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WHO Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human

Genome Editing

Background paper Governance 2 Non-human applications of 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 the non-human applications of 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 and Dr Piers Millett for his comments on an earlier version of this paper.

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Table of contents

1. INTRODUCTION 3

2. GOVERNANCE CONSIDERATIONS AROUND GENOME EDITING 3

Genome editing in a broader context 4

Approaches to governance 5

Public engagement 7

3. GENOME EDITING IN PLANTS AND ANIMALS 9

Applications of genome editing for plant and animal breeding 9

Gene drives 12

4. GENOME EDITING IN MICROORGANISMS AND SYNTHETIC BIOLOGY 15

5. FURTHER CONSIDERATIONS FOR GOVERNANCE 18

Access and fairness 18

Medical countermeasures 18

Biosecurity and dual use considerations 18

REFERENCES 20

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1. Introduction Within a short time after their discovery, genome editing techniques, particularly CRISPR-Cas9, have spread to basic biological research and have been applied to a wide variety of fields ranging from micro-organisms, plants, animals to humans. In basic research, CRISPR-Cas9 has been already used in research to control transcription, modify epigenomes, conduct genome-wide screens and to image chromosomes; in the area of crop and livestock, it has been used to accelerate breeding, to engineer new antimicrobials and to control vector-borne diseases like mosquitoes with gene drives (Barrangou R, Doudna JA, 2016). While some applications of genome editing are directly linked to human health, others in plants and animals breeding, environmental modifications, manufacturing and production have an impact on food security and nutrition1, environment health2 and global health security.3 Emerging science and technologies can be particularly challenging when it comes to the design of oversight and governance mechanisms. Two recurrent and intertwined themes have been observed in the related literature: 1) are policies being outpaced by scientific advances? (Nuffield Council on Bioethics, 2016; Charo RA, 2015) and 2) can current governance systems address the potential risks posed by new emerging biotechnologies? Other associated issues relate to the safety and efficacy of genome editing technologies and public engagement in discussions over the governance of such technologies, and how governance choices will impact the future of societies. However, before addressing these themes, further considerations need to be attended to; namely whether (and if yes, what type) genome editing is generating new kinds of risks; whether new ethical issues are being raised, and if so, are they posing new governance challenges compared to other technologies. Moreover, in reflecting about the appropriateness of current governance mechanisms and the development of potential additional ones, several points have been outlined:

• the broader scientific and governance contexts into which genome editing technologies are emerging;

• the type of governance regimes that could be developed at the international, regional and national levels and how these could be complementary;

• the issues arising from fairness and access to technology in governance mechanisms. It has been noted that existing governance mechanisms may be applicable and robust, but they will not be optimum (given the specific features of the technology) (Nuffield Council on Bioethics, 2016). And yet it would be important to optimize these governance mechanisms in order to address ethical

considerations and to ensure trust. Indeed, some have remarked that governance debates should not focus on a ‘yes’ or ‘no’ but rather than on how genome editing can be used in a manner that safeguards critical moral values (e.g. equality, respect for diversity, alleviation of suffering) and limits potential risks (KNAW, 2016). This background paper reviews the non-human applications of genome editing and their related health implications.4 Section 2 begins by reviewing the broader governance context associated with genome editing and places it as an emerging biotechnology. The section then introduces the specific and distinctives features of genome editing technologies and turns next to present in a succinct manner different governance approaches with a focus on two concepts that have often been suggested as methods to govern emerging biotechnologies: the precautionary approach and public engagement. Section 3 and section 4 review the potential non-human applications of genome editing in microorganisms, plants and animals and examine several issues and their implications on governance systems, showcasing where feasible existing governance approaches at the international, regional and national levels. Section 5 briefly examines additional considerations for governance.

2. Governance considerations around genome editing

1 https://www.who.int/nutrition/publications/foodsecurity/state-food-security-nutrition-2018/en/, accessed 28 May 2019. 2 https://www.who.int/phe/en/, accessed 28 May 2019. 3 https://www.who.int/health-security/en/, accessed 28 May 2019. 4 For the human application of genome editing, see Background paper Governance 1 on human genome editing.

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Genome editing in a broader context The literature on emerging technology, biotechnologies and their governance is rich and beyond the scope of this paper. However, several considerations regarding the specific governance of emerging biotechnologies have been put forward below as a way to support discussions and reflections on the types of governances’ approaches for genome editing.

There are many definitions of governance.5 For the purposes of this background paper, governance refers to a set of regulatory processes and mechanisms through which norms and rules and other tools are developed and enforced and where governance is more than just a set of regulations

(EMBO, 2016). Governance encompasses different policy tools (from ‘hard’ instruments (e.g. mandatory laws and regulations) to ‘softer’ ones (e.g. self-governance, codes of conducts). It also involves different actors (including governments and policy makers, researchers and scientists, private sector and the public) with different interests and values as well as different levels of governance (from local and national to regional and international levels). Governance can in fact been seen as an “ecosystem”, in which there are many different types of actors and where multiple instruments can be used (Charo RA, 2016; NASEM, 2018a). With regards to emerging biotechnologies, they have been characterized by three features (Nuffield Council on Bioethics, 2012):

- their uncertainty. This relates to the range of possible outcomes from a given biotechnology or the likelihood of each coming about;

- their ambiguity of meaning and value attached to their practices, products and outcomes; and - their transformative potential to make profound changes in their social, commercial or

physical environments, and their significant impact on society in general. These specific characteristics of emerging biotechnologies, and by extension genome editing, engender difficulties in a number of areas, including for their regulation (Nuffield Council on Bioethics, 2012). Likewise, it is important to understand the specificities of a particular technology within the circumstances in which it emerges. For instance, it has been repeatedly observed that genome editing technologies differ from previous genetic engineering techniques in that their mode of action is more precise, safe and efficient than earlier methods. The following specific features of genome editing have been identified (Nuffield Council on Bioethics, 2016):

• Novel mode of action. New genome editing techniques, such as CRISPR Cas-9, allow for edits to be made “in a hit-and-run fashion — the nucleases do their job and then are degraded within cells — “hence leaving no trace of the reagents in the altered organism (Carroll D, Charo RA, 2015). From a safety perspective, it has been therefore argued that it would seem reasonable to regulate the product's characteristics independently of the process

used to develop them (Carroll D, Charo RA, 2015; KNAW 2016; EASAC, 2017).6

• Accessibility. Compared to previous methods, current genome editing techniques are cheaper and easier to use. Accessibility and affordability of their use imply a greater number of users, including communities that may be outside the traditional scope of regulatory oversight

mechanisms.7

• Speed of use and uptake. This means that genome editing technologies allow to make genetic manipulation at a higher speed than previous technologies and the spread of its

5 There are many definitions of governance. In 1997, the UNDP defined it as “the exercise of economic, political and administrative authority to manage a country’s affairs at all levels. It comprises the mechanisms, processes and institutions through which citizens and groups articulate their interests, exercise their legal rights, meet their obligations and mediate their differences”. Governance definitions can be state or society centric or more in a general manner such as “governance can be generally defined as the means by which an activity or ensemble of activities is controlled or directed, such that it delivers an acceptable range of outcomes according to some established standard” (Hirst). (http://unpan1.un.org/intradoc/groups/public/documents/un/unpan022332.pdf, accessed 28 May 2019. See also EEA, p. 187: ‘Governance’ is about the manner in which something is governed by methods of management and systems of regulations, be they formal or informal. More broadly, it refers to the conduct of life or business in general and the mode of living, or behaviour, in society. 6 See Section 3. 7 See discussion on DIY and biology amateur communities in Nuffield Council on Bioethics, 2016 and NASEM, 2017.

