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 biology” (Doudna JA, Charpentier E, 2014). Nevertheless, there are still a number of technological risks, including the possibility of incorrect on-target events, off-target events6 and mosaicism.7

More precisely, genome editing8 has been defined as:

• “the practice of making targeted interventions at the molecular level of DNA or RNA function, deliberately to alter the structural or functional characteristics of biological entities.” (Nuffield Council on Bioethics, 2016); • “the deliberate alteration of a selected DNA sequence in a cell, using site-specific DNA nuclease enzymes” (EASAC, 2017); • “the processes by which the genome sequence is changed by adding, replacing, or removing DNA base pairs.” (NASEM, 2017); • Genome editing methods can also change the expression of genes without cutting the DNA sequence (Qi LS et al., 2013). This can be achieved by deactivating the Cas9 enzyme (‘dead’ nuclease or dCas9) and by bringing a transcriptional activator, repressor or chromatin modifying protein specific sequences within the genome (Gilbert LA et al., 2013; Liao HK et al., 2017).

These targeted alterations can be achieved by using different genomic editing techniques.9 The meganucleases, the Zinc Finger Nucleases (ZFNs), the Transcription Activator-Like Effector Nucleases (TALENs) were respectively discovered in 1994, 2005 and 2010. More recently, in 2012, the CRISPR-Cas9 system was understood sufficiently well to be adapted for use in essentially any organism (Doudna, Charpentier, 2014; Hsu et al. 2014). The CRISPR was originally discovered in the bacterium Escherichia coli in 1987 (Ishino Y et al., 1987), and later on, in 2007, it was found that CRISPR exist in many bacteria and archaea as a part of their immune system to protect against bacteriophage infections (Barrangou R et al., 2007; Leopoldina et al., 2015).

3 Recombinant DNA is “the term given to some techniques of molecular biology and genetic engineering which were developed in the early 1970s. In particular, the use of restriction enzymes, which cleave DNA at specific sites, allow sections of DNA molecules to be inserted into plasmid or other vectors and cloned in an appropriate host organism (e.g. a bacterial or yeast cell).” (WHO, 2002). 4 The first version of “gene scissors”, restriction endonucleases, were discovered more than 40 years ago (Leopoldina et al., 2015). For more about the history of genome engineering and the history and biology of CRISPR-Cas systems, see Doudna JA, Charpentier E, 2014. 5 For the CRISPR-Cas9 patenting dispute, see Nuffield Council on Bioethics, 2016. 6 Off-target effect: “A direct or indirect, unintended, short- or long-term con• sequence of an intervention on an organism other than the intended effect on that organism” (NASEM, 2017). 7 Mosaicism: “Variation among cells, such that the cells are not all the same— for example, in an embryo when not all the cells are edited.” (NASEM, 2017). 8 For a review of the concept of genome editing and its difference with ‘gene editing’ and for a review of the terms of gene, genome and epigenome, see Nuffield Council on Bioethics, 2016. 9 For a review of the techniques of genomic editing (Nuffield Council on Bioethics, 2016; NASEM, 2017).

5 Compared to previous methods of genome editing, the CRISPR-Cas systems and their derivative or related methods use RNA sequences instead of protein segments to recognize the specific DNA sequence and the nuclease with which these interact, such as the Cas9 enzyme, which makes a double-stranded cut in the DNA at the targeted location. Once the DNA is cut, the cells will use one of several of their own DNA repair mechanisms, commonly leading to a small deletion or insertion unless researchers have also added a customized DNA sequence (“DNA template”) which can replace the original DNA segment with a new one. These genome editing techniques can make precise changes in the genome, including deletions, substitutions or insertions of anything from a single base pair to many 1000s of base pairs. Genome editing techniques, and mainly CRISPR-Cas9, have been described as a transformative biotechnology (Nuffield Council on Bioethics, 2016), game- changing advance (NASEM, 2017), a revolutionary technology (FEAM, 2017), and a powerful technology (The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015) that are “revolutionising molecular biology research.” (Leopoldina et al., 2015).

Applications in human somatic and germline cells

Genome editing technologies can be used in basic research, preclinical research and clinical applications10 and in both human somatic cells (non-reproductive cells) and human germline cells (early embryos or in eggs, sperm and their precursors). It has been underlined by several reports that it is critical to make these distinctions clear for the development of oversight mechanisms as well as in public engagement initiatives (Reich J et al., 2015; The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015; FEAM, 2017; EASAC, 2017). Different applications of genome editing may raise, for instance, different ethical and legal issues.

• Human somatic cells comprise the nonreproductive cells or tissues of an organism such as skin, liver, lung, and heart cells (NASEM, 2017). Clinical interventions using genome editing in somatic cells affects only the cells of the patient and are not hereditary (Leopoldina, 2015). • Human germline cells comprise the reproductive cells, including human embryos, eggs cells, sperm cells, and their precursor cells (NASEM, 2017). Clinical interventions using genome editing in germline cells may not only affect the cells of the individual brought into existence, but genetic modifications could also be passed on to the next generation.

But while the ethical and legal issues raised by genome editing might differ according to their field of applications, it has also been pointed out that the boundary, between for example, “somatic and germline cells is not 100% impermeable in principle”. (Garden H, Winickoff D, 2018). Similarly, some have questioned “whether this differentiation between somatic and germ line therapy can be upheld and whether germ line effects must also be strictly ruled out in conjunction with somatic gene therapy or could be tolerated as the side-effects of a therapy.” (Reich J et al., 2015).

Basic research using genome editing in human somatic cells and germline cells

Genome editing methods are currently being used in basic research as well as in many commercial applications and in applied and industrial efforts.11 In general, it has been reported that the application of genome editing techniques in basic research, conducted on human somatic cells and tissues or on germline cells can provide a better understanding of human cells and tissues; diseases, and regenerative medicine, and of mammalian reproduction and development (NASEM, 2017). Moreover, the precision and efficiency of the new techniques allow research to be conducted on the functions of genes and gene variants that were until now poorly understood, as well as their interactions with gene networks (Leopoldina et al., 2015). Indeed, it has been underlined that genome editing “plays an

10 The terms R&D (Research and experimental development) covers three activities: “Basic research is experimental or theoretical work undertaken primarily to acquire new knowledge of the underlying foundations of phenomena and observable facts, without any particular application or use in view. Applied research is original investigation undertaken in order to acquire new knowledge. It is, however, directed primarily towards a specific, practical aim or objective. Experimental development is systematic work, drawing on knowledge gained from research and practical experience and producing additional knowledge, which is directed to producing new products or processes or to improving existing products or processes.” Frascati Manual 2015, OECD 2015 (http://www.oecd.org/sti/inno/Frascati-2015-Glossary.pdf, accessed 28 May 2019). 11 For a review of the types and purposes of basic research involving human genome editing, see NASEM, 2017; Nuffield Council on Bioethics, 2016. For a review of on the application of genome editing in somatic cells, see FEAM, 2016; FEAM 2017 and the meetings summaries of the International Summit on Human Gene Editing of 2015 and 2018.

6 important role in driving scientific research into the functions of specific genes, genetic variations and genetic interactions, leading to significant advances in our knowledge.” (KNAW, 2016).

Genome editing research using human cells, tissues, embryos and gametes may therefore not only improve the understanding of human gene function but also DNA-repair mechanisms, genomic rearrangement, early human development, the links between genes and diseases, and diseases such as cancer and other genetic diseases (NASEM, 2017). Genome editing techniques have also enabled modifications in human embryonic stems cells and induced pluripotent stem cells. Genome editing research may also improve the understanding of human development, thereby leading to improve IVF procedures and embryo implantation rates and decrease the rates of miscarriage. It could therefore lead to enhanced fertility treatment (NASEM, 2017).

With the arrival of CRISPR-Cas9 and other CRISPR-Cas systems and their derivatives, research is also expected to focus more on modelling a greater variety of diseases, including ‘rare’ diseases (Nuffield Council on Bioethics, 2016). Likewise, it is reported that the possibility of introducing simultaneously several targeted genetic modifications could also allow for the reconstruction of complex genetic syndromes or human multi-factorial diseases such as Alzheimer’s disease or cardiovascular disease in model organisms (Leopoldina et al., 2015).

In 2015, Chinese scientists published the results of experiments using genome editing to alter genes responsible for a genetic blood disorder known as thalassemia in human embryos (Liang P et al., 2015).12 The aim of the research was to develop fetuses free of this hereditary disease (Danish Council on Ethics, 2016). The following year, in 2016, another Chinese research group reported in an article the use of genome editing as a way to introduce into early human embryos a naturally occurring beneficial allele, CCR5Δ32, which is responsible for generating genetic resistance to HIV infections (Kang X et al., 2016, Callaway E, 2016a). Both research groups used human tripronuclear zygotes, non-viable embryos.

Both studies reported several problems: the first one pointed out, for instance, that “the efficiency of homologous recombination directed repair (HDR) of HBB [β-globin gene] was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes (…)” (Liang P et al., 2015). The scientists also underlined the need to particularly investigate off-target effect of CRISPR/ Cas9 before any clinical application (Liang P et al., 2015). It has also been noted that it is not clear if many of the errors were due because of the use of tripronuclear embryos (Danish Council on Ethics, 2016). The second study also reported that other alleles at the same locus could not be controlled and it demonstrated that there remain significant technical issues to addressed. The authors advocate “preventing any application of genome editing on the human germline until after a rigorous and thorough evaluation and discussion are undertaken by the global research and ethics communities.” (Kang X et al., 2016).

In 2017, an international research consortium based in Oregon, USA published their findings of a research, using genome editing in germline cells, to correct a gene mutation that causes a serious hereditary myocardial disease (Ma H et al., 2017; German Ethics Council, 2017). Compared to the earlier experiments, the findings suggest that, with the approach used in the study, the researchers were able to get a lower proportion of mosaic embryos and that there were no evidence of off-target mutations and that, given the efficiency, accuracy and safety of the approach, it could be used for the “the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis” (Ma H et al., 2017). It has been noted that, although this last research has given rise to a controversial debate, it “(…) will lead to modifications to the human germline which are as precise and effective as possible and are undertaken systematically and intentionally” (German Ethics Council, 2017). It is further noted that the embryos used in this study were specifically produced for the research “in order to demonstrate the viability of the method used, and were destroyed afterwards, the implications of this kind of genetic manipulation in humans are considerable.” (German Ethics Council, 2017).

Another example of human germline research using CRISPR-Cas9 includes the study of a research team based at the Francis Crick Institute in London, under license by the Human Fertilisation and

12 For a review of the scientific community and public attention that this study produced, see, for instance, German Ethics Council, 2017.

7 Embryology Authority.13 The research, which used left over embryos from patients’ fertility treatments that had been donated to research, is aimed at understanding embryonic development and the causes of miscarriage (Fogarty NME et al., 2017; Ledford H, 2017b). Other groups in China as well in the US and Sweden have also conducted (or are conducting) research using normal (potentially viable) embryos (Callaway E, 2016b; Ma H et al., 2017; Ledford H, 2017a).

Genome editing clinical applications using somatic cells

Promising clinical applications using genome editing in somatic cells have been reported to include, for example, “editing the blood stem cells of patients who have a congenital blood disease, metabolic disorder or immune deficiency, or improving the capacity of immune cells to attack cancer cells.” (KNAW, 2016). More generally, genome editing applications in somatic cells are expected to treat, prevent disease and disability, and they could also modify phenotypic traits in the cells or tissues (NASEM, 2017). This could support the development of treatment for a variety of genetic diseases including Sickle-Cell disease, Hemophilia B, Cystic Fibrosis, Duchenne’s Muscular Dystrophy14, Huntington Disease and neurodegenerative diseases, as well as some cancers and diseases caused by viruses such as HIV (NASEM, 2017).15 Promising developments include research with Hepatitis B virus; research on the modification of T cells to attack HIV infection and to treat leukaemia, lymphoma and other types of blood cancer (Nuffield Council on Bioethics, 2016).

Somatic cell applications of genome editing, including gene and cell based therapies, offer significant improvements over previous methods, notably by being more precise, by correcting a gene defect rather than adding additional copies at random in the genome, and by limiting the safety concerns of the virus vector used in gene therapy methods (EASAC, 2017). Genomic editing techniques also have advantages over traditional gene therapy approaches in terms of flexibility, safety and effectiveness, gene disruption and accessibility.

Genome editing, through its particular feature of ‘multiplexing’ could also revive the prospect of xenotransplantation by overcoming limitations of past studies, for instance in reducing the risk of zoonosis, especially in pigs to human transplants (Nuffield Council on Bioethics, 2016). Some have noted that xenotransplantation researchers consider genome editing as having ‘game changing’ potential to accelerate research in this area (Nuffield Council on Bioethics, 2016).

Clinical studies of human somatic cells using genome editing have been undertaken, for some years using zinc finger nuclease (ZFN) and transcription activator-like effector nucleases (TALENs) (COGEM, Health Council of the Netherlands, 2017). These include, for instance, the treatment of a child with acute lymphoblastic leukaemia using TALEN-modified donor cells in the UK (Reardon S, 2015; Nuffield Council on Bioethics, 2016). The first clinical trial was reported in 2016 in China using CRISPR-Cas9 to engineer T cells in treating metastatic non-small cell lung cancer (Cyranoski D, 2016). In the US, the first clinical trials on somatic cells using CRISPR was proposed in 2016 to treat myeloma, melanoma and sarcoma (EASAC, 2017; Baylis F, McLeod M, 2017). In the US, the Recombinant DNA Research Advisory Committee (RAC) at the US National Institutes of Health (NIH) approved a T-cell clinical trial using CRISPR-Cas9 to enhance cancer therapies (Reardon S, 2016). Another clinical trial using CRISPR-Cas9 as a genome editing therapy for the blood disorder β- thalassemia is currently taking place.16

Genome editing clinical application using human germline cells

Genome editing using human germline cells holds the potential to prevent the transmission of inherited genetic disease (Nuffield Council on Bioethics, 2016; NASEM, 2017; COGEM, Health Council of the Netherlands, 2017). Another possible application might be the introduction of certain desirable traits in descendants (KNAW, 2016). Genome editing techniques could for instance allow for

13 https://www.crick.ac.uk/research/labs/kathy-niakan/human-embryo-genome-editing-licence, accessed 28 May 2019. 14 See also Nuffield Council on Bioethics, 2016. 15 See Table 4-1 Examples of Potential Therapeutic Applications of Somatic Cell Genome Editing, see NASEM, 2017; Nuffield Council on Bioethics, 2016; FEAM 2016. 16 https://www.the-scientist.com/news-opinion/us-companies-launch-crispr-clinical-trial-64746, accessed 28 May 2019; https://scienceline.org/2018/11/first-crispr-clinical-trial-begins-in-europe/, accessed 28 May 2019. It was also noted that further research was needed on the basic molecular mechanisms of CRISPR-Cas 9, for improving its efficiency, selectivity and safety and for preventing unintended genome mutations. More research is also needed on the complex interplay between genes, gene variants and the epigenome and the environmental factors (Leopoldina et al., 2015; NASEM, 2017).

8 the avoidance of a genetic disease in embryos created in vitro before being transferred to a woman avoiding that the embryo be discarded or be transferred with the genetic disease (Nuffield Council on Bioethics, 2016). Human germline genome editing could also, for instance, be used in avoiding the transmission of diseases that affect multiple tissues (e.g. Duchenne muscular dystrophy (DMD)) (NASEM, 2017). However, because the changes made to the germline cells would be heritable, their effects would be transmitted to subsequent generation, with unpredictable effects.

