Ordo-Responsibility for Germline Gene Editing

Introduction

Recent history of germline gene editing (GGE) appears as a disruptor of ethical standards. In 2015, the first-time use of these new tools on (non-viable) in vitro embryos in China ¹ led to a public outcry and divided the science community.^2,3 At the end of 2018, just before the Second International Summit on Human Genome Editing in Hong Kong, ⁴ He Jiankui announced the birth of allegedly healthy twins edited at the CCR5 gene. ⁵ Critics immediately condemned He's experimental actions, intentions, and outcomes.^6–9 Intensified appeals for regulation have been forcefully raised.^10,11

In this article, we propose a framework of “ordo-responsibilities,” which is a pragmatic approach open to pluralism and grounded in principles of human dignity. After laying out the basic structure of this approach, we sketch a possible pathway toward an international framework as well as minimal requirements that are needed. We thereby hope to contribute to the ongoing debate on how to govern genome-editing technologies and GGE.^12–15

Establishing a Global Regulatory Framework

GGE has the potential to cure severe medical conditions, although it presents several potential risks for future offspring, societies, and perhaps for humanity. Therefore, a regulatory framework that guarantees a minimum of international (legal) standards is needed. Existing binding regulations, such as the Clinical Trials Regulation of the European Union, which prohibits trials resulting “in modifications to the subject's germ line genetic identity” (EU Regulation 536/2014, Art. 90), apply only to some nations. Declarations from international bodies such as the United Nations Educational Scientific and Cultural Organization constitute “soft law” and only give some guidance.

The Chinese case indicates the need for more binding regulations. Scientists' hope for recognition incentivizes the pursuit of cutting-edge research before consensus is settled by international discussion regarding legitimate GGE practices. In the absence of an efficient regulatory framework, mere moral condemnation has no effect in preventing irresponsible use of genome-editing technologies. ¹⁶ If the recent experiences do not trigger international efforts to find standards, then other researchers may follow. ¹⁷ It is evident that a regulatory framework could not guarantee universal compliance with such rules. Still, violations of global standards would be prosecuted if implemented in domestic legal orders to this effect, and penalties for such transgressions would deter most researchers from embarking on prohibited experiments.

It is the fundamental assumption of ordo-responsibility that the main reason for unwanted behavior is a lack of a functional regulatory framework. When Edward Jenner did his research with an eight-year-old boy in the United Kingdom in the late 18th century, leading to his vaccine discovery, he felt obliged to undertake known risks to the boy's life. Jenner wanted to prevent the boy from contracting smallpox while no adequate research regulation was in place prohibiting this kind of study with children. Similarly, He Jiankui might have felt emboldened in his research because no binding regulation seemed to prohibit his ambitions.

As scientific research is a worldwide endeavor and further studies with GGE might be contemplated, effective international regulations are needed. Lacking an effective framework, researchers are tempted to override unspoken global rules: researchers could look for countries willing to tolerate the exception or at least cover their eyes. States, on the other hand, are tempted to gain advantage to strengthen their domestic scientific capacities. In addressing these challenges, the organizing committee for the first International Summit on Human Genome Editing in 2015 concluded:

“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations. The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.” ¹⁸

At the Second International Summit on Human Genome Editing in 2018, the need for “common regulatory standards” ¹⁹ was confirmed while He Jiankui's experiments were condemned. At the same time, it was clear that scientific bodies alone would fail in effectively restricting similar experiments. Furthermore, finding a common ground for ethical and legal regulation is difficult considering the global diversity of moral and legal cultures.^16,20 For example, analogous attempts to find international consensus on banning cloning were not successful mainly because some states wanted to prohibit not only all forms of reproductive cloning but also all forms of cloning for therapeutic purposes, which was highly contested. The question emerging for GGE is similar: how can a framework for the governance of GGE become feasible in the face of a global pluralism of norms?^12,13

Here, we follow a path recently proposed by Eric Lander et al., who suggested a global moratorium on the clinical use of GGE to establish an international framework of governance. Their approach, however, does not fall victim to the illusion that a maximalist framework on the governance of GGE, acceptable to every nation, can ever be reached. Their proposals “leave room for nations to take differing approaches and reach different conclusions, informed by their history, culture, values and political systems.” ²¹ Though a comprehensive or maximalist framework for governing GGE is not feasible, it may be possible to achieve a minimum standard and some degree of global harmonization. This approach moves the focus away from specific (national) laws and regulations to a rule-finding process for establishing a minimal framework.