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uptake and diffusion across different fields of applications. This may in turn affect existing governance mechanisms.

• Multiplexing. Genome editing has the potential to achieve multiple edits in a genome.

These specific features of genome editing may also challenge current governance mechanisms and need to be taken in to account in the devise or review of governance oversight.

Approaches to governance Although it is beyond the scope of this paper to review the different conceptual approaches that can be used in the governance of genome editing, here are some concepts that could support such endeavor. The governance of biotechnology can be approached by looking at the types of actors involved and the types of different regulatory issues that a governance framework would address (NASEM, 2018a). For instance, the issues covered by the governance of genome editing could include: research governance issues; ethical issues; health, food and environment safety; biosecurity issues; intellectual property rights and issues of access and justice; and public engagement. Likewise, four approaches to govern science and technology have been identified (Paarlberg RL, 2000; Charo RA, 2016; NASEM, 2018a). Options for governance operate along a spectrum of being:

• Promotional: support and remove obstacles to innovation

• Neutral or Absent: neither promote nor hinder biotechnology

• Precautionary: slow advancement or introduction of biotechnology

• Preventative: prevent, defund, or ban certain types of biotechnology applications The general limitations of current regulatory mechanisms governing emerging biotechnologies have also been pointed out (Nuffield Council on Bioethics, 2012). Some limitations concern the fact that 1) regulations tend to be made at the national level while biotechnology innovation tend to be global; 2) the difficulties to function between layers of national and supranational regulation (which in turn raise problems of control and accountability) and 3) the regulatory landscape in which these emerging biotechnologies navigate is made of a patchwork of ad hoc institutions. Moreover, it usually takes time to develop and agree on new rules, which might be out of date when they come into force. Policy makers might also struggle to envisage all possible applications of a technology (Nuffield Council on Bioethics, 2012). As a result, a number of problems can arise including coordination and consistency, of voluntary and involuntary circumvention, and of democratic accountability. It is concluded that regulations “cannot provide all the answers to securing benefits or averting harms from emerging biotechnologies, not least because emerging biotechnologies do not fit into risk-based regulatory models but require instead an approach guided by the virtue of caution which, in turn, requires a continuous and

reflective engagement with broader societal interests.” (Nuffield Council on Bioethics, 2012). The design of regulation will depend on specific and contextual needs and demands and will offer “no magic cure for resolving the ‘mess’ of the regulatory world inhabited by emerging biotechnologies.” (Nuffield Council on Bioethics, 2012). It is also important to put the development of genome editing technology into a broader society context (Nuffield Council on Bioethics, 2016). Indeed, the difference between a tool (an enabling technology like genome editing) and a specific application (e.g. gene drives) can be highlighted. This leads to the argument suggested by some about focusing oversight on specific applications or ‘products’. A similar point is made about the importance of considering the broader scientific context in which technologies have developed. Many reports have underlined, for instance, the convergence of gene drives technologies with the development of genome editing. The governance of biotechnology products is in fact context dependent, and as such, there is not one single approach to govern biotechnology (Tait J, 2008). Likewise, it has also been underlined that one of the most important factor in shaping technological development (i.e. whether, and which, potential technologies will emerge) is human agency (including for instance the decisions made about directions of research, funding, regulatory regimes, the design of institutions and programs as well as the desire for or acceptance of different possible states of

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affairs) (Nuffield Council on Bioethics, 2016). Moreover, some have underlined that by taking a broad view of biotechnology as a matter of social choice, technology governance will be able to also consider a range of alternative pathways (Nuffield Council on Bioethics, 2012). The choices made in the selection of governance approaches for genome editing are therefore crucial for its development. Two specific approaches, which have been adopted in some frameworks associated with emerging biotechnologies are briefly introduced below: the precautionary approach (precautionary principle) and public engagement.

Risk assessment is a probabilistic approach to determine risk associated with any type of hazard (e.g. in food, in chemicals) and risk management involves the identification of risks and strategies to minimize or avoid their impacts. Risk and benefit analysis evaluate the potential risks and benefits of a particular activity on human health or on the environment. These tools have been used in various sectors including in biosafety, food safety and environment. Risk assessments have been described as scientific and precise methods and have been at the core of many decision makings. Conventional risk assessment frameworks are still broadly used by countries for governing technologies, even if there is a recognition for adjusting these frameworks to face the challenges posed by genome editing technologies (Shukla-Jones A et al., 2018). Yet, it has also been emphasized that governance processes, often relying on formal risks assessment, have not been able to forecast many of the profound impact of innovation (Stilgoe J et al., 2013). It was also pointed out that “The uncertainties of emerging technologies can make it difficult or even impossible for regulators to apply traditional risk-benefit analyses, because they may have neither a definitive idea of what to look for nor a means to identify it.” (Charo RA, 2015). Given these limits, other approaches, including a precaution approach, have been developed as another, and sometimes complementary, tool upon which to base decision making under uncertainty. Although there is no common formulation on the precautionary principle (or approach) (Nuffield

Council on Bioethics, 2003)8, in the context of the environmental hazards and the protection of biodiversity, it could be understood as “(…) where there is a threat of significant reduction or loss of biological diversity, lack of full scientific certainty should not be used as a reason for postponing

measures to avoid or minimize such a threat”.9 In other words, in situations where there are potentially serious or irreversible threats to health or the environment and these threats may not be apparent in the short term, the precautionary view requires public policy action to be taken to anticipate them (e.g. to reduce potential hazards) before there is a scientific evidence of their likelihood, taking into account the likely costs and benefits of action and inaction (EEA, 2001; Nuffield Council on Bioethics, 2016). In recent years, the precautionary principle became controversial in its applications in areas such as genetically modified organisms (GMOs) within the EU (UK House of Lords, 2015) but also between the U.S. and the EU and with issues concerning climate change at the international level (EEA, 2001). For some, the precautionary principle is arbitrary, non-scientific (Marchant G, Mossman K, 2004; Resnik DB, 2003); others challenged its implementation (NASEM, 2016a; Sunstein CR, 2009; El-Zahabi-Bekdash L, Lavery JV, 2010;) and claimed it could lead to paralysis and suppressing innovation and human progress. Others have also noted that innovation and precaution can be complementary with public understanding and effective oversight (NASEM, 2016a; Baltimore D et al., 2015; Carroll D, Charo RA, 2015). In fact, it was pointed out that “Innovation is not something that is in conflict with precaution. They are complementary strategies in which precaution will facilitate innovation and give us the confidence we need to support these new and risk-taking technologies.” (Charo RA, 2016). Several existing regional and international regulatory mechanisms, which could affect the governance of genome editing technologies, have taken a precautionary approach in the management of benefits and risks of technologies. The Convention on Biodiversity (CBD), which entered into force on 29 December 1993, and its Cartagena Protocol, which entered into force 11 September 2003, as well as

8 The concept of ‘precautionary approach’ has been used as a response to too conservative application of the ‘precautionary principle’. (Nuffield Council on Bioethics, 2003). 9 Preamble of the Convention on Biodiversity (https://www.cbd.int/convention/articles/default.shtml?a=cbd-00, accessed 28 May 2019).