Other have also suggested that “At the moment, the greatest potential of germline gene editing is for treating monogenic disorders – genetic diseases caused for the most part by a mutation in a single gene – because changes only have to be made at a single locus in the gene. Scientists believe that germline modification has little chance of success for polygenic disorders (disorders caused by several different genes) and disorders that are not fully heritable.” (COGEM, Health Council of the Netherlands, 2017).

Although the details need to be verified, the announcement in November 2018 of the birth of twins whose genomes had been modified using CRISPR-Cas 9 to edit the gene CCR5 (which encodes a protein that allows HIV to enter a cell) illustrates a very controversial example of such application (Cyranoski D, Ledford H, 2018).

9

3. Key issues associated with human genome editing

Although gene modification methods are not new, the new genome editing technologies and their associated features have brought old issues into a new scientific reality, bringing profound challenges and demanding new regulatory requirements to protect individuals (UNESCO, 2015). In the area of genome editing using human somatic cells, it has been suggested that there are important ethical, legal and societal issues that “are not new and reflective of the challenges in realising the opportunities of emerging technologies and advanced therapies.” (Garden H, Winickoff D, 2018). 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). Similarly, others have suggested that it is the context into which these ethical issues arise that is dramatically different (The Hinxton Group, 2015). And, as mentioned before, while many emerging technologies cause social concerns, “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). It was also suggested that there could be a learning opportunity from the case of genome editing in that “As policies and institutional capacities are developed around the use of gene editing, these could serve as a model for policies in other areas of advanced therapies and emerging technologies for health.” (Garden H, Winickoff D, 2018).

One distinguishing feature of genome editing is the degree of public concern and interest that most likely stems from human germline genome editing as well as the speed and precision of genome editing methods (Garden H, Winickoff D, 2018). A similar point was made by others who have noted that even if genome editing techniques “do not raise fundamental new biological risks that have not already been encountered by existing technologies (…)”, the new tools have made genome editing “much easier, cheaper and faster than with the previously available technologies; these new applications must be thoroughly assessed.” (Chneiweiss H et al., 2017).

Key issues such as research with animals, research on human embryos, cells and gene therapies, germline intervention, and human enhancement have been raised in the past, particularly in the context of recombinant DNA and gene therapy (Nuffield Council on Bioethics, 2016). There is also a need to differentiate between preventing and treating diseases on one hand and human enhancement on the other, although the distinction is difficult to make (Baltimore D et al., 2015; Danish Council on Ethics, 2016; Nuffield Council on Bioethics, 2016; COGEM, Health Council of the Netherlands, 2017; NASEM, 2017; EASAC, 2017). Moreover, it has been noted that “The boundaries of disease are not fixed. They are continuously being drawn and redrawn in different cultures with different opportunities for treatment.” (Danish Council on Ethics, 2016).

This section will briefly review the key issues deemed to pertain to human genome editing as these will provide insight into the types of policy options put forward in section 4. One question that has guided the literature review is therefore what kind of challenges genome editing is eliciting, according to its field of applications (somatic and germline cells; basic research and clinical trials) as well as whether and how genome editing brings new governance challenges.

Technical issues of genome editing

Despite their already wide-ranging impact on a variety of sectors, genome editing methods are not yet perfect and therefore pose certain risks. Genome editing investigations will therefore need to consider the safety and efficacy of genome editing techniques (Comité Ethique, Inserm, 2016; Nuffield Council on Bioethics, 2016; NASEM, 2017). These methods are indeed relatively novel in that they have only been developed over the last six years or so, being adapted from bacterial systems (Barrangou R et al., 2007; Leopoldina et al., 2015). There is therefore still a need to better understand the mechanisms, and how to best use them and adapt them. But it has been noted that the rate of progress in science is fast and that new methods look promising (Lovell-Badge R, 2019).

Clinical applications involving genome editing on somatic cells will generally evaluate a series of parameters in order to determine the efficacy and potential toxicity of a chosen technique (NASEM,

10 2017).17 These chosen strategies will in turn have an impact on the results of the study and will inform the regulatory process that will proceed from these choices. For instance, a choice will need to be made as to whether the strategy chosen will be in vivo or ex vivo.18 Likewise, studies will be carried out to evaluate the efficiency and specificity of different genome editing techniques (i.e. the type of nuclease platform). Moreover, each application will require a careful analysis of the risks versus the benefits before receiving the approval to proceed.

For germline cells, it has been reported that several scientific and technical issues have to be addressed. The uncertainties around the use of CRISPR technology in human germline genetic modification include “issues of effectiveness and accuracy: will the intended alterations to the genetic code always be done properly? A further uncertainty concerns the efficiency of the technique: for instance, what is the success rate and how many embryos will be needed on average to carry out a successful germline modification? The long-term effects of germline modification are also not known with any certainty [emphasis in original].” (COGEM, Health Council of the Netherlands, 2017). In addition to ensuring correct on-target and no off-target events, issues include mosaicism, possible effects on the human gene pool and on subsequent generations, and the ability to select the appropriate gene targets. The impact of mosaicism can be dependent to a certain extent on the choice of the targeted gene (NASEM, 2017). There are questions regarding the health risks associated with mosaicism as well as “difficulty of predicting the effects of genetic alterations on individual functioning.” (KNAW, 2016).

Likewise, versions of a gene (specific alleles) can have different functions (i.e. one allele can be highly correlated with a risk of disease, but at the same time confer protection against other diseases (heterozygous sickle-cell and protection against malaria)), it is important to target those genes for which sufficient knowledge is available, and preferably to restrict any changes to those found naturally in alleles present at high frequencies to minimize the risk of unintended effects on the human gene pool (NASEM, 2017). Similar issues arise as to the current state of knowledge regarding the interactions between human genes, genomes and the environment and lifestyle (epigenomics).

While some of these issues are sometimes put forward as a way to delay the use of genome editing techniques on somatic and human germline cells and human embryos until more understanding and knowledge are gathered, it seems likely that many of the technical and safety concerns will be resolved by scientific advances. Yet crucial ethical, social and regulatory issues remain and discussions must be held about whether and under which circumstances genome editing using germline cells and embryos is acceptable or not (Leopoldina et al., 2015).

Ethical, social and governance issues

Ethical considerations

It has been underlined that many of the ethical issues raised around the human application of genome editing are similar to those raised in the context of gene therapy, human genetics and disease, and those dealing with the use of research on human embryos (UNESCO, 2015; Leopoldina et al., 2015; Nuffield Council on Bioethics, 2016; Bonas U et al., 2017; NASEM, 2017). For instance, ethical issues that are raised in the context of genome editing may also include questions about the use of animals in research (e.g. use of animals; whether larger animal models will be needed) (Nuffield Council on Bioethics, 2016). Despite their importance, these are not new nor unique to the field of genome editing (Nuffield Council on Bioethics, 2016). Some have suggested that the application of genome editing techniques on human somatic cells with the following purposes “drug screening to develop new or better medicines, for identifying biomarkers for target-group-specific diagnostic procedures, and for somatic gene therapy does not raise any new specific ethical or legal issues requiring discussion.” (Bonas U et al., 2017).

Although many issues around genome editing are familiar to human genetic literature, it has been suggested that genome editing and its associated development raise important conceptual questions

17 For a review of scientific and technical considerations associated with the design and application of genome-editing strategies in somatic cells, see NASEM, 2017. 18 In vivo (i.e. administrating the genome editing technique directly into the blood of a patient) may likely increase the safety and technical risks of a treatment.

11 (Nuffield Council on Bioethics, 2016). These include: because of its aforementioned unique features, there is an effacement between basic and applied research (Nuffield Council on Bioethics, 2016; EGE, 2016). This has implications for the review or development of oversight regulatory framework. A second set of questions is associated with the ground of public interest in the application of genome editing and how this relates to the jurisdictional scope of governance: for instance, should it be local, national or regional or global. A third set of questions concerns the current distinctions consistent with the current state of scientific knowledge: for instance, the current distinction between ‘germ line’ and ‘somatic’ cells, which is required to do normative work, and between genomic and epigenomic changes. Further conceptual questions concern “how to distinguish need and preference, treatment, prevention and enhancement, fair access and just distribution” (Nuffield Council on Bioethics, 2016).

One of the most controversial issues concerns the genome editing of a human embryo in vitro19 and its transfer to a woman to give birth to a baby with an altered genome. Put differently, genome editing using human germline cells, gametes and embryos will make edits that will affect the person treated but these edits will also be passed on to future generations. In this regard, it has been noted that in the genome editing of “future humans, exposure to unintended risks assumes a whole new perspective compared to cell therapy in the developed body.” (Danish Council on Ethics, 2016). This raises ethical, social and governance issues. Addressing these issues will require that citizens and their representatives make choices about the future directions of their societies. These choices will reflect the values and interests of different stakeholders and will most likely be cultural and context dependent.

It has also been underlined that “the international community’s views about gene editing for clinical purposes, and especially the possibility of germline editing, vary enormously.” (Brokowski C, 2018). A study reviewing 61 ethics reports and statements shows the diversity of opinions on some key bioethical issues as well as it elicits the contradictions of these statements. (Brokowski C, 2018). It is argued that “Despite their inability to fully address all important considerations, many of the statements may advance debate and national and international law and public policy.” (Brokowski C, 2018).

Some ethical considerations in human germline applications include those of safety, dignity and justice (equity of sharing the benefits) (UNESCO, 2015), proportionality, autonomy and informed consent (EASAC, 2017). Issues of clinical applications of human germline applications are also reported to include the desire to have one’s own genetic child; the alternatives to germline modification; arguments about human dignity and identity; human enhancement and eugenics; and issues around equity, justice and social value of the technology (COGEM, Health Council of the Netherlands, 2017). Clinical applications of human germline using genome editing also involve ethical issues that include “ones that look at the consequences for the respective individual but also ones that address the potential repercussions for society as a whole.”, and these ethical have been already discussed in the past with different methods (e.g. in the context of cloning, pre-implantation and prenatal diagnosis) (Reich J et al., 2015). For instance, it has been noted that there are ethical dilemmas that concerns the desire of people “to have children that are genetically their own and whether or not germline modification is necessary for this (instead of an alternative such as embryo selection). There are also broader societal concerns about the desirability of germline modification: it could widen existing differences between people if the technology is available only to a select group.” (COGEM, Health Council of the Netherlands, 2017).

In addition, germline therapy is reported to also raise ethical issues around self-determination and physical integrity as well as dignity (Reich J et al., 2015). Another report also put forward several ethical themes and arguments around the applications of human germline editing including weighing the risks; the interests of the future child and of the parents; the right to an open future; genetic modification increases and fortifies inequalities; the natural order; biological diversity 1: tolerance and solidarity and biological diversity 2: standardisation and totalitarianism (Danish Council on Ethics, 2016).

Another ethical consideration revolves around the opportunity cost of not developing and using tools that could potentially alleviate suffering. Indeed, it has been noted that banning germline editing “would raise the question of the moral justification for consciously failing to remove a serious risk of

19 For “Potential Alternative Routes to Heritable Edits”, see NASEM, 2017.

12 disease for the potential progeny” (Reich J et al., 2015). Or put differently, if the objective of human germline application using genome editing is to prevent the suffering by removing the cause of a disease, then, as long as the technique is safe, it might be considered as a form of respect for human dignity in that it “does not prejudice the interests of the future persons, but rather serves them.” (COGEM, Health Council of the Netherlands, 2017).20

In their 2016 report, the Nuffield Council on Bioethics identified two issues that required further ethical scrutiny: human reproduction and livestock.21 In 2018, the Nuffield Council published the report “Genome editing and human reproduction: social and ethical issues” examining the ethical issues arising from heritable genome editing interventions in human reproduction (Nuffield Council on Bioethics, 2018).

Not only do the clinical applications into human germline cells and embryos using genome editing pose ethical questions, but ethical concerns also arise by research into the human germline using genome editing. Issues include, for instance, research on human embryos as “Such research involves interfering with the very earliest stage of human life and this affects fundamental values of varying significance to different groups of people. The question is how the intrinsic value of the human embryo is interpreted in terms of its right to protection.” (COGEM, Health Council of the Netherlands, 2017). Likewise, human germline research using genome editing also raises ethical issues around the use of cultured embryos and surplus embryos. (COGEM, Health Council of the Netherlands, 2017). As it has been underlined “The destruction of embryos implied in some of these techniques revives the well-known controversy on the principle of respect for human life [emphasis in original] and the related issue of the status of zygotes, embryos, and foetuses. Here, consensus is impossible to attain.” (UNESCO, 2015)

Governance considerations

Since the 2012 discovery of CRISPR-Cas 9, there have been several international meetings and national workshops (see section 3),22 reports and statements issued by a variety of stakeholders on this topic: from national and regional academies of sciences and medicines, professional societies, bioethics groups, funding bodies, patient groups to international organizations.23 The 2017 NASEM report draws similarities between genome editing and other medical advances in that they all come with their “own set of benefits, risks, regulatory frameworks, ethical issues, and societal implications.” It further outlines several important questions with respect to genome editing that include: “how to balance potential benefits against the risk of unintended harms; how to govern the use of these technologies; how to incorporate societal values into salient clinical and policy considerations; and

20 For more about the social and ethical issues about genome editing and human reproduction, see Nuffield Council on Bioethics, 2018. 21 Ethical issues around livestock are outside the scope of this background paper. See Background Paper Governance 2 on the non-human applications of genome editing. 22 For instance, in France, several working groups were established into place and the Inserm Committee on Bioethics has also discussed this issue since 2015 (Inserm Bioéthique Comité). See also the creation in 2018 by the Inserm of ARRIGE (Association for Responsible Research and Innovation in Genome Editing) http://arrige.org/, accessed 28 May 2019. In the Netherlands, KNAW symposiums on gene editing: https://www.knaw.nl/nl/actueel/agenda/genome-editing, accessed 28 May 2019 . In Argentina, a workshop organized by several ministries was held in December 2018. https://www.argentina.gob.ar/noticias/desafios-y-oportunidades-en-edicion-genica, accessed 28 May 2019. 23 These include: UNESCO, 2015; Leopoldina 2015; Reich et al., 2015; Council of Europe (2015); The Hinxton Group, 2015; KNAW, 2016; Nuffield Council on Bioethics, 2016; Danish Council on Ethics, 2016; EGE, 2016; NASEM, 2017; EASAC, 2017; COGEM, Health Council of the Netherlands, 2017; German Ethics Council, 2017; Bonas et al., 2017; Shukla-Jones A et al., 2018; Garden H, Winickoff D, 2018; Australia https://www.science.org.au/curious/technology-future/crispr, accessed 28 May 2019; Genetic Alliance UK report https://www.geneticalliance.org.uk/wp-content/uploads/2018/04/genomeediting_report.pdf, accessed 28 May 2019; Patients Network for Medical Research and Health (EGAN) https://egan.eu/news/gene-editing-and-the- patients-perspective/, accessed 28 May 2019; African Statement on Human Germline Genetic Editing, Spanish Bioethics statement http://assets.comitedebioetica.es/files/documentacion/en/CBE%20On%20Genome%20Editing%20In%20Humans.pdf, accessed 28 May 2019; Inserm https://www.inserm.fr/information-en-sante/dossiers-information/edition-genomique, accessed 28 May 2019; Institut national de la santé et de la recherche médicale (Inserm) https://www.inserm.fr/sites/default/files/2017- 10/Inserm_Saisine_ComiteEthique_Crispr-Cas9_Fevrier2016.pdf, accessed 28 May 2019; Royal Society of New Zealand Te Apā rangi. Gene Editing. Evidence Update https://royalsociety.org.nz/assets/documents/Gene-editing-evidence-update2.pdf, accessed 28 May 2019 and Discussions exploring the ethics of gene editing for New Zealand https://royalsociety.org.nz/news/discussions-exploring-the-ethics-of-gene-editing-for-new-zealand/, accessed 28 May 2019; Gene editing with CRISPR (2015) Australian Academy of Science: http://www.nova.org.au/technology-future/crispr, accessed 28 May 2019; Synthetic gene drives in Australia: implications of emerging technologies https://www.science.org.au/support/analysis/reports/synthetic-gene-drives-australia-implications-emerging-technologies, accessed 28 May 2019.

