRISPR-Cas9 stands for clustered regularly interspaced short palindromic repeat (CRISPR) RNA and CRISPR- associated protein 9 (Cas9). (Doudna JA, Charpentier E, 2014; Hsu PD et al., 2014). 2 See Background Paper 2 for the non-human applications of genome editing. 3 It has been underlined that genome editing brings old issues into a new reality, and that technological progress in genetics brings profound challenges and new regulatory requirements to protect individuals (UNESCO, 2015). Likewise, it has been pointed out that while many issues in the sector of human health are similar to the ethical literature around human genetics, genome editing and its associated scientific development are nevertheless raising important conceptual questions (Nuffield Council of Bioethics, 2016). Likewise, in for instance the food sector, the developments in genome editing may bring additional factors into consideration or change the parameters of debate (Council of Bioethics, 2016). One question that has guided the literature review is therefore whether genome editing brings new governance challenges and, and if so, what these are according to the genome editing’s field of applications. In this regard, it has been previously pointed out that many emerging technologies cause social concerns, but “experience teaches that the social and ethical issues arising from the application of new technologies are rarely new or unique to that technology.” (EASAC, 2010). Notwithstanding, irrespective of whether there are new or old social and ethical issues, it has been recognized that these must be addressed (EASAC, 2010). Finally, because the human genome does not have national boundaries (UNESCO, 2015; International Summit on Human Gene Editing, 2015), the governance of genome editing and its implications for societies calls for an inclusive and international perspective, regardless of whether or not countries are currently doing research and applying genome editing. 4 2. Human genome editing and applications Definition of genome editing With the advent of recombinant DNA technology3 in the early 1970s, it became possible to combine different pieces of DNA from two or more species and to insert them into a host organism. The applications of this technology have been multidisciplinary, ranging from medicine, agriculture, animals and the environment. While the technologies for making and manipulating DNA have enabled many advances in biology over the past 60 years (Doudna JA, Charpentier E, 2014), more recently, new genome editing tools, which involve site-specific nucleases (sometimes referred to colloquially as “gene scissors”), have been developed.4 Genome editing techniques comprise a group of technologies that can precisely add, remove and alter selected DNA sequences at a specific location of the genome compared to earlier techniques. The development of these recent techniques, especially the system CRISPR-Cas9 (Doudna JA, Charpentier E, 2014; Hsu PD et al., 2014)5 and, more generally CRISPR-Cas systems and their derivatives, has been reported as making the editing of the human genome much more accurate (specific), simpler, faster, more efficient (in terms of success per attempt) and less expensive than previous methods. The advent of CRISPRC-Cas9 has been described as “transforming