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EU General Food Law Regulations and in its GMOs regulations10 have taken such approach. These international agreements and regional regulations are being implemented at national and regional levels and are discussed in further details in the subsequent section. This approach is however not prevalent in the US. Considering the characteristics of emerging biotechnologies, including genome editing technologies, it has been noted that the precaution (or caution) approach should be seen as a process (and not a rule) that will broaden the process of regulatory appraisal in a variety of different ways, in order to “explore and compare contrasting implications of alternative possible innovation trajectories (including that of ‘business as usual’).”(Stirling A, 2007; Nuffield Council on Bioethics, 2012.) More specifically, it has been observed that this approach should be distinguished from risk assessment method in that it requires to take into account the foreseeable consequences of a proposed intervention but also the consequences of not making the action (i.e. of inaction), and the eventual alternatives to the proposed intervention (Nuffield Council on Bioethics, 2016). Indeed, “the principle of caution involves the comparison of a wider range of policy options than simply saying ‘yes’ or ‘no’ to a single specific proposed technology. These may include other technologies for the same purpose or other social or organisational practices that may offer similar ends.” (Santillo D et al., 1999; Nuffield Council on Bioethics, 2012). Some have however argued that the risk of inaction could also be included in comprehensive risk assessment and that, as such, it does not pertain solely to a precautionary approach. Likewise, a risk management approach may also include a context specific assessment of risks of a specific use of the technology, followed by a detailed plan to manage the risks identified. More usually, the precautionary approach is applied to be a yes or no to an entire technology by arguing that it should not be used until the risks are fully known. It does not allow for its use under circumstances of uncertainty. Advocates of the precautionary approach contend that it “is about steering innovation, not blocking it”. It is not about ‘banning’ anything, “but simply taking the time and effort to gather deeper and more relevant information and consider wider options.” Given that risk assessment is not working under conditions of uncertainty, precaution “offers a means to build more robust understandings of the implications of divergent views of the world and more diverse possibilities for action.” (Stirling A, 2016).

In this regard, it has also been observed that “public concerns [about controversies in science and

technologies] cannot be reduced to questions of risk, but rather encompass a range of concerns

relating to the purposes and motivations of research” (Stilgoe J et al., 2013). Another framework for responsible innovation, takes its roots within a set of questions that have emerged as important within public debates about new areas of science and technology (Stilgoe J et al., 2013). These questions not only focus on products of innovation (the focus of conventional technological risk governance), but also on processes or purposes of innovation. Furthermore, it has also been suggested that an interesting and important principle of regulatory systems for emerging technologies is their “flexibility” (Charo RA, 2015). In this respect, “Iterative regulation, constant monitoring and reevaluation, wider consultation, and a broader array of conditions and restrictions may at times be confusing, but they also might forestall a regulatory “no” or prevent public outcry over a regulatory “yes”, either of which can, in the end, slow innovation.” (Charo RA, 2015).

Public engagement Public engagement has emerged in the past two decades as an additional governance approach for the oversight of science and of technology (Stilgoe J et al., 2013). There are considerable variations among countries about the role of public opinion in the process of policy making (NASEM, 2017). It has been pointed out that public engagement should not be aimed at developing public acceptance of emerging technologies and are thereby deviating from the “knowledge deficit model” (NASEM, 2017). As it has been underlined, “public participation should not be seen as a matter of ‘political correctness’ or as a means to achieve a pre-conceived end, but rather as inherent to the rigour and effectiveness of regulatory assessment. It allows attention to extend beyond crucial questions over ‘how safe?’, to

10 Article 7 of the General Food Law Regulation and in Directive 2001/18/EC (environmental release of GMOs and their placing on the market).

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address equally imperative issues over ‘which way?’ innovation should go in any given field; and ‘who says?’ and ‘why?’ […]. If these substantive kinds of issue are attended to, then regulatory assessment of synthetic biology and gene drives can move from a purely risk-based analysis, to diverse – more

substantive – processes of ‘social appraisal’ […].” (Stirling A et al., 2018). In their report on Emerging biotechnologies: technology, choice and the public good, the Nuffield Council on Bioethics recommends the use of a “public ethics” approach, and therefore public engagement, for the governance of emerging biotechnologies. Indeed, there have been many concurring calls made from various stakeholders for engaging the public, to have an ongoing dialogue

around the governance of genome editing.11 This is further warranted as apart from ethical reasons, these technologies could have a profound impact on societies and a mis-governance could lead to public distrust. Yet the practice of public engagement has been uneven and has also received criticisms (including on their methods and purposes of participation and on their evaluation criteria) (Stilgoe J, 2013). Nevertheless, as it has been argued, given the pace of scientific and technological advances in the life sciences, new forms governance approaches and processes, such as public engagement, are urgently needed (Grove-White R et al., 2000). Finally, some additional considerations have been reported in the literature for the governance of genome editing technologies:

• Given the specific characteristics of genome editing, there are discussions about whether to base governance regimes on products or on the technology/process/traits;

• Given that current governance regimes differ at national and regional levels (EU and US differences on GMOs) and reflect different cultural contexts and risk framings, is a global consensus on governance on genome editing achievable?

• Is there a division of responsibilities in the governance of genome editing? If yes, what are these different levels? The EU approach on Responsible Research and Innovation (RRI) “implies that societal actors (researchers, citizens, policy makers, business, third sector organisations, etc.) work together during the whole research and innovation process in order to better align both the process and its outcomes with the values, needs and expectations of society.”12 Likewise, it has been underlined that the various participants and stakeholders of the global research enterprise have specific responsibilities to ensure and promote responsible research conduct (IAP, 2012).

11 See Background Paper Governance 1. 12 https://ec.europa.eu/programmes/horizon2020/en/h2020-section/responsible-research-innovation, accessed 28 May 2019.

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3. Genome editing in plants and animals This section will first review the potential applications of genome editing in plants and in animals for food production and the related issues associated with governance. The section will subsequently examine the potential applications of genome editing in animals and plants to be released into the wild and the governance issues that arise in this setting.

Applications of genome editing for plant and animal breeding Plants and animals have always been modified by humans to improve food supply (Nuffield Council on Bioethics, 2016). Nowadays, global climate change, environmental hazards and the growing population are putting further challenges on food security and nutrition. Genome editing techniques in plants and animals could be considered as an opportunity for science to address some of these challenges. The IAP report on Food and nutrition security and agriculture (IAP, 2018a) recommends, among others, international scientific priorities to capitalize on opportunities in the biosciences and other advancing sciences, including genome editing. It has however been recognized that the intensification of food production cannot be seen as the only global strategy to achieve food security (Nuffield Council on Bioethics, 2016). Compared to the human field, it has been noted that the use of genome editing in plants has been less groundbreaking (Nuffield Council on Bioethics, 2016). One reason may be due to the long history of plants modification. Cross breeding techniques have been able to modify the DNA sequences in plants before the advent of genome editing techniques (Nuffield Council on Bioethics). Yet genome editing could allow for the design of crops with desirable features such as enhanced crop quality, higher yields and by being disease and pest resistant in a faster manner than conventional breeding techniques (KNAW, 2016; NASEM, 2016b; Royal Society of New Zealand Te Aparangi, 2016; EASAC, 2017). Potential applications could include breeding of bacterial blight-resistant rice (Zhou J et al., 2015) and powdery mildew-resistant wheat (Wang Y et al., 2014), as well as promising model studies in other crops – such as maize, tobacco, potato, soybean, tomato and orange (Jiang W et al.,