13 how to respect the inevitable differences, rooted in national cultures, that will shape perspectives on whether and how to use these technologies.” (NASEM, 2017). Furthermore, several scholars have also put forward the “whether, and not how” (Hurlbut JB, 2019; Baylis F, 2019) questioning and underlined “whether it is (or can ever be) acceptable to genetically engineer children by introducing changes that they will pass on to their own offspring. That question belongs not to science, but to all of humanity.” (Hurlbut JB, 2019).

The need to identify common strategies as well as clear opinions at the international level as to what is acceptable or not in research has also been underlined (Inserm, 2016). Some have however pointed out that this will mostly depend on context and social culture (Nuffield Council on Bioethics, 2016). Attempts in harmonizing governance regimes at the global level may therefore be challenging. Others have indeed pointed out that the synchronization of approaches at local and global levels would be better than pursuing harmonized frameworks (Shukla-Jones A et al., 2018). Moreover, it has been argued that “steering the development of technologies requires the active participation of government, science and society, which makes it important that stakeholders and interested parties determine their positions on germline modification. This does not necessarily mean that a consensus has to be reached, but it does mean that government, science and society must agree on who decides what and when, and on the basis of which arguments. This is called governance.” (Isasi et al., 2016; COGEM, Health Council of the Netherlands, 2017).

Moreover, governance can take place at multiple levels – global, regional, national and even within a country, and given this multiplicity of governance nexus, queries remain about whether global consensus is possible, and if it is, what this could look like – from ‘soft’ instruments (e.g. agreed principles) to legal instruments/treaties) or even a global governance body? ). In a related vein, it has been recommended that, in particular in relation to the human germline genome editing, “states and governments, (…) should renounce to the possibility of going into it alone within their own legal system.” (UNESCO, 2015).

In addition, it has been reported that a number of specific features of genome editing, especially CRISPR/Cas 9 analogues, give rise to issues that require further ethical considerations (Nuffield Council on Bioethics, 2016). These features include: 1) novel mode of action; 2) accessibility of the technology; 3) speed of use and uptake; and finally 4) the potential to achieve multiple and simultaneous edits in a given genome (multiplexing) (Nuffield Council on Bioethics, 2016). These specific features can potentially challenge governance mechanisms. For instance, the novel mode of action of genome editing challenges distinctions “on which important aspects of normative systems, like the system of food regulation in the EU, are based.” (Nuffield Council on Bioethics, 2016). Likewise, the second feature “accessibility” and “the range of interests potentially engaged by the directions in which genome editing technologies may develop represents a challenge to the principles of scientific and commercial freedom, and to political procedures for discovering and asserting the public interest (including the protection of potentially disadvantaged groups).” (Nuffield Council on Bioethics, 2016).

Overall, the reports and statements support the use of genome editing in somatic cells under appropriate oversight. The reports suggest that existing governance mechanisms are largely appropriate to cover research and clinical applications of genome editing on somatic cells, although there are issues relating to assessment of safety and efficacy as well as uses for enhancement (Leopoldina, 2015; KNAW, 2016; NASEM, 2017). Other scholars have also underlined key areas of regulatory confusion which might challenge the clinical translation of somatic therapy using genome editing (Nicol D et al., 2017). The effectiveness of existing regulatory regimes to address the current, and future, applications of genome editing has also been questioned by others (Garden H, Winickoff D, 2018). For instance, several challenges in the governance of human somatic cells were reported in terms of the “legal lag or the pacing problem” or the issue of governance frameworks to keep up with the technological advances (Charo RA, 2015; Garden H, Winickoff D, 2018), the need for better regulatory coordination across jurisdictions and the potential for “leakage, misuse and misleading claims” of therapies (Garden H, Winickoff D, 2018).

In general, most reports and statements support research with genome editing using germline cells. Clinical applications using genome editing on human germline cells and embryos are however reported as controversial.

14 In particular, it has been noted that:

• basic research with genome editing using human somatic cells (non-reproductive cells) are generally supported under appropriate oversight mechanism. • basic research with genome editing using germline cells and embryos is not as widely supported as somatic research. This is explained by the fact that some countries prohibit research on human embryos (see Section 3).24 A majority of reports and statements however support this type of research under appropriate oversight mechanism. • Clinical applications using genome editing on human somatic cells are generally supported. In Europe and in the U.S. It has been reported that there is generally societal support for this type of application (FEAM, 2017; NASEM, 2017). • Clinical applications with genome editing using human germline cells and embryos are very controversial.

- Some countries ban such applications outright. In the European Union (EU), making genetic heritable changes is not currently allowed in any Member States and the EU will not fund these types of studies (EASAC, 2017). In the EU, there is no broad societal consensus on this topic and there are many unresolved ethical, safety and efficacy issues that act as barriers for such application (FEAM, 2017). - Others prohibit such applications until further scientific knowledge is gathered about the potential safety risks and efficiency (e.g. about the risks of inaccurate or incomplete editing and about the difficulty to evaluate the potentially harmful effects) (FEAM, 2017; The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015; ISSCR, 2015; EASAC, 2017; NASEM, 2017).25 - Others believe that “it would be irresponsible to use genome editing to create offspring until (…) [there is] sufficient knowledge of the risks, potential advantages, and available alternatives to make an appropriate assessment [and that] society has reached consensus about the moral acceptability of the applications in question.” (KNAW, 2016). Some also noted that “It must be emphasised that it will never be possible to obtain absolute certainty about the risks and safety of the technique. The acceptability or otherwise of a risk is not just a scientific question, but a political and social one as well.” (COGEM, Health Council of the Netherlands, 2017).

It has been observed that scientists’ views differ about the ethics and governance of human genome editing of germline cells (Baylis F, Darnovsky M, 2019). While there is agreement on that fact that it would be irresponsible to currently proceed with human germline genome editing, some emphasize the need to develop, prior to any applications, “criteria and standards” for human germline genome editing, while others however have pointed out that developing a system to regulate genome editing should not start on the premises that germline editing is “a foregone conclusion” and that “is a question for society, not scientists, and one that demands the input of different stakeholders from across the world.” (Nature ed., 2018; Baylis F, Darnovsky M, 2019).

In addition to these reports, several surveys of public opinions have been carried out on genome editing. Some have pointed out that opinion polls and engagement activities have generally showed that there is widespread public support for germline genome editing to prevent genetic disease, if determined to be safe, and that there is strong opposition to editing genomes to enhance human traits

24 In the EU, some countries (e.g. Italy and Germany) prohibit research on human embryos. In the US, research on human embryos is legal at the Federal level but some states ban it. There is however a ban on federal funding for such research. The NASEM report notes that while some disagree with such policies, it states that “this research is necessary for medical and scientific purposes that are not directed at heritable genome editing, though it will also pro• vide valuable information and techniques that could be applied if heritable genome editing were to be attempted in the future.” (NASEM, 2017). 25 Some reported that more legal, ethical and moral debates are needed on this matter and more public engagement is needed to agree “on whether, and if so how, these scientific developments should be taken forward in Europe.” (FEAM, 2017). Others reported that “In light of the technical and social concerns involved, the committee concluded that heritable genome-editing research trials might be permitted, but only following much more research aimed at meeting existing risk/benefit standards for authorizing clinical trials and even then, only for compelling reasons and under strict oversight. It would be essential for this research to be approached with caution, and for it to proceed with broad public input.” (NASEM, 2017). Another view emphasizes that if genome editing techniques were to become efficient and reliable, such applications could be realized in rare and specific occasions, such as the “treatment” of an embryo carrying a genetic disease. It was noted that in this case “it would not be unethical to treat it rather than destroy it.” (French National Academy of Science, 2016).

15 (Daley GQ et al., 2019). And while some have underlined that “Public opinion cannot and should not tell us what is right to do”, there is a recognition that surveys can contribute “to understanding the practical and contextual dimensions of the ethical question; how can gene-editing technology contribute to human flourishing?” (Gaskell G et al., 2017). Similarly, it has been noted that “Maintaining a record of all these differing opinions can be a useful tool for identifying aspects of importance for governance and policymaking. Opinion polls often use extreme examples (…) and therefore have little relevance to grey areas and borderline cases, which can only be grasped through a more detailed dialogue.” (COGEM, Health Council of the Netherlands, 2017). As an illustration, several types of surveys are reported below:

• In a survey of more than 1,000 respondents in 11 countries (Austria, Denmark, Germany, Hungary, Iceland, Italy, the Netherlands, Portugal, Spain, UK and the United States), it was found that “support is consistently greater for treatment than enhancement (…). Similarly, there is greater support across all countries for intervention on adults than prenatals,(…)” (Gaskell G et al., 2017). • A worldwide opinion poll of 12,000 people from 185 countries was reported by the Netherlands Commission on Genetic Modification (COGEM) and the Health Council of the Netherlands that “shows that many people are critical of germline modification for ‘non-health purposes’. Another striking result from this survey is that having a genetic disease or not could not be associated with a positive or negative attitude towards germline modification. This illustrates the diversity of individual opinions within stakeholder and concerned groups, such as patients.” (COGEM, Health Council of the Netherlands, 2017). • In the US, a 2016 Pew Research Center survey reported that a majority of Americans (68%) “would be “very” or “somewhat” worried about gene editing (…)”26. About the possibility of gene editing to reduce disease, the survey shows that “36% think it will have more benefits than downsides, while 28% think it will have more downsides than benefits.” Moreover, the survey indicated that “U.S. adults are closely split on the question of whether they would want gene editing to help prevent diseases for their babies (48% would, 50% would not).” In 2018, another Pew Research Center survey reported that 72% of Americans said “that changing an unborn baby’s genetic characteristics to treat a serious disease or condition that the baby would have at birth is an appropriate use of medical technology, while 27% say this would be taking the technology too far.”27 It is also reported that “American’s views on the appropriateness of changing a baby’s genetic characteristics depend in large part on the intended purpose and on whether or not human embryos would be used in testing these techniques.”28 • In the Netherlands, the Netherlands Commission on Genetic Modification (COGEM) and the Health Council of the Netherlands reported that “A Dutch poll suggested that an overwhelming majority (85% of respondents) would have their DNA altered to prevent the onset of a genetic disease. The respondents were a bit more hesitant about altering the DNA of their children: 65% would have the DNA of their unborn child altered to prevent it inheriting a genetic disease. They were considerably less enthusiastic about altering DNA to obtain resistance to disease (30%) or increase intelligence (15%).” (COGEM, Health Council of the Netherlands, 2017). • In the UK, a survey found that “Genome editing to correct a disorder so that the correction would also be inherited by any children of that person was seen as ‘very positive’ to society by 43% and ‘to some extent positive’ by 33% (76% in total).” In the same study, it was also found that, as far as the dialogue participants were concerned, “it is important to explore all alternative options before going down the route of genome editing of human embryos.”29 In another survey done by Genetic Alliance UK, it is shown that “more than 75% of respondents,

26 U.S. Public Wary of Biomedical Technologies to ‘Enhance’ Human Abilities, July, 26, 2016. https://www.pewresearch.org/science/2016/07/26/u-s-public-wary-of-biomedical-technologies-to-enhance-human-abilities/, accessed 28 May 21019. 27 Public Views of Gene Editing for Babies Depend on How It Would Be Used, July 26, 2018. https://www.pewresearch.org/science/2018/07/26/public-views-of-gene-editing-for-babies-depend-on-how-it-would-be-used/, accessed 28 May 2019. 28 Public Views of Gene Editing for Babies Depend on How It Would Be Used, July 26, 2018. https://www.pewresearch.org/science/2018/07/26/public-views-of-gene-editing-for-babies-depend-on-how-it-would-be-used/, accessed 28 May 2019. 29 van Mil A, Hopkins H, Kinsella S (2017). Potential uses for genetic technologies: dialogue and engagement research conducted on behalf of the Royal Society. Findings Report December 2017 https://royalsociety.org/- /media/policy/projects/gene-tech/genetic-technologies-public-dialogue-hvm-full-report.pdf, accessed 28 May 2019.

16 those with a genetic condition or family members, supported the use of genome editing technology but made a clear distinction between tackling medical conditions (where it was supported) and the enhancement of physical or cognitive attributes in healthy people (where it was not supported).” (EASAC, 2017, Genetic Alliance UK, 2016).

Another reported issue associated with governance concerns the vagueness of basic definitions in regulatory frameworks and in distinguishing between clinical and research applications (Isasi et al., 2016). In the EU, several reports have noted the need to develop common definitions (EASAC, 2017; FEAM, 2017). Yet, it has been reported that a specific consideration associated to genome editing is the fact these techniques are bringing basic research and translation closer to clinical treatment, thereby blurring the traditional distinction between basic and applied research and translational research (Nuffield Council on Bioethics, 2016; EGE, 2016).

Human enhancement and eugenics

Moreover, the difficulty in the governance of genome editing also stems from the difficulty to establish clear boundaries between addressing severe diseases and those of non-therapeutic purposes (enhancement) and eugenics (Danish Council on Ethics, 2016; Nuffield Council on Bioethics, 2016; EASAC, 2017, COGEM, Health Council of the Netherlands, 2017). This has been described as the “concerns about initiating a “slippery slope” from disease-curing applications toward uses with less compelling or even troubling implications.” (Baltimore D et al., 2015).

Enhancement could occur either through a somatic therapy or though reproductive methods (Nuffield Council on Bioethics, 2016). Indeed, as noted, the new genome editing techniques might “blur” the lines between clinical applications for therapeutic purposes and enhancement goals (EGE, 2016). Yet enhancement concerns pre-date genome editing and have been discussed for instance in relation to gene therapy and embryo selection following preimplantation genetic diagnosis (Nuffield Council on Bioethics, 2016). Likewise, eugenics have been debated also in the context of recombinant DNA and genomics (WHO, 2002) and human enhancement and eugenics have been strongly opposed (Nuffield Council on Bioethics, 2016; Genetic Alliance UK, 2016; FEAM, 2017; EASAC, 2017; NASEM; 2017). In general, there is little support for the application of genome editing techniques that would go beyond prevention and treatment of diseases.30 Human enhancement is also prohibited under the 1997 Convention on Human Rights and Biomedicine (also called the Oviedo Convention)31 and its provision against misuse for enhancement (CoE, 2015).

Security implications

Reports have also underlined that the advances in genome editing may also be deliberately misused to cause harm and to develop biological weapons.32 Some have also considered that genome editing may pose a threat to national security (Clapper JR, 2016). An international workshop to assess the security implications of genome editing was convened in 2017 by EASAC, NASEM, the global InterAcademy Partnership (IAP) and the German National Academy of Sciences Leopoldina. The workshop reviewed concerns about potential misuse; underlined that issues pertaining to genome editing should be set into a broader context and the workshop also emphasized the need for public engagement and global coordination (IAP, 2017).

30 For transhumanism arguments, see for instance Savulescu J, Bostrom N (Editors) (2011). Human enhancement Oxford: Oxford University Press as referred in Nuffield Council on Bioethics, 2016. 31 The Oviedo Convention is “the first legally-binding international text designed to preserve human dignity, rights and freedoms, through a series of principles and prohibitions against the misuse of biological and medical advances”. It was open to signature in 1997 and entered into force in 1999. https://www.coe.int/en/web/conventions/full-list/-/conventions/treaty/164, accessed 28 May 2019. 32 See Background paper Governance 2 on the non-human applications of genome editing.

17

4. Policy options and stakeholders

Section 3 has pointed out that one of the key issues associated with genome editing is its governance. In terms of the governance of genome editing in human somatic cells, a recurring question was about the appropriateness of existing oversight and regulatory regimes to ensure the safe and responsible use of genome editing in both research and clinical applications. In relation to the governance of genome editing in human germline cells, the questions about the appropriateness of current oversight and regulatory regimes was also raised in the area of research, but the governance of its clinical application is very controversial and is banned by several countries. In general, however, if these governance regimes, or some parts thereof, are found inadequate, there remains the subsequent question of what kind of new measures might be needed. In other words, what are the governance gaps in relation to genome editing in human somatic and germline cells?

Background

The discovery of recombinant DNA in the early 1970s and the associated potential to modify the genome triggered considerable concerns among the public and the research community. In order to review scientific progress in research on recombinant DNA molecules and to discuss appropriate ways to address the potential biohazards of this research, a conference was organized in Asilomar, California in February 1975 (hereinafter the Asilomar Conference). Researchers called for a moratorium on recombinant DNA research, and to establish standards for research and regulation of biotechnologies until a set of guidelines to regulate the conduct of DNA research was established (Nuffield Council on Bioethics, 2016).33 Retrospectively, it was noted that although many of the concerns did not occur, this should not be a reason to underestimate or disregard the potential risks and hazards. These “must never be underestimated, and they must be fully addressed, allowing science to progress and society to reap the benefits in safety” (Fukuyama F, 2002; WHO, 2002).

In January 2015, a group of leading scientists and legal scholars met in Napa, California, U.S. to discuss the scientific, medical, legal and ethical implications of the new prospects for genome editing (Baltimore D et al., 2015). The group underlined the urgent need for open discourses on the use of genetic engineering and germline gene modification. Several recommendations were made including the creation of forums of experts from the scientific and bioethics communities to provide information and education on genome editing and, on the risks and benefits of this powerful technology. They also recommended the holding of a global meeting with a variety of stakeholders including the developers and users of genome engineering technology and genetics, lawyers, and bioethicists, members of the scientific community, the public, and relevant government agencies and interest groups, to debate these important issues and recommend policies. The group also strongly discouraged any attempts at germline genome modification for clinical application in humans until risks were better evaluated and while discussions on the societal, environmental and ethical implications of such activity are being held among scientific organizations and governments. Transparent research on the efficacy and specificity of CRISPR-Cas9 genome editing technology was encouraged.

In December 2015, the first International Summit on Human Gene Editing was held in Washington DC,34 co-hosted by the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society of the United Kingdom and the Chinese Academy of Sciences. The first International Summit was aimed at discussing the scientific, ethical, and governance issues associated with human genome editing. In a statement following their discussions, the organizing committee reached the following conclusions:

1) basic and preclinical research are needed and should proceed under appropriate legal ethical frameworks;

33 See Box 3.1: The Asilomar Conference on Recombinant DNA (Nuffield Council on Bioethics, 2016). 34 International Summit on Gene Editing. On Human Gene Editing: International Summit Statement. December 3, 2015. (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a, accessed 28 May 2019).

18 2) clinical use on somatic cells are promising and their risks and benefits should be reviewed on each proposed genetic modification under the appropriate regulatory frameworks for gene therapy; 3) clinical use on germline cells poses many important issues and “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: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis”35; 4) the need for an ongoing forum “to discuss potential clinical uses of gene editing; help inform decisions by national policymakers and others; formulate recommendations and guidelines; and promote coordination among nations. The forum should be inclusive among nations and engage a wide range of perspectives and expertise – including from biomedical scientists, social scientists, ethicists, health care providers, patients and their families, people with disabilities, policymakers, regulators, research funders, faith leaders, public interest advocates, industry representatives, and members of the general public.”36

At the second International Summit on Human Genome Editing (Hong-Kong, November 2018),37 the organizing committee stated that “While we, the organizing committee of the second summit, applaud the rapid advance of somatic gene editing into clinical trials, we continue to believe that proceeding with any clinical use of germline editing remains irresponsible at this time.”38

• The organizing committee noted that basic and preclinical research on somatic and germline editing is rapidly advancing and that “As was anticipated, somatic genome editing is now being tested in patients.”39 • As for heritable genome editing of either embryos or gametes, it “poses risks that remain difficult to evaluate”.40 The organizing committee stated that “Nevertheless, germline genome editing could become acceptable in the future if these risks are addressed and if a number of additional criteria are met. These criteria include strict independent oversight, a compelling medical need, an absence of reasonable alternatives, a plan for long-term follow-up, and attention to societal effects. Even so, public acceptability will likely vary among jurisdictions, leading to differing policy responses.”41 The organizing committee concluded “that the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at this time. Progress over the last three years and the discussions at the current summit, however, suggest that it is time to define a rigorous, responsible translational pathway toward such trials.”42

35 International Summit on Human Gene Editing. A global discussion, December 1-3, 2015, Washington D.C. (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a, accessed 28 May 2019). 36 International Summit on Human Gene Editing. A global discussion, December 1-3, 2015, Washington D.C. (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a, accessed 28 May 2019). 37 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019). 38 Second International Summit on Human Genome Editing. On Human Genome Editing II. Statement by the Organizing Committee of the Second International Summit on Human Genome Editing. November 29, 2018. There was also the report at the summit that “human embryos had been edited and implanted, resulting in a pregnancy and the birth of twins. (…) Even if the modifications are verified, the procedure was irresponsible and failed to conform with international norms. Its flaws include an inadequate medical indication, a poorly designed study protocol, a failure to meet ethical standards for protecting the welfare of research subjects, and a lack of transparency in the development, review, and conduct of the clinical procedures.” (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b, accessed 28 May 2019). 39 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019). 40 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019). 41 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019). 42 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019).

19 • The committee proposed to develop a translational pathway to germline editing and called for “an ongoing international forum”.43

Existing oversight regimes applying to somatic and human germline cells

In general, in countries with regulatory regimes in place, the governance of human genome editing falls under the scope of pre-existing regulations developed for gene therapy and for the use of human embryos in research. It is however noted that it is not evident to identify similar regulations in the vast majority of countries in the world. In addition, even where applications may be covered by existing rules, these might not be universally established. As noted earlier, an important point in the evaluation of whether current regulatory systems are adequate to regulate human genome editing is about the need to make clear distinctions between:

1) the use of genome editing in basic research, pre-clinical and clinical studies and; 2) the use of genome editing on somatic cells (cell-based therapies, tissues, regenerative medicine) and on human embryos and germline cells (reproductive cells).44

Regulation of research on germline cells and human embryos using genome editing

Research with germline cells, and in particular human embryos, has been controversial for many countries. This has led to a variety of governance mechanisms regulating such research, reflecting the different national views on the legal and moral status of human embryos. Public policies range from being permissive to regulated and to prohibitionist (NASEM, 2017). The use of genome editing in the context of research on human embryos also raises issues that are similar to those discussed in the past, including: “the moral status of the embryo, the acceptability of making embryos for research or using embryos that would otherwise be discarded, and the legal or voluntary limits that apply to the use of embryos in research” (NASEM, 2017).

• In Europe, the regulatory regimes that could apply to the use of genome editing on human germline cells differ significantly among Member States and are sometimes ambiguous.45 Such variations in regulations, particularly those concerned with the use of embryos in research, reflect the different national ethical perspectives on this issue. This is also reflected by the fact that all European Member States have not signed nor ratified the Oviedo Convention (FEAM, 2017).46 It has been noted that these variations can challenge the development of a European framework on the use genome editing and impact research cooperation among EU Member States. Likewise, the unclarity of certain regulations regimes may hinder the sharing of data (Kipling, J, 2016). • For example, Italy prohibits research on embryos, including the use of embryos to derive stem cell lines, and bans the creation of embryos for research purposes (Kipling J, 2016), yet, permits the use of imported embryonic stem cells lines for research purpose. In Germany, the Embryo Protection Act of 1990 prohibits the generation and use of human embryos for basic research purposes and for harvesting embryonic stem cells (Bonas U et al., 2017). The importation of embryonic stem cell lines into Germany is permitted under strict conditions (Kipling J, 2016). • Research on human embryos is however allowed in other European countries such as France, the United Kingdom and Sweden. In France, the new 2013 regulatory framework legislation now permits the use of surplus IVF embryos for research purposes but prohibits the creation of human embryos as well as the creation of transgenic human embryos (French

43 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019). 44 Note regarding the advances in iPS and the blurring frontiers between somatic versus germline cells – focus on intent (i.e. reproductive purpose) (Kipling J, 2016). 45 For more, see Appendix 1 A review of regulatory governance for genome editing in Europe (Kipling J, 2016). 46 17 European Member States (out of 28) have ratified the Oviedo Convention. Austria, Belgium, Germany, Ireland, Malta and the UK are not parties. Italy, Luxembourg, the Netherlands, Poland and Sweden have signed but not ratified the Convention.

20 National Academy of Medicine, 2016).47 Some countries, including Belgium, the UK and Sweden however allow for the creation of human embryos for research.48 • In the UK, the legislation permits the use of surplus IVF embryos and the creation of human embryos for research purpose by IVF or cloning; the use of such IVF-derived embryos is allowed for up to 14 days after fertilization (Kipling J, 2016). The Human Fertilisation and Embryology Act 1990 regulates research on human embryos and gametes. Since 2008, it is permitted to apply genome editing technique in embryos and a further review in 2009 allows for the use of gametes for the purposes of research where fertilization is not involved (FEAM, 2016; The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015). Since October 2015, UK Regulations also permits mitochondrial donation treatment.49 Research on human embryos and gametes is subject to review by the Human Fertilisation and Embryology Authority. A license is required for each specific experiment. • In addition, the European Union also has a number of directives and regulations that are relevant to genome editing.50 Regarding European funding activities concerning genome editing research, while the EU funds research and clinical applications of somatic cells using genome editing, the European Commission Horizon 2020 states, in Article 19 (3), that the following fields of research shall not be financed:

“(a) research activity aiming at human cloning for reproductive purposes; (b) research activity intended to modify the genetic heritage of human beings which could make such changes heritable (1) (Research relating to cancer treatment of the gonads can be financed); (c) research activities intended to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including by means of somatic cell nuclear transfer.”51

Likewise, the European Commission has agreed to not fund research leading to the destruction of embryos (FEAM, 2016). However, this does not impede some Member States to undertake research on human embryos if their national legislation allows it.

Other countries, like Japan, allow the creation of human embryos for research. In Japan, draft guidelines have been issued to allow the use of gene-editing tools in human embryos (Cyranoski D, 2018). It is reported that the guidelines would restrict the editing of human embryos for reproduction purposes and would not be legally binding. The draft guidelines were open for public comment and are expected to be implemented in 2019.

In Australia, research is allowed on human embryos but prohibits modifications of embryonic cell of the human genome.52 In Chile (NASEM, 2017), Lithuania, Slovakia and Poland (Kipling J., 2016),

47 Law of 6 August 2013 and article L 2151-5 of the Public Health Code. 48 In the Netherlands, the Dutch Health Council recommended the creation of human embryos for research purposes. Xavier Symons, Dutch health council authorises the creation of human embryos for research, 1 April 2017, BioEdge.(https://www.bioedge.org/bioethics/dutch-health-council-authorises-the-creation-of-human-embryos-for- research/12249, accessed 28 May 2019). 49 The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 (https://www.legislation.gov.uk/ukdsi/2015/9780111125816/contents, accessed 28 May 2019). The UK regulations allow for mitochondrial replacement treatment in order to correct faulty mitochondrial DNA and using healthy mitochondria from a donor. Although the changes will be inherited and passed to other generations, because the changes do not affect DNA in the nucleus, it was not considered as “genetic modification”. (EASAC, 2017). Moreover, mitochondrial replacement therapy does not use genome editing. (NASEM, 2017; Nuffield Council on Bioethics (2012) Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review, available at: http://nuffieldbioethics.org/project/mitochondrial-dna-disorders/, accessed 28 May 2019. 50 Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells; Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products; Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use (Art.9 para. 6) and Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (Art.90). 51 Regulation (EU) no 1291/2013 of the European Parliament and of the Council of 11 December 2013 establishing Horizon 2020 - the Framework Programme for Research and Innovation (2014-2020) and repealing Decision No 1982/2006/EC. Official Journal of the European Union. L 347/104. 20.12.2013 (https://ec.europa.eu/research/participants/data/ref/h2020/legal_basis/fp/h2020-eu-establact_en.pdf, accessed 28 May 2019) 1 Research relating to cancer treatment of the gonads can be financed. 52 Article 15 of Prohibition of Human Cloning for Reproduction Act 2002.

21 research on human embryos is prohibited. South Korea also has strict regulations on human embryos research (Zastrow M, 2017).

In the United States, research using viable embryos is permitted in most U.S. States (a small number of U.S States prohibits such research) and, at the federal level, there is no prohibition on such research. However, it has been noted that research that exposes embryos to risk generally may not be funded by the U.S. Department of Health and Human Services (HHS).53 Research can however be funded from individual states and private sources (NASEM, 2017).

In the U.S., a report on genome editing made an in-depth analysis on the adequacy of U.S. oversight systems to address the specific technical and ethical issues raised by genome editing (NASEM, 2017). It is reported that, overall, while improvements could be made, the structure of the U.S. regulatory system is adequate. The report notes that both somatic and germline human genome editing would be regulated in the U.S. with the framework for research on gene-transfer and, once approved, for gene therapy (which cover work with human tissues and cells from laboratory research through preclinical testing, to human clinical trials, approval for medical therapy and post-approval surveillance) (NASEM, 2017).The report concludes that laboratory research involving human genome editing follows the same regulatory regimes than other basic laboratory in vitro research with human tissues. Moreover, the issues raised by genome editing are to be managed under existing ethical norms and regulatory regimes (NASEM, 2017). The report recommends that “Existing regulatory infrastructures and processes for reviewing and evaluating basic laboratory genome-editing research with human cells and tissues should be used to evaluate future basic laboratory research on human genome editing.” (NASEM, 2017).

Regulation of research and applications on somatic cells using genome editing

In Europe, it has been reported that regulations for gene therapy were generally appropriate for the oversight of genome editing applications in somatic cells and harmonized across European countries (Kipling J, 2016; EASAC, 2017, FEAM, 2016). Yet there might be a need to reconsider some aspects of the regulatory oversight in the clinical aspects of human somatic cell-based therapy, particularly where the methods of genome editing and therefore safety issues differ from those of conventional gene therapy (Kipling, 2016; FEAM 2017).