2013; Bortesi L, Fischer R, 2015; Leopoldina et al., 2015; Wang Y et al., 2015).13 Genome editing is also being used to remove food allergens and to increase nutritional content (IAP, 2018a; Nuffield Council on Bioethics, 2016). In the specific area of animal breeding, genome editing is expected to revolutionize current practices, notably by allowing research that was previously unfeasible (Nuffield Council on Bioethics, 2016). In livestock breeding, the objectives of genome editing include improving animal health by being disease resistant; as well as improving their productivity traits and their adaptation to farming or environmental conditions (EASAC, 2017, Nuffield Council on Bioethics, 2016). As an illustration, recent applications include: to protect pigs’ reproductive and respiratory syndrome virus (Whitworth KM et al., 2016; Nuffield Council on Bioethics, 2016), to modify the genes of the immune system of the pig to protect them against African Swine fever (Lillico SG et al., 2013; Lillico SG et al., 2016; Nuffield Council on Bioethics, 2016; EASAC, 2017) and research to make the cattle resistant to trypanosome parasites responsible for the sleeping sickness (IAP, 2018a). Other research to improve animal agricultural traits include genetic de-horning and how to increase muscle mass by modification of the myostatin gene (Carlson DF et al., 2016; Crispo M. et al., 2015; Cyranoski D, 2015; Wang X et al., 2015; EASAC, 2017) as well as the production of chicken eggs without allergens; editing chicken to make them resistant to infectious diseases (such as avian influenza) and editing ‘hygienic” gene of bees gene to make them less susceptible to mites, fungi and other pathogens (Reardon S, 2016). It has also been noted that it is important to recognize the economic issues at stake in the modifications of animal traits in order to augment their yield (for example, experimental animal farms in Argentina and Uruguay that modify sheep and veal’s muscle

genomes in order to double the production of meat).14

13 For a review, see Leopoldina et al., 2015; Nuffield Council on Bioethics, 2016; NASEM, 2016b; EASAC, 2017. 14 Inserm, Édition du génome : des possibilités inouïes qui posent des questions éthiques, 19 June 2018 (https://www.inserm.fr/actualites-et-evenements/actualites/edition-genome-possibilites-inouies-qui-posent-questions-ethiques, accessed 28 May 2019).

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The general aim of regulation on genetically modified food is, from a food safety standpoint, to demonstrate that the manipulated food does not contain additional toxic or allergenic components and that the composition of the food, apart from the introduction of the modification, is indistinguishable

from the original unmodified food (Nuffield Council on Bioethics, 2016). The regulations of GMOs are

however different among jurisdictions, notably leading to different approaches.15 In the US, where genetically modified foods are regulated by the U.S. Food and Drug Administration (FDA), if substances found in food are considered as ‘generally recognized as safe’ (GRAS), they do not require separate pre-market approval (Nuffield Council on Bioethics, 2016). If the GMO product differs significantly from substances currently found in food, then that product will require pre-market

approval as a ‘food additive’ (Nuffield Council on Bioethics, 2016). In the US, with the ‘Coordinating

framework’, biotechnology products (such as genetically modified animals) are being regulated based on their characteristics and intended uses rather than through their method of production (Carroll D; Charo RA, 2015). In Canada, all foods that are genetically altered, including those though conventional breeding, are classified as ‘novel foods’. All novel foods require a pre-market notification to Health Canada and a safety assessment. The method focuses on the characteristics of the product rather than on the process through which the product was made (Nuffield Council on Bioethics, 2016). In South Africa, GMOs are regulated under the South African GMO Act (Act 15 of 1997), amended in 2006 to accommodate, among other things, the provisions of the Cartagena Protocol on Biosafety

(ASSAf, 2017).16 It was reported that the regulatory status of genome editing, which is considered as one of these New Breeding Techniques (NBTs), as “undetermined”, and it has been concluded that there is a need to consider to what extent newly developed NBTs and/or their products should be regulated or excluded from regulation (ASSAf, 2017). In the European Union (EU), regulation on food products (animal and plant products) are subject to the General Food Law and other Regulations and Directives applying to GMOs (Nuffield Council on

Bioethics, 2016).17 A GMO means “an organism, with the exception of human beings, in which the

genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination;” and the genetic modification “occurs at least through the use of the techniques listed in Annex I A, part 1”.18 Additional regulations associated with the welfare of the animals involved in such research are also pertinent since it has been noted that current EU and Member States regulations relating to the welfare of animals would cover the use of genome editing in animal research (EASAC, 2017). A major issue that has been reported in Europe, is whether genome edited plants and animals should fall under the scope of the EU regulations on GMOs or not. Whilst GMOs involve the insertion of DNA into an organism, genome editing plants may be ‘altered’ in a manner that is identical to the natural or induced mutation, although the mutation is specific and targeted (Nuffield Council on Bioethics, 2016).

15 “In the EU, the classification of GMOs is based on whether the alteration has been made “in a way that does not occur naturally by mating and/or natural recombination”, and is elaborated as ‘at least’ requiring the use of a listed technique.233 This is conventionally thought to capture transgenic organisms but not those with alterations that might be achieved through natural breeding (however demanding), including those produced by cisgenics (where new genes are introduced from closely related organisms) and, arguably, certain genome editing protocols. In Canada, by contrast, all foods that are genetically altered, including by conventional breeding, are classed as ‘novel foods’ without further distinction. All novel foods require a pre-market notification to Health Canada (the Canadian federal department of health), following which a full safety assessment is made. This is done on the basis of the characteristics of the product itself, rather than the process by which it was produced.234 In the US, genetically altered foods are regulated by the FDA. Where they are like substances currently found in food (‘generally recognized as safe’ – GRAS) they do not require separate pre-market approval. However, where a GMO product “differs significantly in structure, function, or composition from substances found currently in food,” pre-market approval of the substance as a ‘food additive’ would be required.” Nuffield Council on Bioethics (2016). 16 The Academy of Science of South Africa (ASSAf) report has reviewed the development of new techniques in animal, plant and microbial breeding (New Breeding Techniques (NBTs)) and their regulatory status with the view of ensuring that appropriate policies and regulations are in place to address biosafety requirements. Academy of Science of South Africa (ASSAf), 2017. 17 EU Directive 2001/18/EC on the deliberate release into the environment of GMOs and repealing (https://eur-lex.europa.eu/resource.html?uri=cellar:303dd4fa-07a8-4d20-86a8-0baaf0518d22.0004.02/DOC_1&format=PDF, accessed 28 May 2019); (https://ec.europa.eu/food/safety/general_food_law_en, accessed 28 May 2019). 18 (https://eur-lex.europa.eu/resource.html?uri=cellar:303dd4fa-07a8-4d20-86a8-0baaf0518d22.0004.02/DOC_1&format=PDF, accessed 28 May 2019).