In terms of governance of gene therapy, a NASEM report provides some information regarding regimes in place in South Korea, the United Kingdom, Japan and Singapore (NASEM, 2017). It is noted that the regulatory pathways for gene therapy are similar to those in the United States in many points, in particular regarding the centrality of premarket risk and benefit assessment.54

In the US, where it is observed that there is substantial public support for the use of gene therapy, the NASEM committee underlines that the existing ethical norms and regulatory regimes developed for gene therapy can be applied to somatic cells genome editing applications. More specifically, four recommendations were made:

“(…) Existing regulatory infrastructure and processes for reviewing and evaluating somatic gene therapy to treat or prevent disease and disability should be used to evaluate somatic gene therapy that uses genome editing. (…) At this time, regulatory authorities should authorize clinical trials or approve cell therapies only for indications related to the treatment or prevention of disease or disability. (…) Oversight authorities should evaluate the safety and efficacy of proposed human somatic cell genome- editing applications in the context of the risks and benefits of intended use, recognizing that off-target events may vary with the platform technology, cell type, target genomic location, and other factors.

53 This is due to the Dickey-Wicker amendment, Public Law No.114-113, Division H, Title V, §508. Embryo research is therefore legal in most U.S. States but generally not funded by HHS (U.S. Federal funding for research on embryos is generally prohibited) (NASEM, 2017). 54 See also Appendix B (NASEM, 2017).

22 (…) Transparent and inclusive public policy debates should precede any consideration of whether to authorize clinical trials of somatic cell genome editing for indications that go beyond treatment or prevention of disease or disability.” (NASEM, 2017).

Genome editing applications on human germline cells

In Europe, the EU legislation prohibits deliberate changes to the genetic material in human germline cells and human embryos that could be used to establish a pregnancy (EASAC, 2017). As a result, it has been noted that if human germline cells and human embryo is to be allowed in the future, a change in the legislation would be required (Danish Council on Ethics, 2016). Moreover, 35 Member States of the Council of Europe have signed the Convention on Human Rights and Biomedicine (also known as the Oviedo Convention), 55 which is “the first and only internationally binding legal instrument in the field of biomedicine.” (Council of Europe, 2017a). Out of the 35 signatories States Parties to the Oviedo Convention, 29 States Parties have ratified the convention, which means that these States Parties are bound by the Oviedo Convention and that they have to implement the provisions of the Convention in their national laws (Council of Europe, 2017c).56

The Oviedo Convention, which provides a “common framework for the protection of human rights and human dignity in both longstanding and developing areas concerning the application of biology and medicine” (Council of Europe, 1997), includes a provision that prohibits any intervention with the aim of introducing a modification in the genome of any descendants.

Article 13 of the Oviedo Convention states that:

“An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes, and only if its aim is not to introduce any modification in the genome of any descendants.”

Some have underlined that the provision enclosed in Article 13 would benefit from greater clarity “to adequately address differences between basic research and potential clinical applications, and between somatic gene therapy and germline genetic alteration.” (FEAM, 2017). It was also noted that the Oviedo Convention was drafted to mostly address gene therapy developments and before the derivation of induced Pluripotent Stem Cells (iPS) cells (Kipling J, 2016). Others also maintained that “the Council of Europe should not reaffirm the ban on germline genome editing in humans” because this approach is “now outdated, overly restrictive and will hamper promising research for germline gene therapy.” (Sykora P, Caplan A, 2017a). Others have disagreed with this view and have pointed out that the Oviedo Convention is “firmly rooted in the principles of human rights and dignity” and it “mischaracterizes the Convention” to explain that “the original ban on germline modification as motivated by concerns about safety and efficacy” (Baylis F, Ikemoto L, 2017).57 In October 2017, the Parliamentary Assembly of the Council of Europe adopted a recommendation urging “Member States which have not yet ratified the Oviedo Convention to do so without further delay, or, as a minimum, to put in place a national ban on establishing a pregnancy with germ-line cells or human embryos having undergone intentional genome editing; (…)” and to “foster a broad and informed public debate on the medical potential and possible ethical and human rights consequences of the use of new genetic technologies in human beings; (…)” (Council of Europe, 2017b).

Moreover, 16 European Member States are reported to ban research on human germline modification (particularly that involving human embryos) (FEAM, 2016). For instance, France prohibits the introduction of any alteration into the genome of any descendant (French National Academy of Medicine, 2016).58 In Germany, section 5 of the 1990 Embryo Protection Act on the artificial alteration of human germ line cells, states that “(1) Anyone who artificially alters the genetic information of a human germ line cell will be punished with imprisonment up to five years or a fine. (2) Likewise

55 The 1997 Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164, “Oviedo Convention”) (https://www.coe.int/en/web/conventions/full-list/-/conventions/rms/090000168007cf98, accessed 28 May 2019). 56 For the difference between signature and ratification, see http://ask.un.org/faq/14594, accessed 28 May 2019. 57 See reply by Sykora P, Caplan A (2017b). 58 France Article 16-4 Civil Code (https://www.legifrance.gouv.fr/affichCodeArticle.do?cidTexte=LEGITEXT000006070721&idArticle=LEGIARTI000006419299, accessed 28 May 2019).

23 anyone will be punished who uses a human germ cell with artificially altered genetic information for fertilisation. (…)”.59 In the UK, the use of genome editing for reproductive purposes is illegal, but this prohibition does not however apply to mitochondrial replacement therapy. Since 2015, mitochondrial donation is permitted in the UK.60

A survey on the international regulatory environment has shown that the international legislative oversight of genome editing is diverse and sometimes ambiguous. Out of the 39 countries surveyed, 29 were prohibiting human germline gene modification (Araki M, Ishii T, 2014). Among these 29 countries, it was noted that China, India, Ireland and Japan had prohibited germline gene editing with guidelines, which are less enforceable than laws, and that could be subject to amendment. The remaining 10 countries, which include Argentina, Greece, Iceland, Peru, Russia, Slovakia, South Africa and the USA, were reported as having ambiguous legislations on the status of the human germline gene modification (Kipling J, 2016).

In another study, 16 countries were sampled to provide a global “snapshot” of the array of policies and legislatives approaches “regarding human germline editing, human embryonic stem cell research, human reproductive cloning, human research cloning, human somatic gene therapy, and pre- implantation genetic diagnosis (…).” (Isasi et al., 2016). The study reviews the different countries’ legislations and policies along a spectrum ranging from restrictive to more permissive approaches. The authors of the study reported that one problem that was found in all the approaches was “vagueness in distinctions between clinical and research applications, as well as in basic definitions.” (Isasi et al., 2016).

Another report has also reviewed the legal frameworks governing the research and possible clinical applications of human genome editing at the international level (including the Oviedo Convention and the EU Charter of Fundamental Rights) and in selected domestic jurisdictions (Australia, France, Germany, India, Israel, Japan, Mexico Russia, USA) (Yotova R, 2017). Another group of scholars has also analyzed the regulatory and legal situation of human embryo, gamete and germ line gene editing research and clinical applications in the People’s Republic of China (Rosemann A et al., 2017). It is reported that although there are legal and regulatory instruments to influence researchers’ decisions and possibilities, there is no regulation that directly addresses basic and preclinical human genome editing and that “The regulatory landscape for basic and preclinical research in this field is permissive” (Ishii T, 2015; Rosemann A et al., 2017).61

Australia has also prohibited heritable alterations to the genome as a criminal offence.62 In Canada, the Assisted Human Reproduction Act states under section 5 (f) that “No person shall knowingly (…) alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants; (…).”63

In India, it has been reported that the most relevant legislation to genome editing is the Pre- Conception and Pre-Natal Diagnostic Techniques Act 1994 (as amended 2002) which prohibits sex selection before and after conception and regulate pre-natal diagnostic techniques (Yotova R, 2017). India also has two non-binding guidelines issued by the Indian Council of Medical Research that address genome editing (Yotova R, 2017). The National Ethical Guidelines for Biomedical Research and Health Research involving Human Participants64 includes a prohibition on germ line therapy “under the present state of knowledge”, enhancement of genetic characteristics and eugenic genetic engineering (Indian Council of Medical Research, 2017). The National Guidelines for Stem Cell Research65 includes a prohibition in the following areas of stem cell research: “(…) Research related

59 Act for Protection of Embryos (The Embryo Protection Act) Of 13th December 1990. Federal Law Gazette, Part I, No. 69, issued in Bonn, 19th December 1990, page 2746. (https://www.rki.de/SharedDocs/Gesetzestexte/Embryonenschutzgesetz_englisch.pdf?__blob=publicationFile, accessed 28 May 2019). 60 Human Fertilisation and Embryology. The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015. 2015 No. 572 (http://www.legislation.gov.uk/uksi/2015/572/pdfs/uksi_20150572_en.pdf, accessed 28 May 2019). 61 For more details, see Rosemann A et al., 2017. 62 Australia’s Prohibition of Human Cloning for Reproduction Act 2002 (https://www.legislation.gov.au/Details/C2017C00306, accessed 28 May 2019). 63 Assisted Human Reproduction Act, S.C. 2004, c. 2, Assented to 2004-03-29 (https://laws-lois.justice.gc.ca/eng/acts/a- 13.4/page-1.html, accessed 28 May 2019). 64 https://www.icmr.nic.in/sites/default/files/guidelines/ICMR_Ethical_Guidelines_2017.pdf, accessed 28 May 2019. 65 https://www.icmr.nic.in/sites/default/files/guidelines/Guidelines_for_stem_cell_research_2017.pdf, accessed 28 May 2019.

24 to human germ line gene therapy and reproductive cloning. (…) Use of genome modified human embryos, germ-line stem cells or gametes for developmental propagation. (…) Research involving implantation of human embryos (generated by any means) after in vitro manipulation, at any stage of development, into uterus in humans or primates.” (Indian Council of Medical Research, Department of Biotechnology, 2017).

In New Zealand, it has been reported that “(…) any treatment that is aimed at altering the genomic constitution of a person or introducing genetic material from another organism for therapeutic purposes would be regulated primarily by the Hazardous Substances and New Organisms Act 1996 (HSNO Act). This is a non-exclusive code for new organisms, limited to new organisms identified post 1998, and genetically modified organisms developed using in vitro techniques. An added level of regulation is imposed when the modification is made in the reproductive context (e.g. pre-implantation genetic modification of embryos) governed by the Human Assisted Reproductive Technology Act 2004 (HART Act). Restrictions on specified biotechnical procedures, referring primarily to xenotransplantation, are regulated by the Medicines Act 1981 (Medicines Act).”66 The 2004 Human Assisted Reproductive Technology Act states, under section 8 “Prohibited actions” (1) that “Every person commits an offence who takes an action described in Schedule 1.” Schedule 1 includes “8. Implant into a human being a genetically modified gamete, human embryo, or hybrid embryo.”67

In the U.S., it is currently impossible for authorities to review proposals for clinical trials of heritable genome editing. There is an ongoing prohibition on the U.S. Food and Drug Administration (FDA) to use federal funds to review “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.”68 Likewise, the NIH has stated that they will not fund any use of gene editing technologies in human embryos (Collins FS, 2015). Moreover, given the recent scientific and clinical advances in the field of gene therapy, the NIH and the FDA are currently working together to streamline the oversight framework in order to eliminate “unnecessary duplicative reporting requirements” (Collins FS, 2018a). The NIH also plans to restore the NIH Recombinant DNA Advisory Committee (RAC).69

For others, in some situations, such as heritable genetic diseases, “heritable genome editing would provide the only or the most acceptable option for parents who desire to have genetically related children while minimizing the risk of serious disease or disability in a prospective child.” (NASEM, 2017). The NASEM committee however recognizes there is significant public discomfort about heritable genome editing in other situations. It is concluded that “Heritable genome-editing trials must be approached with caution, but caution does not mean they must be prohibited.” (NASEM, 2017). Some have pointed out that by taking such a stance, “the report reveals a subtle but, at the same time, important shift in the evaluation of ethical accountability. It switches from “not allowed as long as the risks have not been clarified” to “allowed if the risks can be assessed more reliably”. It is clear that the US-American academies are no longer focusing on a partially fundamental, partially risk-related strong rejection of germline therapy by genome editing but on a fundamental permission guided by individual formal and material criteria.” (German Ethics Council, 2017).

Proposed additional policies on genome editing

In addition to the tenure of the aforementioned international summits and other national and regional meetings, the governance of genome editing is already taking place in several countries under existing regulatory mechanisms and ethical frameworks.70 Choosing this path of governance would therefore be equivalent to not taking any additional or specific action to govern genome editing and relying on the implementation of existing regulations and regimes. It does not mean however that

66 Royal Society Te Apā rangi Gene Editing Panel (2017). Gene Editing in a Healthcare Context. https://royalsociety.org.nz/assets/Uploads/Gene-editing-in-healthcare-technical-paper.pdf, accessed 28 May 2019. The 1981Medicine Act is currently under review https://www.health.govt.nz/our-work/regulation-health-and-disability- system/therapeutic-products-regulatory-regime, accessed 28 May 2019. See https://www.health.govt.nz/our-work/regulation- health-and-disability-system/therapeutic-products-regulatory-regime, accessed 28 May 2019. 67 New Zealand Act and Human Assisted Reproductive Technology Act (http://www.legislation.govt.nz/act/public/2004/0092/latest/whole.html#DLM319832, accessed 28 May 2019). 68 Consolidated Appropriations Act of 2016, HR 2029, 114 Cong., 1st sess. (January 6, 2015) (NASEM, 2017) 69 See also https://www.federalregister.gov/documents/2018/08/17/2018-17760/national-institutes-of-health-nih-office-of- science-policy-osp-recombinant-or-synthetic-nucleic-acid, accessed 28 May 2019. 70 Governance is understood as more than just a set of regulations. See Background paper 2 on the non-human applications of genome editing.

25 those choosing this path do not recognize concerns associated with genome editing but rather that they believe that existing oversight regimes fit the purpose. Inaction could however mean that genome editing is not perceived as a risk and that there is therefore no need to manage it.

Different stakeholders (from international organizations, to national academies of sciences and medicine, bioethics committees, journal editors, patient and some representatives of the private sector) have proposed additional policy options to govern genome editing technologies. These policy options are not necessarily exclusive to each other; some could in fact be complementary. They differ in their nature and range from “soft” instruments (i.e. principles for governance, self-governance) to “hard” laws (i.e. legally binding) ones. Indeed, it has been underlined that there is an “ecosystem” with various legal and regulatory initiatives and that “The ecology of this system is one in which there are many legal or policy issues that combine to affect whether biotechnology is promoted or hindered in any particular country.” (Charo RA, 2016). Moreover, different approaches and visions as to how countries will address the governance of biotechnology have been identified: from a promotional approach; a more neutral approach; a precautionary and; to an absolutely prohibitive system (Charo RA, 2016).

Review of existing regulations and development of standards for safety and efficacy for genome editing

Some reports have underlined a number of points to consider in the review and adoption of oversight regimes and decisions about research and clinical uses of genome editing for genome editing technologies. These include:

• Policies/regulations should demarcate research use of genome editing from potential clinical use, carefully distinguishing the use of somatic and germ cells (The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015); • Policies should consider using a product-based approach instead of a processed/technology- based approach (KNAW, 2016; EASAC, 2017);71 • Regulations of applications should be evidence-based, taking into account both the potential risks and benefits, proportionate and flexible to cope with future scientific and technologies advances (EASAC, 2017).

Others have also pointed out that regulations should be made through inclusive and deliberative processes that will make engagement with the public and policymakers substantive. Decisions should aim to strike the best possible balance between free scientific inquiry and social values (The Hinxton Group, 2015). Likewise, it was reported that regarding the policies about the regulation of clinical applications, some have noted that there should be a distinction between objections which are based on technical and safety concerns and objections that reflect additional moral considerations. While technical and safety concerns might be resolved over time by further scientific research and advances, moral considerations may continue to be the focus of public debate (The Hinxton Group, 2015). Moreover, as mentioned in section 3, the use genome editing technologies still poses a number of scientific challenges that need to be addressed. Proposals to support this endeavor have been reported (The Hinxton group, 2015).72

In Europe, FEAM supports a review of the European regulatory framework to review the techniques associated with somatic gene therapy (which fall under the Advanced Therapy Medicinal Products (ATMP) and the European Medicines Agency (EMA)) with the participation of researchers involving both academic and commercial sectors as well as patient’s sector (FEAM, 2017). As noted earlier, genome editing is different from gene therapy, which uses viral vectors, and it has therefore been underlined that it is not clear whether the current safety assessments would be appropriate for genome applications (Kipling J, 2016; FEAM, 2017).