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Instead of inserting DNA from another species, the genome of the plant could be directly modified to make it resistant to diseases for instance. Given that the genome editing techniques could also insert DNA, including from other species, in the plant, it has been underlined that it would be important to focus on the nature of the product/trait rather than the technology with which the product was manufactured (Nuffield Council on Bioethics, 2016; KNAW 2016; EASAC, 2017). One reason put forward is that the genome edited resulting plant product that does not differ from variations that could occur in nature should not fall under the GMOs regulations. It would however apply to genome editing plants in which genetic material originating from a different organism would have been inserted (KNAW, 2016). Several reports have in fact recommended that genome edited plants and animal products that do not contain DNA from another organism, should not fall within the scope of legislation

on GMOs (KNAW, 2016; EASAC, 2017). This will have implications in terms of the safety and

regulatory processes that will unfold. The situation of genome editing products is still uncertain in Europe and some are concerned that this may lead to disinvestment and a loss in international competitiveness for plant breeders (Nuffield Council on Bioethics, 2016; EASAC, 2017). Others however argue that genome edited products should be regulated like GMOs because the method of production is included in the annex 1 of the GMOs Directive. Their views are that genome editing is not similar to ‘traditional’ mutagenesis breeding and therefore deserve more “exacting regulation” (Nuffield Council on Bioethics, 2016). Similarly, some also put forward the need to have a stricter regulatory framework on the basis on the potential health, safety and environmental risks posed by genome edited products (Nuffield Council on Bioethics, 2016). The issue of whether genome edited products would be classified as GMOs or not would have an impact on the types of regulatory scrutiny products will face, but also in terms of political control and market conditions. These are reported as crucial given that such measures can impact the biotechnology industry, the economy and the food supply (Nuffield Council on Bioethics, 2016). Some have also reported that the current EU risk assessment framework may need to be revised “to enhance suitability for evaluating impacts of products by new and emerging gene-editing techniques on environmental, human, and animal health” and that there is an opportunity “to advance GM plant risk governance anchored in biosafety research and RRI [Responsible research and innovation] approaches” (Agapito-Tenfen SZ et al., 2018). Moreover, some have criticized the 2018 decision by the European Court of Justice19 stipulating that gene editing crops should be governed by the GMO regulations as this will inhibit research, affect commercial applications and agricultural innovation in the EU (Callaway E, 2018). Others have also emphasized that some consumers may want to know how food products were produced and this

regardless of the degree of genetic modification (Araki M, Ishii T, 2015). It has been argued that a European Commission decision on the status of genome edited plants and food products is urgent as research is being translated into novel products and EU Member States are starting to regulate this area individually (EASAC, 2017). It has also been reported for EU regulators should take into account current reforms taking place outside the EU (EASAC, 2017). For instance, in the U.S with the update of their “Coordinate framework” for regulating biotechnology and in Australia, which conducted a review and public consultation on GMOs regulations and new technologies (EASAC, 2017).

19http://curia.europa.eu/juris/document/document.jsf?docid=207002&mode=req&pageIndex=1&dir=&occ=first&part=1&text=&d

oclang=EN&cid=6484089, accessed 28 May 2019.

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Gene drives Gene drives are systems that enable the biased inheritance of a particular DNA sequence so that the gene is being transmitted to offspring at an increased rate (more frequently than by Mendelian inheritance rate of 50%). There are natural gene drive systems and researchers are now examining the potential to develop new systems using synthetic biology techniques (Royal Society of the United Kingdom, 2018). The advent of genome editing technologies, particularly CRISPR-Cas 9, within the field gene drives has been described as a ‘game changer’ (Ledford H, 2015) as it has made gene drive more accessible and cheaper, enabling the ability to design synthetic gene drives (Royal Society of the United Kingdom, 2018). These synthetic gene drives are aimed at being released into the environment, and they will be spreading ‘self-sustainingly ’ into wild populations; these are two important characteristics that make gene drives distinct from other synthetic applications and that have raised significant debate about this technology (Royal Society of the United Kingdom, 2018). Gene drives have the potential of being applied in three main sectors: human health, agriculture and the environment, noting that while gene drives could apply both to plants (e.g. to eliminate invasive plant species, in controlling plant pathogens) and animals, there has been until now no application of gene drives in the production of domesticated plant varieties (Nuffield Council on Bioethics, 2016). Among these sectors, the most active research areas are those controlling vector-borne disease and

those controlling invasive species (Royal Society of the United Kingdom, 2018). Vector-borne diseases: gene drive can be used to limit the reproduction of mosquitoes (known as ‘population suppression drives’ or ‘population suppression’) or to add or remove a specific trait in the population (known as ‘population conversion drives’ or ‘population replacement’). A current application is the development of genetically modified Aedes aegypti mosquito (although not using genome editing techniques), which are a vector of dengue fever in South America. Trials have been done in Brazil and Panama (Nuffield Council on Bioethics, 2016). Potential uses of genome editing in gene drives could include editing ticks so as to prevent them from transmitting the bacteria responsible for Lyme diseases (Reardon S, 2016). In addition to human health applications (for Malaria, Dengue, Chikungunya, West Nile Fever, Chagas), genetically modified insects could be used for the control of agricultural pests, including the Mediterranean fruit fly, Diamondback moth and Spotted Wing Drosophila (SWD) and livestock diseases, including bluetongue and Schmallenberg virus, as reported in a UK House of Lords Science and Technology committee reports on GM insects (UK House of Lords, 2015). Genes drives can be used for controlling or removing invasive species and as a means increasing the resistance of endangered species to disease and other threats. For example, gene drives are being used in a public-private project in New Zealand in order reduce the populations of non-indigenous

predators (such as rats, weasels and possums) (Gemmell NJ et al.,2013). Other projects in New Zealand were on wasps (Lester PJ et al., 2013) and cane toads in Australia (Australian Academy of Science, 2017). In terms of governance, there have been several reports on the regulations of gene drives (Oye K et al, 2014; Champer J et al., 2016; NASEM, 2016a; Australian Academy of Science, 2017; NEPAD, 2018; Royal Society of the United Kingdom, 2018). While reports evaluate how gene drives can be governed trough existing risk assessment frameworks, they also highlight the need to review current regulatory regimes. For instance, it has been reported that the application of genome editing in gene drives raises a number of concerns regarding biosafety and environmental release that are similar to those on potentially hazardous biological research and GMOs. Concerns have been raised about the potential risks of this not yet fully developed technology, both in terms of efficacy and safety (Oye K et

al., 2014; Nuffield Council on Bioethics, 2016; NASEM, 2016b; EASAC, 2017).20 In addition, reports have also recommended clear communication and consultation with the public (Australian Academy of Science, 2017) as well as early engagement with stakeholders (NEPAD,

20 These concerns involve the risk for gene drives to spread to other species; the ecological consequences of eradicating a mosquito population on biodiversity; the risks linked to an accidental release of gene drives given their self-sustaining nature and the long term effects on environment; as well as how to stop the spread of the gene drive in case of loss of control. See also EASAC, 2017; Nuffield Council on Bioethics, 2016; Royal Society of the United Kingdom, 2018; NASEM, 2016a.

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2018). Moreover, in New Zealand, the Royal Society of New Zealand Te Aparangi has established an expert panel in 2016 “to consider the implications of gene-editing technologies for New Zealand society, including the ethical, social, legal, environmental and economic considerations that reflect current and future trends in New Zealand’s population and community diversity.” (Royal Society of New Zealand Te Aparangi, 2016). At the international level, several regulatory regimes include provisions that could apply to the release of gene drives in the environment.

• The Convention on Biodiversity (CBD) 21, which entered into force on 29 December 1993, has three main goals: conservation of biodiversity; sustainable use of biodiversity; fair and equitable sharing of the benefits arising from the use of genetic resources. Its overall objective is to encourage action, which will lead to a sustainable future and specific points of relevance outline the following: - In regards to the use and release of GMOs in the environment, Article 8 (g) In-situ

Conservation states that each Contracting Party shall “(g) Establish or maintain means to regulate, manage or control the risks associated with the use and release of living modified organisms resulting from biotechnology which are likely to have adverse environmental impacts that could affect the conservation and sustainable use of biological

diversity, taking also into account the risks to human health;”.22

- In regards to the fair and equitable sharing of the benefits arising from the use of genetic resources, Article 19 (2) Handling of Biotechnology and Distribution of its Benefits, states that: “Each Contracting Party shall take all practicable measures to promote and advance priority access on a fair and equitable basis by Contracting Parties, especially developing countries, to the results and benefits arising from biotechnologies based upon genetic resources provided by those Contracting Parties. Such access shall be on mutually agreed terms.”23

The CBD also takes a precautionary approach, by stating in its preamble that: “Noting also that where there is a threat of significant reduction or loss of biological diversity, lack of full scientific certainty should not be used as a reason for postponing measures to avoid or

minimize such a threat”. 24

• The Nagoya Protocol on Access and Benefit-sharing (The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization (ABS) to the Convention on Biological Diversity) is a supplementary agreement to the Convention on Biological Diversity. The Nagoya Protocol, which entered into force on 12 October 2014, is an agreement that aims at the fair and equitable sharing of benefits arising out of the utilization of genetic resources.

• The Cartagena Protocol on Biosafety to the Convention on Biological Diversity is an international agreement dealing with the safe handling, transport and use of living modified organisms (LMOs) resulting from modern biotechnology that may have adverse effects on biological diversity, taking also into account risks to human health. It was adopted on 29 January 2000 and entered into force on 11 September 2003. The Cartagena Protocol applies the ‘precautionary approach’ as contained in Principle 15 of the Rio Declaration on Environment and Development and specifically focus on transboundary movements.

• The Nagoya – Kuala Lumpur Supplementary Protocol on Liability and Redress to the Cartagena Protocol on Biosafety, which entered into force on 5 March 2018, was adopted as a supplementary agreement to the Cartagena Protocol on Biosafety. It applies to damage resulting from living modified organism during a transboundary movement. It aims at contributing to the conservation and sustainable use of biodiversity by providing international rules and procedures in the field of liability. It requires that response measures are taken in the event of damage resulting from LMOs. Some have however pointed out that there is a concern that conventional biosafety approaches do not reflect the technical specificities of

21 http://www.un.org/en/events/biodiversityday/convention.shtml, accessed 28 May 2019. 22 https://www.cbd.int/convention/articles/default.shtml?a=cbd-08, accessed 28 May 2019. 23 https://www.cbd.int/convention/articles/default.shtml?a=cbd-19, accessed 28 May 2019. 24 https://www.cbd.int/convention/articles/default.shtml?a=cbd-00 accessed 28 May 2019.

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gene drives system as they do not take into account its ‘self-sustaining’ nature (Nuffield

Council on Bioethics, 2016). While international instruments may provide some harmonization for governance, regulatory regimes may still differ at regional and national levels.

• In the EU, the environmental release of modified organisms is governed by Directive 2001/18/EC on the deliberate release into the environment of genetically modified

organisms.25 The EU regulatory mechanism for GMOs is based on process/technology approach (vs. product approach). The Directive contains a definition of GMOs that applies also to plants but the applicability of this definition to organisms altered using genome editing has not been resolved and is contested by some (Nuffield Council on Bioethics, 2016). The UK House of Lords Science and Technology committee reports on genetically modified (GM) insects, which includes a review of the EU and international regimes, underlined that there no consistent and internationally regulatory protocol or convention for the testing and release of GM insects, which are not contained by national borders. The report, which underlines that the EU regulatory regimes for GMOs is not working as intended for GM crops and was not designed for GM insects, advocates for a review of EU regulatory regime for GMOs (UK House of Lords, 2015). The report also briefly mentions other countries regulatory approaches, including Brazil and Canada where a ‘trait-based approach’ is applied (as opposed to a ‘process-based approach’ of the EU). The report also emphasized the need for new tools to monitor GM insects in the environment and to include benefits of a technology in the regulatory regime. In Australia, a report, which includes a review of the current national regulatory status, notes that regulatory framework for gene technology is well established (Australia Academy of Science, 2017). The regulatory framework is a process-based system identifying and managing the risks of live and viable GMOs.

• In the US, gene drives will most likely fall under the scope of “1986 Coordinated Framework for the Regulation of Biotechnology” which regulates biotechnology products (NASEM, 2016a). This regulatory policy aims at ensuring the safety of biotechnology products (GMOs) based on their intended use. The U.S. agencies in charge of regulating the products of biotechnology – the U.S. Environmental Protection Agency (EPA), the U.S. Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) – have updated the Coordinated Framework to clarify the roles and responsibilities of the agencies (noting the Centers for Disease Control and Prevention has regulatory authority if public health is threatened) and to develop a long-term strategy to ensure that the federal biotechnology regulatory system is prepared for the future products of biotechnology (NASEM, 2016a). This led to the updated 2017 “Coordinating framework”, where one of the recommendations for

agencies was to clarify that “genetic engineering” encompasses genome editing.26 A NASEM report on gene drive recognizes that because of their intrinsic features of rapid spread and irreversibility, gene drives raise many questions with respect to their safety relative to public and environmental health (NASEM, 2016a). The report calls for a robust method to assess risks and recommends a phased testing approach. Such approach, along with the public engagement, an ecological risk assessment, and a clarified regulatory oversight are expected to facilitate a precautionary, step-by-step approach to research on gene drives without hampering the development of new knowledge (NASEM, 2016a).

It has been underlined that the release into the environment of genome edited organisms, such as malaria resistant mosquitoes, will take place in sub-Saharan Africa, southern Asia and South America. Some have therefore emphasized the importance of having regulation in place in these

25 https://eur-lex.europa.eu/resource.html?uri=cellar:303dd4fa-07a8-4d20-86a8-0baaf0518d22.0004.02/DOC_1&format=PDF accessed 28 May 2019. 26 For instance, EPA OPP intends to clarify its approach to pesticidal products derived from genome editing techniques and FDA intends to clarify its policy for the regulation of products derived from genome editing techniques, including, as appropriate, identifying and/or updating relevant existing guidance documents. Executive Office of the President of the United States. National Strategy for Modernizing the Regulatory System for Biotechnology Products. Product of the Emerging Technologies Interagency Policy Coordination Committee’s Biotechnology Working Group, September 2016. (https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/biotech_national_strategy_final.pdf, accessed 28 May 2019).

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regions as well (UK House of Lords, 2015). In 2014, the World Health Organization (WHO) developed guidelines for testing of genetically modified mosquitoes.27 Moreover, the report observes that the Cartagena Protocol on Biosafety (CPB) entered into force in many developing countries and it is anticipated to be an important influence on genetically modified mosquitoes regulatory processes and risk assessments (WHO, 2014). In 2018, the High-Level African Panel on Emerging Technologies made several recommendations about the development and regulation of gene drive technology, which includes: the establishment of a network of Africa-based scientists and developers to register their studies; the facilitation and adaptation of essential guidelines and frameworks and where necessary, enact enabling legislation for the development and adjudication of the technology; the support for bio-banking and data archiving; and the early engagement with stakeholders (NEPAD, 2018). In respect to gene drives, it is noted that “While there is currently no standardized procedure for addressing potential transboundary movement of GMMs [genetically modified mosquitoes] that are self-sustaining or with gene drive, some precedent is provided by prior introductions of classical biological control agents in agriculture. A regional notification and agreement process may be advisable for planned introductions capable of autonomous international movement beyond the scope of provisions in the Cartagena Protocol and may best involve a multilateral organization in a