71 This risk framing approach has been criticized by others. For more, see Nuffield Council on Bioethics, 2016 and Background paper 2 on the non-human applications of genome editing. 72 The Hinxton Group is an international and interdisciplinary consortium on stem cells, ethics and law, established to explore the ethical and policy challenges of transnational scientific collaboration. (http://www.hinxtongroup.org/au.html, accessed 28 May 2019).

26 Moratorium

Several stakeholders have also proposed another policy, namely the call for a moratorium on human germline editing.

In March 2015, some representatives from the gene therapy industry (working in companies developing therapeutics involving somatic cells) called for a voluntary moratorium in the scientific community (Lanphier E et al., 2015). This moratorium could be used to discourage human germline modification and raise public awareness on the difference between these two techniques (germline and somatic modifications). It is underlined that “heritable human genetic modifications pose serious risks, and the therapeutic benefits are tenuous”. They underlined the grave concerns regarding the ethical and safety implications of this research but also their fears that these concerns could negatively impact the important work involving the use of genome-editing techniques in somatic (non- reproductive) cells (Lanphier E et al., 2015).

In September 2015, a statement from German Academies called for an international voluntary moratorium “on all forms of human germline engineering that could have an impact on the genome of the offspring.” (Leopoldina et al., 2015). It is argued that such moratorium would provide opportunities to debate unresolved concerns, to harmonize the definitions of certain terms, to assess the benefits and risks of the technologies as well as develop recommendations for regulations. It is noted that it should however not constitute a general restriction on methodological developments or limit any promising genome editing approaches for use in research and application.

Later that year, in October 2015, the report of the International Bioethics Committee (IBC) of UNESCO on Updating Its Reflection on the Human Genome and Human Rights called on states and governments to: “ (…) agree on a moratorium on genome engineering of the human germline editing, at least as long as the safety and efficacy of the procedures are not adequately proven as treatments” (UNESCO, 2015).73 In accordance with Article 24 of the Universal Declaration on the Human Genome and Human Rights (11 November 1997),74 the IBC provided a report updating its reflection on the human genome and human rights and also called for a wide public debate on the modification of human DNA. The report was triggered by recent advances in genetics and their associated ethical responsibilities. The IBC made several recommendations to different stakeholders (States and governments; scientists; media an educators and economic actors), and in addition to the call for a moratorium, States and governments are called on to:

(…) “c. Renounce the possibility of acting alone in relation to engineering the human genome and accept to cooperate on establishing a shared, global standard for this purpose, building on the principles set out in the Universal Declaration on the Human Genome and Human Rights and the Universal Declaration on Bioethics and Human Rights; d. Encourage, through the means of national legislation as well as international regulations, the adoption of rules, procedures and solutions, which can be as non-controversial as possible, especially with regard to the issues of modifying the human genome and producing and destroying human embryos. (…)

The IBC also underlined the crucial importance of a discussion, at the global level, involving scientists and bioethicists to reflect on the consequences of new human genome technologies. It also

73 UNESCO International Bioethics Committee (IBC) (2015). Report of the IBC on Updating its Reflection on the Human Genome and Human Rights. SHS/YES/IBC-22/15/2 REV.2, Paris (https://unesdoc.unesco.org/ark:/48223/pf0000233258, accessed 28 May 2019). See also: Universal Declaration on Bioethics and Human Rights (2005) (http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/bioethics-and-human-rights/, accessed 28 May 2019; International Declaration on Human Genetic data (2003) (http://www.unesco.org/new/en/social-and-human- sciences/themes/bioethics/human-genetic-data/, accessed 28 May 2019); Universal Declaration on the Human Genome and Human Rights (1997) (http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/human-genome-and- human-rights/, accessed 28 May 2019). 74 “Article 24 The International Bioethics Committee of UNESCO should contribute to the dissemination of the principles set out in this Declaration and to the further examination of issues raised by their applications and by the evolution of the technologies in question. It should organize appropriate consultations with parties concerned, such as vulnerable groups. It should make recommendations, in accordance with UNESCO’s statutory procedures, addressed to the General Conference and give advice concerning the follow-up of this Declaration, in particular regarding the identification of practices that could be contrary to human dignity, such as germ-line interventions.” The Universal Declaration on the Human Genome and Human Rights, which was adopted 11 November 1997 by the UNESCO's 29th General Conference, is an international instrument for the protection of the human genome (http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/human-genome-and- human-rights/, accessed 28 May 2019).

27 recommended that the precautionary principle should be respected, “ensuring that substantial consensus of the scientific community on the safety of new technological applications be the premise for any further consideration.” (UNESCO, 2015).

Professional societies such as the Society for Developmental Biology and the Editors of the journal Developmental Biology supported “a voluntary moratorium by members of the scientific community on all [emphasis in original] manipulation of pre- implantation human embryos by genome editing.” (SDB, 2015). The International Society for Stem Cell Research has also called for a moratorium on attempts to apply nuclear genome editing of the human germ line in clinical practice (ISSCR, 2015). This moratorium should enable more extensive scientific analysis of the potential risks of genome editing and broader public discussion of the societal and ethical implications.

In January 2016, the European Group on Ethics in Science and New Technologies expressed the view that there should be a moratorium on gene editing of human embryos or gametes that would result in the modification of the human genome (EGE, 2016). The group also noted that it did not support the idea of a moratorium on research with a clinical application, as distinct from basic research. They note that there should be caution in terms of whether there is such a clear-cut distinction between basic and translational research.75

Others, such as the Federation of European Academies of Medicine (FEAM), while recognizing the existence of many unresolved questions, in particular those associated with ethical, safety and efficacy issues, and the lack of societal consensus on this subject in Europe, did not support the idea of a moratorium (FEAM, 2017). Likewise, the Inserm Bioethics Committee did not support the idea of a moratorium because it was thought not credible and would not have the same international consensus as the Asilomar moratorium (Inserm, 2016). In the UK, the call for a moratorium was also rejected by scientists on the ground that it would be unenforceable and “would risk driving research underground” (Hawkes N, 2015). In this respect, a moratorium was therefore deemed not feasible, even if it were desirable (Adashi EY, Cohen IG, 2015; Hawkes N, 2015; Nuffield Council on Bioethics, 2016).

Public engagement and ongoing public dialogue

Over the course of these past years and since the discovery of CRISPR-Cas 9, there has been a broad consensus for the need to engage the public in the genome editing debate. This was expressed in different statements and reports calling for an ongoing international forum (Baltimore D et al., 2015)76, public engagement (The Hinxton Group, 2015; NASEM, 2017; FEAM, 2017; EASAC, 2017; Shukla-Jones A et al., 2018), inclusive (EGE, 2016) and public debate (ISSCR, 2015; Leopoldina et al., 2015; CoE, 2015; French National Academy of Medicine, 2016; KNAW, 2016), ongoing public dialogue (FEAM, 2017), dialogue with civil society (COGEM, Health Council of the Netherlands, 2017), broad public and international dialogue (ISSCR, 2015), multistakeholder approach to regulatory decisions (Genetic Alliance UK, 2016); active (…) engagement (The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015). These calls have been made from different stakeholders (e.g. scientific societies, professional institutions, national academies and bioethicists and patient sector).

One of the first international call for public engagement was made in 2015 at International Summit on Human Gene editing. The organizing committee called for an ongoing forum. Recognizing that the genome is shared among all nations, the international community should aim at establishing norms concerning acceptable uses of human germline editing and at harmonizing regulations.77

More specifically, the ongoing forum would be aimed at discussing the potential clinical uses of gene editing; helping to inform decisions by national policymakers and others; to develop recommendations and guidelines; and to encourage coordination among nations. Moreover, this forum should be

75 Some EGE members considered that research into human germline gene modification for reproductive purposes cannot be ethically justified. Moreover, because of the blurring lines between basic and applied research, they called for a moratorium on any basic research involving human germline modification until a regulatory framework is developed. For other EGE members, some aspects of research are justified (EGE, 2016). 76 First and Second International Summits on Genome Editing 2015 and 2918. 77 On Human Gene Editing: International Summit Statement by the Organizing Committee, December 2015, (https://www.nap.edu/read/21913/chapter/1 - 7, accessed 28 May 2019).

28 “inclusive and engage a wide range of perspectives and expertise – including from biomedical scientists, social scientists, ethicists, health care providers, patients and their families, people with disabilities, policymakers, regulators, research funders, faith leaders, public interest advocates, industry representatives, and members of the general public.”78

In 2018, the organizing committee called for an ongoing international forum “to foster broad public dialogue, develop strategies for increasing equitable access to meet the needs of underserved populations, speed the development of regulatory science, provide a clearinghouse for information about governance options, contribute to the development of common regulatory standards, and enhance coordination of research and clinical applications through an international registry of planned and ongoing experiments.”79

In the US, public engagement has been reported as an important part of regulation and oversight of new technologies (NASEM, 2017). In particular, the NAS committee notes that such engagement should precede any clinical trials for the human germline trials and that public participation should be sought for the policy process concerning “enhancement”. Funding of human genome editing research should also consider funding research activities on public engagement and communication associated with this issue. The NASEM report also reviews the current mechanisms in place in the U.S. for public engagement and concludes that existing public communication and engagement infrastructures are sufficient to address oversight of basic and laboratory research on human genome editing. A similar conclusion is drawn to address somatic applications of human genome editing techniques, with some areas for improvement. With regard to the applications of genome editing of the human germline, it is underlined that more formalized efforts will be required to solicit public input and public debate (NASEM, 2017).

In Europe, the Council of Europe Bioethics Committee underlined that the Oviedo Convention provides the principles that could be used to inform debates at the international level (CoE, 2015). Furthermore, the FEAM underlined the need for increased public engagement in the development of genome editing and calls upon the DG Research and Innovation, with DG SANCO [Directorate- General for Health and Food Safety], to establish a new public engagement initiative (FEAM, 2017). FEAM also underlined the importance of developing an agreed lexicon and the need to make clear distinctions in public communication programs between genome editing techniques in basic and applied research and in somatic and human germline cells.

In their joint statement, the five leading UK funding agencies for biomedical research note the need for an “active early engagement with a wide range of global stakeholders” which should include, but not be limited to, “biomedical and social scientists, ethicists, healthcare professionals, research funders, regulators, affected patients and their families, and the wider public.” (The Academy of Medical Sciences, Association of Medical Research Charities, BBSRC, MRC and Wellcome Trust, 2015).

The EASAC also recommends public engagement as a way of building trust between the scientists and the public. Stakeholders, such as patients, clinicians, farmers, consumers and NGOs, need to be engaged in discussions concerning risks and benefits. Moreover, “scientists need to articulate the objectives of their research, potential benefits and risk management practices adopted. This is not a special responsibility for genome researchers, as all scientists have the responsibility to be open and candid about their work (…). There is need for additional social science and humanities research to improve public engagement strategies.” (EASAC, 2017).

Similarly, the EGE considers that there is a need for a broad public and inclusive debate, which includes civil society, to discuss the acceptability and desirability of gene editing. The EGE warned against reducing the debate to safety issues and the potential health risks or health benefits of gene editing technologies. Moreover, it noted that ethical principles such as human dignity, justice, equity, proportionality and autonomy clearly need to be considered.

78 On Human Gene Editing: International Summit Statement by the Organizing Committee, December 2015, https://www.nap.edu/read/21913/chapter/1 - 7, accessed 28 May 2019). 79 Second International Summit on Human Genome Editing. November 27-29, 2018, Hong-Kong. (http://www.nationalacademies.org/gene-editing/2nd_summit/, accessed 28 May 2019).

29 The German Ethics Council has been calling for a global debate and international regulations (German Ethics Council, 2017). There should be a debate and a decision on “whether systematic, transgenerational modifications to the human genome are to be prohibited or authorised and, if they were to be authorised in principle, the extent to which they would need to be limited by conditions and restrictions” (German Ethics Council, 2017). Moreover, it is noted that “it is not an internal affair of the scientific community. Nor is it a matter for one country alone (…)”. It is argued that the scientific community must engage “in open-ended discussions with all relevant groups amongst the public at large. In parallel to this, the political institutions can and must find ways and initiate processes to discuss the numerous, as yet, unanswered questions and possible consequences of systematic genome manipulations through genome editing in an intensive, differentiated and, above all, global manner, and draw up the necessary regulatory standards as quickly and comprehensively as possible.” (German Ethics Council, 2017). The report puts forward a set of issues and problems that should be answered and clarified “on all levels up to the politically constituted global community (…)” (German Ethics Council, 2017).

Some have also underlined the importance of “being systematic about public engagement” and that there is a “need for public engagement at an early stage in the process of research and development. Engagement processes must be balanced, and stakeholders should be wary of “overselling” the technology. A central lesson of systematic work on public engagement is that openness, transparency and participation are key. It is more appropriate to talk about different “publics” that need to be engaged in different contexts than a single “public”.” (Garden H, Winickoff D, 2018). In this regard, it has been suggested that “Governance frameworks under the rubric of “Responsible Research and Innovation” are seeking to address this issue in a more systematic way by bringing together an array of mechanisms into toolkits and usable resources.” (Garden H, Winickoff D, 2018).

Given that genome editing is likely to generate a broad set of social and moral questions, a new kind of public engagement model has been argued for (Burall S, 2018). A consortium composed initially of 10 to 15 organizations would have two functions: “connecting people to the science and policy debates, and connecting scientists and policy makers to other people.” (Burall S, 2018). The consortium would disseminate information, promote debates and connect communities. As a first step, the consortium could commission social scientists and others to map out the level of engagement and knowledge of different communities regarding genome editing and in the longer term, there might be the commissioning of “more-conventional engagement processes around specific policy decisions”.

Some have further analyzed the idea of global involvement under the idea of a “global observatory” on gene editing, which would be an international network of scholars and organizations to exchange ideas on the governance of genome editing in a different manner to the ones that may have been done until now (Jasanoff S, Hurlbut JB, 2018). For instance, a global observatory would serve as a clearing house and gather information from sources and perspectives that have been often overlooked, it would broaden the analysis from the risks and benefits of the new technology to a richer range of concerns that may have been disregarded and would promote exchange across disciplinary and cultural divides and would convene regular meetings. The global observatory would “reframe the questions”, moving from the limited ethical analysis of human genome editing on the physical safety of the technology to the “central question of how to care for and value human life, individually, societally and in relation to other forms of life on Earth.” (Jasanoff S, Hurlbut JB, 2018).

It has also been observed that the “public have an interest [emphasis in original] in science, in terms of its expectation of net social benefits, and invests [emphasis in original] in science both financially and through the trust placed in scientists to contribute to the delivery of these benefits. But more profoundly than this, the public have an underlying public interest in the overall moral and ethical texture of the society in which they live.” (Nuffield Council on Bioethics, 2016). Issues arising from the governance of genome technologies need to be addressed at a public level and there is an importance of having an effective public sphere.

Nonetheless, even if the idea of public engagement itself is not new, its implementation is still challenging (NASEM, 2017). Indeed, there might be challenges to replicating such engagement processes in some settings for a variety of reasons (including cultural and resource constraints). Moreover, in countries where it is a requirement to engage the public in the policy-making process, weaknesses in public engagement processes may arise (NASEM, 2017). Nevertheless, as it has

30 been pointed by some, “good deliberative processes need to be recursive as well as inclusive” (Jasanoff S et al., 2015). Public engagement has also been reported as being a constituent of the trust between scientists and the public (EASAC, 2017). It is further reported that the debates on risks and benefits of the technologies and of their management as well as discussions on the objectives of research need to involve stakeholders including, for instance, patients, clinicians, farmers, consumers and NGOs (EASAC, 2017).80

Development of principles and specific regulatory mechanisms for governing human genome editing

The NASEM committee has recommended 7 overarching principles and corresponding responsibilities for the Governance of the Human Genome editing that countries might adopt for the governance of human genome editing. These are: 1) Promoting well-being; 2) Transparency; 3) Due care; 4) Responsible science; 5) Respect for persons; 6) Fairness; and 7) Transnational cooperation. (This is for basic research and clinical applications, both on somatic and germline cells) (NASEM, 2017). The committee also recommended a regulatory framework comprising a set of ten criteria if clinical trials on the human germline are to proceed, either if the U.S. restrictions were to change or for countries that have no prohibition on modifying the human germline (NASEM, 2017).

Representatives from more than 20 European partners have also recommended “the foundation of an expert group (European Steering Committee) to assess the potential benefits and draw-backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology.” (Chneiweiss H et al., 2017). The authors of this consensus paper also proposed to adopt a set of general principles: “(1) To foster research that will assess the feasibility, the efficacy and the safety of genome editing techniques (…); (2) To evaluate the potential adverse effects of gene drive applications (…); (3) To reassess the ban on all modifications of the germ line nuclear genome for clinical application in human reproduction (…); (4) To be pro-active to prevent this technology from being hijacked by those with extremist views and to avoid misleading public expectation with overinflated promises (…); (5) To raise awareness about the distinction between the care/treatment of human diseases and human enhancement.” Moreover, it is reported that “this European Steering Committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation.” (Chneiweiss H et al., 2017). In 2017, an international association named “Association for Responsible Research and Innovation in Genome Editing”, ARRIGE, was established to promote a global governance of genome editing.81

Another group of funding organizations has endorsed a set of guiding principles for gene drive research and their endorsement would represent “a pledge to advance the foundational elements of efficient and responsible research conduct: evidence, ethics, and engagement (…)”. (Emerson C et al. 2017). These principles are: advance quality of science to promote the public good; promote stewardship, safety, and good governance; demonstrate transparency and accountability; engage thoughtfully with affected communities, stakeholders, and publics; foster opportunities to strengthen capacity and education. Although gene drive is a non-human application of genome editing, these guiding principles are an illustration of another set of principles developed by the funders and sponsors of research.

The setting up of global registry (or national registries) has also been proposed. This regulatory system would be established by funding bodies or governments to record preclinical research associated with gene editing in human embryos (Nature Ed., 2018). This registry would include the objectives of the research, describe the ethical and research oversight processes, as well include the risks and benefits of the research and eventually of its applications.

80 See for instance public engagement and gain-of-function research, Monica Schoch-Spana. Public deliberation and Gain-of- Function. Research policy: putting it into practice. Gain-of-Function Research: The Second Symposium (March 10-11, 2016) at the National Academies of Sciences, Engineering, and Medicine (https://www.scribd.com/document/305218577/Public- Deliberation-and-GOF-Research-Policy-Putting-It-Into-Practice-Monica-Schoch-Spana, accessed 28 May 2019). 81 https://arrige.org/arrige_initial_document.pdf, accessed 28 May 2019.

31 References

Academy of Medical Sciences, Association of Medical Research Charities, Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust (2015). Genome editing in human cells – initial joint statement. (https://wellcome.ac.uk/sites/default/files/wtp059707.pdf, accessed 28 May 2019).

Adashi EY, Cohen IG (2015). Editing the genome of the human germline: may cool heads prevail. The American Journal of Bioethics 15(12):40-42. DOI: 10.1080/15265161.2015.1103805

Araki M, Ishii T (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reproductive Biology and Endocrinology 12(1):108. (https://doi.org/10.1186/1477-7827-12-108, accessed 28 May 2019).

ARRIGE Steering Committee (2018). Statement from ARRIGE Steering Committee on the possible first gene-edited babies. 3 December 2018. (https://arrige.org/ARRIGE_statement_geneeditedbabies.pdf, accessed 28 May 2019).

Australian Academy of Science (2017). Synthetic gene drives in Australia: implications of emerging technologies. Discussion paper. May 2017. (https://www.science.org.au/support/analysis/reports/synthetic-gene-drives-australia-implications-emerging-technologies, accessed 28 May 2019).

Baltimore D, Berg P, Botchan M, Carroll D, Charo RA, Church G, Corn JE, Daley GQ, Doudna JA, Fenner M, Greely HT, Jinek M, Martin GS, Penhoet E, Puck J, Sternberg SH, Weissman JS, Yamamoto KR (2015). A prudent path forward for genomic engineering and germline gene modification. Science 348(6230):36-38. DOI: 10.1126/science.aab1028

Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819):1709–1712. DOI: 10.1126/science.1138140

Baylis F (2019). Questioning the proposed translational pathway for germline genome editing. Nature Human Behaviour 3(3):200. DOI: 10.1038/s41562-019-0544-3

Baylis F, Darnovsky, M (2019). Scientists Disagree About the Ethics and Governance of Human Germline Editing. Bioethics Forum Essay. 17 January 2019. (https://www.thehastingscenter.org/scientists-disagree-ethics-governance-human-germline-genome-editing/, accessed 28 May 2019).

Baylis F, Ikemoto L (2017). The Council of Europe and the prohibition on human germline genome editing. EMBO reports 18(12):2084-2085. DOI 10.15252/embr.201745343 (http://embor.embopress.org/content/18/12/2084, accessed 28 May 2019).

Baylis F, McLeod M (2017). First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready? Current Gene Therapy 17(4): 309–319. DOI: 10.2174/1566523217666171121165935 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769084/, accessed 28 May 2019).

Bonas U, Friedrich B, Fritsch J, Mü ller A, Schö ne-Seifert B, Steinicke H, Tanner K, Taupitz J, Vogel J, Weber M, Winnacker E- L (2017). Ethical and legal assessment of genome editing in research on human cells. Discussion Paper Nr 10. German Academy Leopoldina. (https://www.leopoldina.org/uploads/tx_leopublication/2017_Diskussionspapier_GenomeEditing_01.pdf, accessed 28 May 2019).

Brokowski C (2018). Do CRISPR Germline Ethics Statements Cut It? The CRISPR Journal 1(2):115-125 (https://doi.org/10.1089/crispr.2017.0024, accessed 28 May 2019).

Burall S (2018). Rethink public engagement for gene editing. Nature 555(7697):438-439. DOI: 10.1038/d41586-018-03269-3 (https://www.nature.com/magazine-assets/d41586-018-03269-3/d41586-018-03269-3.pdf, accessed 28 May 2019).

Callaway, E (2016a). Second Chinese team reports gene editing in human embryos. Nature News DOI:10.1038/nature.2016.19718 (https://www.nature.com/news/second-chinese-team-reports-gene-editing-in-human-embryos-1.19718, accessed 28 May 2019).

Callaway, E (2016b). Embryo-editing research gathers momentum. Nature 532(7599):289-290. DOI: 10.1038/532289a (https://www.nature.com/polopoly_fs/1.19767!/menu/main/topColumns/topLeftColumn/pdf/532289a.pdf, accessed 28 May 2019).

Charo RA (2015). Yellow lights for emerging technologies. Science 349(6246):384-385. DOI: 10.1126/science.aab3885

Charo RA (2016). The Legal and Regulatory Context for Human Gene Editing. Issues in Science and Technology 32(3) (Spring 2016). (https://issues.org/the-legal-and-regulatory-context-for-human-gene-editing/, accessed 28 May 2019).

Chneiweiss H, Hirsch F, Montoliu L, Müller AM, Fenet S, Abecassis M, Merchant J, Baertschi B, Botbol-Baum M, Houghton JA, Kritikos M, Mifsud J, Bartnik E, Rath J, Druml C, Friedrich B, Carvalho AS, Lanzerath D, Saint-Raymond A (2017).

32 Fostering responsible research with genome editing technologies: a European perspective. Transgenic Research 26(5):709– 713. DOI 10.1007/s11248-017-0028-z (https://link.springer.com/content/pdf/10.1007%2Fs11248-017-0028-z.pdf, accessed 28 May 2019).

Clapper JR (2016). Statement for the Record. Director of National Intelligence February 9, 2016. Worldwide Threat Assessment of the US Intelligence Community Senate Armed Services Committee. (https://www.dni.gov/files/documents/SASC_Unclassified_2016_ATA_SFR_FINAL.pdf, accessed 29 May 2019).

Collins FS (2015). Statement on NIH funding of research using gene-editing technologies in human embryos. 28 April 2015 (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using-gene-editing- technologies-human-embryos, accessed 28 May 2019)

Collins FS (2018a). Director National Institutes of Health. Statement on modernizing human gene therapy oversight, August 16, 2018. (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-modernizing-human-gene-therapy-oversight, accessed 28 May 2019).

Collins FS (2018b). Director National Institutes of Health. Statement on Claim of First Gene-Edited Babies by Chinese Researcher, November 28, 2018. (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-claim-first-gene-edited-babies-chinese- researcher, accessed 28 May 2019)

Comité de Bioética de España (CBE)(2019). Statement issued by the Spanish Bioethics Committee on Genome Editing in Humans. (http://assets.comitedebioetica.es/files/documentacion/en/CBE%20On%20Genome%20Editing%20In%20Humans.pdf, accessed 28 May 2019).

Council of Europe (1997). Explanatory Report to the Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine, Oviedo, 4.IV.1997, European Treaty Series - No. 164, https://rm.coe.int/16800ccde5IIn (https://rm.coe.int/16800ccde5IIn, accessed 28 May 2019).

Council of Europe Committee on Bioethics (DH-BIO) (2015). Statement on genome editing. Adopted by the DH-BIO. DH- BIO/INF (2015) 13 FINAL, Strasbourg, 2 December 2015. (https://rm.coe.int/168049034a, accessed 28 May 2019).

Council of Europe (2017a). 20th Anniversary of the Oviedo Convention. Rapporteur Report, 24-25th October 2017, Strasbourg. (https://rm.coe.int/oviedo-conference-rapporteur-report-e/168078295c, accessed 28 May 2019).

Council of Europe (2017b). Parliamentary Assembly of the Council of Europe. The use of new genetic technologies in human beings. Recommendation 2115 (2017). Adopted 12 October 2017. (https://assembly.coe.int/nw/xml/XRef/Xref-XML2HTML-en.asp?fileid=24228&lang=en, accessed 28 May 2019)

Council of Europe (2017c). Committee on Bioethics (DH-BIO). Chart of signatures and ratifications. CDBI/INF (2017b) 7 REV, Strasbourg, 14 November 2017. (https://rm.coe.int/inf-2017-7-rev-etat-sign-ratif-reserves/168077dd22, accessed 28 May 2019).

Cyranoski D (2016). CRISPR gene-editing tested in a person for the first time. Nature 539(7630):479. DOI: 10.1038/nature.2016.20988 (https://www.nature.com/polopoly_fs/1.20988!/menu/main/topColumns/topLeftColumn/pdf/nature.2016.20988.pdf, accessed 28 May 2019).

Cyranoski D (2018). Japan set to allow gene editing in human embryos. Nature News. DOI: 10.1038/d41586-018-06847-7 (https://www.nature.com/articles/d41586-018-06847-7, accessed 28 May 2019).

Cyranoski D, Reardon S (2015). Chinese scientists genetically modify human embryos. Nature News. DOI:10.1038/nature.2015.17378 (https://www.nature.com/news/chinese-scientists-genetically-modify-human-embryos-1.17378, accessed 28 May 2019).

Cyranoski D, Ledford H (2018). Genome-edited baby claim provokes international outcry. Nature 563(7733):607-608. DOI: 10.1038/d41586-018-07545-0 (https://www.nature.com/magazine-assets/d41586-018-07545-0/d41586-018-07545-0.pdf accessed 28 May 2019).

Daley GQ, Lovell-Badge R, Steffann J (2019). After the Storm - A Responsible Path for Genome Editing. The New England Journal of Medicine 380(10):897-899. DOI: 10.1056/NEJMp1900504.

Doudna JA, Charpentier E (2014). The new frontier of genome engineering with CRISPR-Cas9. Science 346(6213):1077;1258096-11258096-9. DOI: 10.1126/science.1258096

Editorial (2018). How to respond to CRISPR babies. Nature 564(7734):5. DOI: 10.1038/d41586-018-07634-0 (https://www.nature.com/magazine-assets/d41586-018-07634-0/d41586-018-07634-0.pdf, accessed 28 May 2019).

Emerson C, James S, Littler K and Randazzo FF (2017). Principles for gene drive research. Science 358(6367):1135-1136. DOI: 10.1126/science.aap9026

33 European Academies Science Advisory Council (EASAC) (2010). Realising European potential in synthetic biology. EASAC policy report 13. (https://easac.eu/publications/details/realising-european-potential-in-synthetic-biology-scientific-opportunities-and-good- governance/, accessed 28 May 2019).

European Academies Science Advisory Council (EASAC) (2017). Genome editing: scientific opportunities, public interests and policy options in the European Union. EASAC policy report 31. (https://www.easac.eu/fileadmin/PDF_s/reports_statements/Genome_Editing/EASAC_Report_31_on_Genome_Editing.pdf, accessed 28 May 2019).

European Group on Ethics in Science and New Technologies (EGE) (2016). Statement on Gene Editing. (https://ec.europa.eu/research/ege/pdf/gene_editing_ege_statement.pdf, accessed 28 May 2019).

Ethics, Community Engagement, Patient Advocacy and Support (ECEPAS) (2018). African Statement on Human Germline Genetic Editing.

Federation of European Academies of Medicine (FEAM) (2016). Human genome editing in EU. Report of a workshop held on 28th April 2016 at the French Academy of Medicine. (http://www.interacademies.org/31271/FEAM-Human-Genome-Editing-in-the-EU, accessed 28 May 2019).

Federation of European Academies of Medicine (FEAM) (2017). The application of Genome Editing in humans. A position paper of FEAM – the Federation of European Academies of Medicine. (https://www.feam.eu/wp-content/uploads/HumanGenomeEditingFEAMPositionPaper2017.pdf, accessed 28 May 2019).

French National Academy of Medicine (2016). Genetic editing of human germline cells and embryos. April 2016 (http://www.academie-medecine.fr/wp-content/uploads/2016/05/report-genome-editing-ANM-2.pdf accessed 28 May 2019).

Fogarty NME, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, Lea R, Elder K, Wamaitha SE, Kim D, Maciulyte V, Kleinjung J, Kim J-S, Wells D, Vallier L, Bertero A, Turner JMA and Niakan KK (2017). Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550(7674):67–73. DOI: 10.1038/nature24033

Fukuyama F (2002). Our Posthuman Future: Consequences of the Biotechnology Revolution. New York, Farrar, Strauss and Giroux.