coordinating capacity.” (WHO, 2014).28 Indeed, concerns have been raised that traditional biosafety provisions like those of the Cartagena Protocol on Biosafety are not well suited to the specific ‘self-sustaining’ inheritance characteristics of gene drive systems and that ecological risk assessment may not be sufficiently developed to be applied in the context of gene drives. New forms of innovation governance (‘responsible innovation’) are needed for the governance of gene drives (Nuffield Council on Bioethics, 2016). Principles for the governance of gene drive research have also been developed by several funding organizations and sponsors of research (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 (Emerson C et al. 2017). It is reported that the endorsement of this set of principles would represent “a pledge to advance the foundational elements of efficient and responsible research conduct: evidence, ethics, and engagement (…)”. (Emerson C et al. 2017). A new governance model for environmental gene editing, which proposes to link local needs with global governance, has also been developed (Kofler N et al., 2018). This approach, which is aimed at putting “great weight on local perspectives within a larger global vision”, proposes the establishment of an “environmental gene editing coordinating body that can convene communities, technology developers and non-governmental organizations in ways that ensure inclusive deliberations.” (Kofler N et al., 2018). Moreover, a “certification model for integrated deliberation” is suggested as “one way to lend immediate authority and impact.” (Kofler N et al., 2018). Several steps were also identified in the development of such coordinating body, including the design of the integrated deliberative framework; the creation of an online registry for all projects aiming to release genetically engineered organisms into the environment and the establishment of an communication task force and an online space to share information resources, expertise and discuss issues (Kofler N et al., 2018).

4. Genome editing in microorganisms and synthetic biology The use of genome editing techniques in the modification of microorganisms has helped to reduce the time and cost of previously used genetical engineering technologies and has allowed for research on some parasites, fungi and prokaryotic species that were until now difficult to study (EASAC, 2017).29

27 The guidance framework aims at fostering quality and consistency among processes for testing and regulating new genetic technologies by proposing standards of efficacy and safety testing comparable to those used for trials of other new public health tools. The WHO guidance also notes the importance of public involvement in the regulatory decisions process to ensure implementation without adverse public reaction. (https://www.who.int/tdr/publications/year/2014/guide-fmrk-gm-mosquit/en/ accessed 28 May 2019) 28 See also Appendix 2 (WHO, 2014). 29 For a review, see also Leopoldina et al., 2015; Nuffield Council on Bioethics, 2016; EASAC, 2017.

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This area of genome editing application is also of particular interest to industrial biotechnologies as they can transform current manufacturing processes and, for example, produce new products, reducing pollution and reducing costs (Nuffield Council on Bioethics, 2016). Current and potential applications of genome editing resulting in modified microorganisms include the production of third-generation bio-fuels in bacteria, fungi and microalgae (Liao JC et al., 2016; EASAC, 2017), modified yeasts for food production and flavouring (Callaway E, 2016) and also to generate novel pharmaceuticals such as antibacterials and antivirals (Citorik RJ et al., 2014; Barrangou R, Doudna JA, 2016; EASAC 2017). Synthetic biology is the design, modelling and construction of artificial biological organisms, devices and systems using biological materials for research purposes, specific engineering and biomedical applications.30 Synthetic biology is an interdisciplinary discipline drawing from molecular biology, computer science, chemistry and engineering (Nuffield Council on Bioethics, 2016). Synthetic biology, which was developed in the 1990s, has been rapidly developing with potential medical and environmental benefits and potential fields of application include: medicine (manufacture of new drugs, vaccines, gene therapy, development of biosensors for the identification of diseases; personalized medicine); agriculture (e.g. creation of novel food additives), environment (novel means to detect pollutants, bioremediation) and energy (e.g. creation of new microbes that would generate hydrogen; creation of ‘second-generation biofuels; artificial photosynthesis) (EASAC, 2010; EASAC, 2011; UK Synthetic biology Roadmap Coordination Group, 2012). In terms of governance, at the EU level, it has been argued that the use of genome editing techniques in microorganisms do not raise new ethical issues or regulatory issues, although it will depend on the interpretation as to whether genomic altered product will be considered as GMOs or not (EASAC,

2017). It was also noted that microbial genome editing research will fall with the scope of synthetic biology (EASAC, 2017). Furthermore, the advances of genome editing in the field of synthetic biology would fall within the scope of current regimes of EU regulations and codes of conduct established for synthetic biology (EASAC, 2010; Nuffield Council on Bioethics, 2016; EASAC, 2017). Moreover, the advice of the European Commission’s scientific committees on synthetic biology with respect to environmental risks has underlined that new genome editing technologies accelerate genetic modification as well as increase the range and number of possible genome modifications. “The increased speed of modifications might pose challenges to risk assessment, while not in itself creating new risks” (SCENIHR, SCHER, SCCS, 2015). In terms of biosafety, genome edited organisms may represent a risk to those who are handling them in a laboratory environment and, if they are accidently released, a risk to other people and their ecosystems. Laboratory biosafety regulations will cover the use of genome editing in laboratory settings (i.e. in terms of the risks posed to those handling microorganisms and if there is an accidental release from laboratories to the environment).

• In the EU, if genome editing organisms are considered as genetically modified organisms (GMOs), they would fall under the purview of EU directives for the contained use and deliberate release of GMOs, depending as to whether genetic altered microorganisms will be

considered as GMOs or not. 31 Countries have also developed national laws and regulations for the transport of GMOs as well as for their release in the environment.

• In the US, laboratory experiments in academic settings are overseen through Institutional Biosafety Committees (IBCs). These committees are the cornerstone of institutional oversight of recombinant DNA research and are the primary oversight mechanism for research associated with genetic modification at National Institutes of Health (NIH)-funded institutions (NASEM, 2016a). Given the recent advances in gene therapy, the NIH and FDA are currently working together to review the federal framework for oversight in order to streamline it by

eliminating unnecessary duplicative reporting requirements.32 Proposed changes to the NIH

30 For more about definitions on synthetic biology, see EASAC, 2010; Nuffield Council on Bioethics, 2016; NASEM, 2018b. 31 See EU Directive 2001/18/EC on the deliberate release of GMOs and Directive 2009/41/EC on contained use of GM microorganisms (GMMs). 32 NIH Director, Statement on modernizing human gene therapy oversight, 16 August 2018. (https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-modernizing-human-gene-therapy-oversight, accessed 28 May 2019). See

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Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) also include the proposition to restore the NIH Recombinant DNA Advisory Committee (RAC) to its original role, focusing on the scientific, safety, and ethical issues

associated with new and emerging biotechnologies.33

• At the international level, the Convention on Biodiversity (CBD) and its Cartagena Protocol on Biosafety respectively address the release of biotechnology products in the environment and their transboundary movements of GMOs resulting from modern biotechnology that may have adverse effect on the conservation and sustainable use of biological diversity. In decision XI/11 on the subject of synthetic biology, the Conference of the Parties “urges Parties and invites other Governments to take a precautionary approach, in accordance with the preamble of the Convention and with Article 14, when addressing threats of significant reduction or loss of biological diversity posed by organisms, components and products resulting from synthetic biology, in accordance with domestic legislation and other relevant

international obligations;(…)”.34 Article 14 provisions include that each Contracting Party shall “introduce appropriate procedures requiring environmental impact assessment of its proposed projects that are likely to have significant adverse effects on biological diversity with a view to avoiding or minimizing such effects and, where appropriate, allow for public participation in such procedures; (…)”. Yet some have expressed concerns as to what extent synthetic biology differ from genetically modified organisms (GMOs) already under the scope of the CBD and there is a need for a balanced and evidence-based way the potential risks and the potential benefits. In their views, a moratorium of synthetic biology would be counterproductive and global policy should not introduce excessive restrictions on synthetic biology (IAP, 2014).