Garden H, Winickoff D (2018). Gene editing for advanced therapies: Governance, policy and society. OECD Science, Technology and Industry working papers 2018/12, OECD. (https://doi.org/10.1787/8d39d84e-en, accessed 28 May 2019)

Gaskell G, Bard I, Allansdottir A, da Cunha RV, Eduard P, Hampel J, Hildt E, Hofmaier C, Kronberger N, Laursen S, Meijknecht A, Nordal S, Quintanilha A, Revuelta G, Saladié N, Sándor J, Santos JB, Seyringer S, Singh I, Somsen H, Toonders W, Torgersen H, Torre V, Varju M, Zwart H. Public views on gene editing and its uses. Nature Biotechnology 35(11):1021-1023. DOI: 10.1038/nbt.3958.

Genetic Alliance UK (2016) Genome editing technologies: the patient perspective, 23 November 2016. (https://www.geneticalliance.org.uk/media/2623/nerri_finalreport15112016.pdf, accessed 28 May 2019).

German Ethics Council (2017). Germline intervention in the human embryo: German Ethics Council calls for global political debate and international regulation, Ad Hoc Recommendation. (https://www.ethikrat.org/fileadmin/Publikationen/Ad-hoc-Empfehlungen/englisch/recommendation-germline-intervention-in-the- human-embryo.pdf, accessed 28 May 2019).

Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginossar N, Brandman O, Whitehead EH, Doudna JA, Lim WA, Weissman JS and Qi LS (2013). CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154(2):442-51. DOI: 10.1016/j.cell.2013.06.044

Hawkes N (2015). UK scientists reject call for moratorium on gene editing. BMJ 350: h2601. DOI: 10.1136/bmj.h2601

Hsu PD, Lander ES, Zhang F (2014). Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262-1278. DOI: 10.1016/j.cell.2014.05.010

Hurlbut JB (2019). Human genome editing: ask whether, not how. Nature 565(7738):135. DOI: 10.1038/d41586-018-07881-1

Indian Council of Medical Research (2017). National ethical guidelines for biomedical and health research involving human participants. New Delhi: Indian Council of Medical Research. (https://www.icmr.nic.in/sites/default/files/guidelines/ICMR_Ethical_Guidelines_2017.pdf, accessed 28 May 2019).

Indian Council of Medical Research, Department of Biotechnology (2017). National Guidelines for Stem Cell Research. New Delhi: Indian Council of Medical Research. October 2017. (https://www.icmr.nic.in/sites/default/files/guidelines/Guidelines_for_stem_cell_research_2017.pdf, accessed 28 May 2019).

Institut national de la santé et de la recherche médicale (Inserm) (2016). Saisine concernant les questions liées au développement de la technologie CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9. Note du Comité d’éthique. Février 2016. (https://www.inserm.fr/sites/default/files/2017-10/Inserm_Saisine_ComiteEthique_Crispr-Cas9_Fevrier2016.pdf, accessed 28 May 2019).

34

International Summit on Gene Editing. On Human Gene Editing: International Summit Statement. December 3, 2015. (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a, accessed 28 May 2019).

International Society for Stem Cell Research (2015). The ISSCR Statement on Human Germline Genome Modification. 19 Mars 2015. (http://www.isscr.org/professional-resources/news-publicationsss/isscr-news-articles/article-listing/2015/03/19/statement-on- human-germline-genome-modification, accessed 28 May 2019).

Isasi R, Kleiderman E, Knoppers BM (2016). Editing policy to fit the genome. Science 351(6271):337-339. DOI: 10.1126/science.aad6778

Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A (1987). Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. Journal of Bacteriology 169(12): 5429–5433. DOI: 10.1128/jb.169.12.5429-5433.1987. (https://jb.asm.org/content/jb/169/12/5429.full.pdf, accessed 28 May 2019).

Jasanoff S, Hurlbut JB, Saha K (2015). CRISPR Democracy: Gene Editing and the Need for Inclusive Deliberation. Issues in Science and Technology. 32(1). Fall 2015. (https://issues.org/crispr-democracy-gene-editing-and-the-need-for-inclusive-deliberation/, accessed 28 May 2019).

Jasanoff S, Hurlbut JB (2018). A global observatory for gene editing. Nature 555(7697): 435-437. DOI: 10.1038/d41586-018- 03270-w (https://www.nature.com/magazine-assets/d41586-018-03270-w/d41586-018-03270-w.pdf, accessed 28 May 2019).

Kang X, He W, Huang Y, Yu Q, Chen Y, Gao X, Sun X, Fan Y (2016). Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing. Journal of Assisted Reproduction and Genetics 33(5): 581-588. DOI: 10.1007/s10815-016-0710-8

Kipling J (2016). The European Landscape for Human Genome Editing. A review of the current state of the regulations and ongoing debates in the EU. Federation of European Academies of Medicine (FEAM). (https://acmedsci.ac.uk/file-download/41517-573f212e2b52a.pdf, accessed 28 May 2019).

Lanphier E, Urnov F, Haecker SE, Werner M, Smolenski J (2015). Don’t edit the human germ line. Nature 519(7544):410–411 DOI:10.1038/519410a (https://www.nature.com/news/don-t-edit-the-human-germ-line-1.17111, accessed 28 May 2019).

Ledford H (2017a). CRISPR fixes embryo error. Nature 548(7665):13-14. DOI:10.1038/nature.2017.22382 (https://www.nature.com/news/crispr-fixes-disease-gene-in-viable-human-embryos-1.22382, accessed 28 May 2019).

Ledford H (2017b). CRISPR used to peer into human embryos' first days. Nature News, 20 September 2017. DOI:10.1038/nature.2017.22646 (https://www.nature.com/news/crispr-used-to-peer-into-human-embryos-first-days-1.22646, accessed 28 May 2019).

Leopoldina (The National Academy of Sciences); acatech (the National Academy of Science and Engineering), the Union of the German Academies of Sciences and Humanities, and the German Research Foundation (DFG) (2015). The opportunities and limits of genome editing. Statement. September 2015. (https://www.leopoldina.org/uploads/tx_leopublication/2015_3Akad_Stellungnahme_Genome_Editing_01.pdf, accessed 28 May 2019).

Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C, Huang J (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein &Cell 6(5):363-372. DOI: 10.1007/s13238-015-0153-5

Liao HK, Hatanaka F, Araoka T, Reddy P, Wu MZ, Sui Y, Yamauchi T, Sakurai M, O'Keefe DD, Núñez-Delicado E, Guillen P, Campistol JM, Wu CJ, Lu LF, Esteban CR and Izpisua Belmonte JC (2017). In Vivo Target Gene Activation via CRISPR/Cas9- Mediated Trans-epigenetic Modulation. Cell 171(7):1495-1507.e15. DOI: 10.1016/j.cell.2017.10.025.

Lovell-Badge R (2019). CRISPR babies: a view from the centre of the storm. Development 146(3). pii: dev175778. DOI: 10.1242/dev.175778.

35

Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, Koski A, Ji D, Hayama T, Ahmed R, Darby H, Van Dyken C, Li Y, Kang E, Park AR, Kim D, Kim ST, Gong J, Gu Y, Xu X, Battaglia D, Krieg SA, Lee DM, Wu DH, Wolf DP, Heitner SB, Belmonte JCI, Amato P, Kim JS, Kaul S, Mitalipov S. (2017). Correction of a pathogenic gene mutation in human embryos. Nature 548(7668):413-419. DOI: 10.1038/nature23305. (https://www.nature.com/articles/nature23305, accessed 28 May 2019).

Miller HI (2015). Recasting Asilomar’s lessons for human germline editing. Nature Biotechnology 33(11):1132-1134. DOI: 10.1038/nbt.3402

National Academies of Sciences, Engineering, and Medicine (NASEM) (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. (https://doi.org/10.17226/24623, accessed 28 May 2019).

Nicol D, Eckstein L, Morrison M, Sherkow JS, Otlowski M, Whitton T, Bubela T, Burdon KP, Chalmers D, Chan S, Charlesworth J, Critchley C, Crossley M, de Lacey S, Dickinson JL, Hewitt AW, Kamens J, Kato K, Kleiderman E, Kodama S, Liddicoat J, Mackey DA, Newson AJ, Nielsen J, Wagner JK, McWhirter RE (2017). Key challenges in bringing CRISPR-mediated somatic cell therapy into the clinic. Genome Medicine 9:85. (https://doi.org/10.1186/s13073-017-0475-4, accessed 28 May 2019).

Nuffield Council on Bioethics (2012) Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. London: Nuffield Council on Bioethics. June 2012 (http://nuffieldbioethics.org/wp- content/uploads/2014/06/Novel_techniques_for_the_prevention_of_mitochondrial_DNA_disorders_compressed.pdf, accessed 28 May 2019).

Nuffield Council on Bioethics (2016). Genome editing: an ethical review. London: Nuffield Council on Bioethics. (http://nuffieldbioethics.org/wp-content/uploads/Genome-editing-an-ethical-review.pdf, accessed 28 May 2019).

Nuffield Council on Bioethics (2018). Genome editing and human reproduction: social and ethical issues. London: Nuffield Council on Bioethics. (http://nuffieldbioethics.org/project/genome-editing-human-reproduction, accessed 28 May 2019).

Patients Network for Medical Research and Health (EGAN) (2017). Gene editing and the patients perspective. 28 September 2017. (https://egan.eu/news/gene-editing-and-the-patients-perspective/, accessed 28 May 2019).

Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152(5):1173-1183. DOI: 10.1016/j.cell.2013.02.022.

Reardon S (2015). Leukaemia success heralds wave of gene-editing therapies. Nature 527(7577):146-147. DOI: 10.1038/nature.2015.18737 (https://www.nature.com/polopoly_fs/1.18737!/menu/main/topColumns/topLeftColumn/pdf/nature.2015.18737.pdf, accessed 28 May 2019).

Reardon S (2016). First CRISPR clinical trial gets green light from US panel. Nature News. 22 June 2016. DOI:10.1038/nature.2016.20137. (https://www.nature.com/news/first-crispr-clinical-trial-gets-green-light-from-us-panel-1.20137, accessed 28 May 2019).

Reich J, Fangerau H, Fehse B, Hampel J, Hucho F, Kö chy K, Korte M, Mü ller-Rö ber B, Taupitz J, Walter J, Zenke M (2015). Human Genome Surgery – Towards a responsible evaluation of a new technology. Analysis by the Interdisciplinary Research Group Gene Technology Report. Berlin-Brandenburg Academy of Sciences and Humanities (BBAW). (http://www.bbaw.de/publikationen/neuerscheinungen/pdf/BBAW_Human-Genome-Surgery_PDF-A1b-1.pdf, accessed 28 May 2019).

Rosemann A, Jiang L, Zhang X (2017). The regulatory and legal situation of human embryo, gamete and germ line gene editing research and clinical applications in the People’s Republic of China. Background Paper commissioned by the Nuffield Council on Bioethics. May 2017. (http://nuffieldbioethics.org/wp-content/uploads/Background-paper-GEHR.pdf, accessed 28 May 2019).

Royal Netherlands Academy of Arts and Sciences (KNAW) (2016). Genome editing. Position Paper of the Royal Netherlands Academy of Arts and Sciences. November 2016. (https://www.knaw.nl/en/news/publications/genome-editing, accessed 28 May 2019).

Royal Society of New Zealand Te Apā rangi (2016). Gene Editing. Evidence update. October 2016 (https://royalsociety.org.nz/assets/documents/Gene-editing-evidence-update2.pdf, accessed 28 May 2019).

Royal Society Te Apā rangi Gene Editing Panel (2017). Gene Editing in a Healthcare Context. December 2017. (https://royalsociety.org.nz/assets/Uploads/Gene-editing-in-healthcare-technical-paper.pdf, accessed 28 May 2019).

36

Sarewitz D (2015). Science can’t solve it. Nature 522(7557):413–414. DOI:10.1038/522413a (https://www.nature.com/polopoly_fs/1.17806!/menu/main/topColumns/topLeftColumn/pdf/522413a.pdf, accessed 28 May 2019).

Savulescu J, Bostrom N (Editors) (2011). Human enhancement. Oxford: Oxford University Press.

Second International Summit on Human Genome Editing. On Human Genome Editing II. Statement by the Organizing Committee of the Second International Summit on Human Genome Editing. November 29, 2018. (http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b, accessed 28 May 2019).

Shukla-Jones A, Friedrichs S, Winickoff DE (2018). Gene editing in an international context: Scientific, economic and social issues across sectors. OECD Science, Technology and Industry Working Papers, 2018/04, OECD Publishing, Paris. (http://dx.doi.org/10.1787/38a54acb-en, accessed 28 May 2019).

Society for Developmental Biology. Position Statement from the Society for Developmental Biology on Genomic Editing in Human Embryos. 24 April 2015. (http://www.sdbonline.org/uploads/files/SDBgenomeeditposstmt.pdf, accessed 28 May 2019).

Sykora P, Caplan A (2017a). The Council of Europe should not reaffirm the ban on germline genome editing in humans. EMBO reports 18(11):1871-1872. DOI: 10.15252/embr.201745246 (http://embor.embopress.org/content/18/11/1871, accessed 28 May 2019).

Sykora P, Caplan A (2017b). Germline gene therapy is compatible with human dignity. EMBO reports 18(12):2086. DOI: 10.15252/embr.201745378 (http://embor.embopress.org/content/18/12/2086, accessed 28 May 2019).

The Danish Council on Ethics (2016). Statement from the Danish Council on Ethics on genetic modification of future humans. In response to advances in the CRISPR technology. Denmark: Danish Council on Ethics. (http://www.etiskraad.dk/~/media/Etisk-Raad/en/Publications/Statement-on-genetic-modification-of-future-humans-2016.pdf, accessed 28 May 2019).

The Hinxton Group (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. (http://www.hinxtongroup.org/Hinxton2015_Statement.pdf, accessed 28 May 2019).

The InterAcademy Partnership (IAP) (2017). Assessing the security implications of genome editing technology. Report of an International Workshop, 11-13 October 2017, Herrenhausen, Germany. (http://www.interacademies.org/43251/Assessing-the-Security-Implications-of-Genome-Editing-Technology-Report-of-an- international-workshop, accessed 28 May 2019).

The Netherlands Commission on Genetic Modification (COGEM), Health Council of the Netherlands (Gezondheidsraad) (2017). Editing Human DNA: Moral and social implications of germline genetic modification. COGEM; Bilthoven, the Netherlands. (https://www.cogem.net/index.cfm/en/publications/publication/editing-human-dna-moral-and-social-implications-of-germline- genetic-modification, accessed 28 May 2019).

UNESCO International Bioethics Committee (IBC) (2015). Report of the IBC on Updating its Reflection on the Human Genome and Human Rights. SHS/YES/IBC-22/15/2 REV.2, Paris. (https://unesdoc.unesco.org/ark:/48223/pf0000233258, accessed 28 May 2019).

WHO (2002). Genomics and world health. Report of the Advisory Committee on Health Research. Geneva: World Health Organization. (https://www.who.int/rpc/genomics_report.pdf, accessed 28 May 2019).

Yotova R (2017). Report on Regulation. The Regulation of Genome Editing and Human Reproduction Under International Law, EU Law and Comparative Law. June 2017. Paper commissioned by the Nuffield Council on Bioethics. (http://nuffieldbioethics.org/wp-content/uploads/Report-regulation-GEHR-for-web.pdf, accessed 28 May 2019).

Zastrow M (2017). South Korean researchers lobby government to lift human-embryo restrictions. Nature 549(7671):141 DOI:10.1038/nature.2017.22585 (https://www.nature.com/polopoly_fs/1.22585!/menu/main/topColumns/topLeftColumn/pdf/nature.2017.22585.pdf, accessed 28 May 2019).

37