In addition, it has been noted that the community of synthetic biologists has been described as having embraced responsible approaches and practices for innovation (Stilgoe J et al., 2013) as well as ethical reflections on their work since the beginnings of their discipline (Nuffield Council on Bioethics, 2016).

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. 33 Federal Register, National Institutes of Health (NIH) Office of Science Policy (OSP) Recombinant or Synthetic Nucleic Acid Research: Proposed Changes to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), Federal Register/Vol. 83, No. 160/Friday, August 17, 2018. 34 Conference of the Parties to the Convention to the Convention on Biological Diversity, Decision adopted by the Conference of the Parties to the Convention on Biological Diversity at its Eleventh meeting. XI/11. New and emerging issues relating to the conservation and sustainable use of biodiversity, UNEP/CBD/COP/DEC/XI/11 5 December 2012.

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5. Further considerations for governance

Access and fairness The tension between technological knowledge as ‘public good’ and the development of intellectual property regimes as a way to provide incentives for the production of such ‘informational goods’ has also been witnessed within the field of genome editing with the patent dispute on CRISP-Cas9 (Nuffield Council on Bioethics, 2016). It has been underlined that, while genome editing has been characterized by its speed of uptake and accessibility, there might be risk of inequity and tension between those who have access to genome editing and its applications and those who do not (EASAC, 2017). Such inequities would have consequences for global development, access and distribution, and distributive justice (Nuffield Council on Bioethics, 2016). Some measures have been proposed such as “active knowledge transfer, collaboration between researchers worldwide, open access to tools and education, and education efforts.” (EASAC, 2017).35

Medical countermeasures The use of genome editing in human applications will also affect the development of medical countermeasures and biodefense activities. Investment in research on novel therapeutics and vaccines and the development of novel methods of detection and diagnostic will provide tools for addressing both naturally emerging diseases and the deliberate release of biological agents, hence improving public health preparedness and responsiveness.

Biosecurity and dual use considerations Biosecurity36 and dual use concerns as well as the potential for misuse are not unique to genome editing (i.e. nuclear and chemical technologies). Biological agents and associated technologies might be misused as well as research and knowledge. This is known as dual use research: dual use life science research can be defined as knowledge and technologies generated by legitimate life sciences research that may be appropriated for illegitimate intentions and applications. In fact, life sciences and most of the reviewed emerging biotechnologies, including synthetic biology and gene drives, have raised concerns in terms of their dual use and their potential to be misused to cause harm (US NAS

NRC, 2004; NASEM, 2016a, NASEM, 2018b). Genome editing technologies have also raised similar concerns (Regalado A, 2016). The misuse of the life sciences for harmful purposes has been banned by the Biological and Toxin Weapons Convention (BWC), which entered into force on 26 March 1975. The BWC bans the development, production, stockpiling and transfer of biological and toxin weapons. Since 2003, the States Parties to the Biological Weapons Convention, have been holding annual meetings with experts from the scientific community, academia, professional associations and international organizations whose aims include the review of science and technology and their relevance to the BWC. In this regard, concerns arising from genome editing were raised in 2015 during an international inter-academy meeting in preparation of the 2016 8th Review Conference of the BWC (IAP, 2015). In particular, it was reported that the design and synthesis of novel agents could be done using genome editing, hence challenging current export controls regimes. It was also reported that as genome editing technologies, such as CRISPR/CAS-9, often do not leave evidence indicating that that an organism had been altered, this would in turn make difficult to distinguish between a natural or a deliberate disease outbreaks. In 2004, the National Research Council of the US National Academies of Sciences published a seminal report “Biotechnology Research in an Age of Terrorism: Confronting the Dual-Use Dilemma”. The report reviewed the issues associated with dual-use research, proposed several risk

35 See also discussions under the Convention on Biodiversity and Nagoya Protocol and issues around “bounded openness” and natural information. 36 “’Laboratory biosafety’ is the term used to describe the containment principles, technologies and practices that are implemented to prevent unintentional exposure to pathogens and toxins, or their accidental release. ‘Laboratory biosecurity’ refers to institutional and personal security measures designed to prevent the loss, theft, misuse, diversion or intentional release of pathogens and toxins.” WHO, 2004. Biosecurity is also used in a wider sense to refer to the risks posed by the deliberate misuse of agents, associated technologies and knowledge.

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management measures and identified seven classes of experiments of concern involving dual use

research of concern37 that warrant review prior to being carried out and before publication (US NAS NRC, 2004). These concerns have also been addressed through a range of national policy measures

ranging from oversight regimes38 to self-governance (BBSRC et al., 2015) codes of conduct and educational measure (IAP, 2016). These regimes could therefore be envisaged to cover biosecurity risks posed by genome editing. In 2018, the IAP published the report of an international workshop, which was held in Germany, on 11-13 October 2017, on the security implications of genome editing technology (IAP, 2018b). The meeting participants reviewed the security risks posed by the use of genome editing in several fields (in human cells, agriculture, gene drive and microbes) and the current governance mechanisms to address security issues. Although the misuse of genome editing could lead to research altering pathogens to enhance their virulence or transmissibility (i.e. gain of function research), the misuse of gene drives on humans could result in new types of neurological weapons and the enhancement of military capabilities (‘super soldiers’), it has been reported that it is quite challenging to review the risks of misuse posed by genome editing (IAP, 2018b). Regarding the mitigation measures, it was observed that there is concern that additional governance measures would not reduce the risks of intentional misuse but may hinder responsible research (IAP, 2018b). It was also noted that regulations should focus on the product and not the process, i.e. a restriction on the access of genome editing technologies is inappropriate and probably unfeasible. The risk of intentional misuse in the research and application settings has been so far governed through existing regulatory frameworks and the self-governance of scientists. It was finally reported that these discussions on the potential risk for misusing genome editing technologies have not concluded that there is no risk but rather that there is no extra risk. Uncertainty will therefore remain and demands ongoing and inclusive dialogue, including to address public concerns (IAP, 2018b). Yet, risk assessments may differ in other settings. In February 2016, the U.S. Director of National Intelligence identified genome editing as one of the six weapons of mass destruction and proliferation in his report on global threats (Clapper JR, 2016). It is reported that “Given the broad distribution, low

cost, and accelerated pace of development of this dual-use technology genome editing, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications.” (Clapper JR, 2016). Finally, as noted, one major impact of genome editing has been its wide-ranging applications, its speed, efficacy and accessibility. Even though genome editing techniques have not generally raised issues that are different in kind from previous research, the fact that it can make the realization of this

research easier is a matter of concern for the BWC (Nuffield Council on Bioethics, 2016). In this

regard, it has been noted that the scientific community should continue to inform and provide advices during the reviews of the Biological and Toxin Weapon Convention (EASAC, 2017).

37 “Dual Use Research of Concern (DURC) is life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.” US NAS NRC, 2004. 38 See for instance in the US, the Department of Health and Human Services (HHS) government policy Science, Safety and Security (S3) that have developed several policies for the oversight of dual use research of concern. (https://www.phe.gov/S3/dualuse/Pages/default.aspx, accessed 28 May 2019).

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