Taking Ordo-Responsibility Seriously

Ordo-responsibility is a pragmatic ethical approach commonly associated with business ethics. It focusses on rule-finding processes that are fair, implementable, and optimally efficient in terms of limiting transactional burdens of regulatory systems.^22,23 Instead of focusing on single-actor morality, implementable rules are developed that respect organizational structures, such that actors are incentivized to act in ways consistent with long-range ethical goals. Hence, blaming He Jiankui has limited effectiveness from an ordo-responsibility perspective. Rather, the international community is culpable for ineffective research-science rule frameworks.

A well-known example for such a kind of rule-finding-process is the Vienna Convention for the Protection of the Ozone Layer (1985), a framework convention leading to the Montreal Protocol on Substances that Deplete the Ozone Layer (UN-resolution 49/114). The protocol was agreed upon in 1987 and was ratified by numerous states in 1989. Other states followed successively, such that the Montreal Protocol became the first universally ratified treaty in 2009. According to the former General Secretary of the United Nations, Kofi Annan, it is “perhaps the single most successful international agreement to date.” ²⁴

The Protocol set out a timetable for ending the production and use of approximately 100 substances endangering the ozone layer. Before it was agreed upon, companies had good reasons to produce refrigerators using chlorofluorocarbon (CFC), for example, although they knew that CFC endangers the ozone layer. (This strategy was rational: if company A did not use CFC, the cost of its products was higher than the products of competitors that relied on CFC.) The moment a binding agreement was reached and sanctions for those violating the Protocol were implemented, all companies could follow easily and had incentives to do so because companies no longer had to fear that the competitors still using CFC would benefit from doing so.

The first step in establishing the Convention and then the Protocol was to discuss rules and relative potential costs/benefits among stakeholders such as the media, public-interest groups, and national bodies. This can be described as a meta-meta-game. ²² The discussion was successful because of the increasingly evident risk of losing the ozone layer and endangering lives. Therefore, the Convention and the Protocol could be drafted by the respective bodies of the United Nations. The rules in these documents are ordonomically called the meta-game. The basic game is played on the field where the new rules take action—in this case by the companies now producing products without CFC and nearly 100 other substances. The Montreal Protocol is an excellent example of well-functioning ordo-responsibility and could also serve as a paradigm for how a regulatory framework for emerging technologies such as genome editing could be established.

Ordo-responsibility focusses on the rule-finding process and on institutions rather than on the deeds of actors (i.e., “the game”) or their motivation. The meta-meta level should not deal with individual infractions or bad actors but might use these infractions as examples to generate legal frameworks and incentive structures that benefit the public good by preventing infractions. Thus, ordo-responsibility avoids finger-pointing moralism and scapegoating strategies while aiming for collectively beneficial solutions.

The Meta-Meta-Game for GGE

For GGE, an ordo approach suggests following the Montreal Protocol example. During the 1980s, media coverage and public debates of the risks of substances destroying the ozone layer gave incentives to create a regulatory framework. Similarly, momentum from the recent incident in China can be used to initiate a rule-finding process to establish minimum standards for GGE. While agreement on GGE common goals presents problems unique from the Montreal Protocol development, analogous aims do exist. First, a minimalist international framework would likely better safeguard stakeholder interests than the absence of such a framework. Second, despite international norm pluralism, commonality exists on the level of basic human cultural values and interests. So much is at stake for humanity regarding the use of GGE, and so consensus on avoiding harm and moral hazards is within reach.^12,13

Instead of focusing blame on one scientist, the meta-meta-game should use the CRISPR babies case as proof that international regulation is needed. First steps for such an effort were realized more than 20 years ago. The Convention for the Protection of Human Rights and Dignity of the Council of Europe (the so-called Oviedo Convention) prohibited heritable germline modifications in 1997. However, this treaty was not ratified by key players in Europe, and was considered too restrictive by some nations (e.g., the United Kingdom) and too permissive by others (e.g., Germany). ²⁵

CRISPR's vast potential and risks make binding regulatory frameworks necessary. Various distinguished bodies have published recommendations to that effect.^26,27 Other stakeholders are also involved. Religious leaders and organizations, scientists, ethicists, politicians, businesses, and other groups have expressed their opinions. Some scientists would push for minimal regulation; others might endorse more rigorous regulations to protect professional reputations and public goodwill. Companies seek opportunities for financial profit, patient groups hope for new treatments, and interest groups want to see their moral values protected. In this meta-meta-game, several positions as well as objectives can conflict. Positions rejecting all forms of GGE because of the assumed intrinsic value of the human genome are in disagreement with positions limiting interventions to prevent diseases, or positions seeing some forms of germline modification even as an imperative.

From a perspective of ordo-responsibility, it is crucial that the meta-meta-game suggests rules—the ordo—that enjoy broad consensus. The rules ought to incentivize actors optimally to comply with those norms. For globally applicable rules, the discourse of relevant actors provides a discovery function for underlying interests and possible options necessary for achieving good rules and motivating “buy in.” At this time, even the rule-finding discourse needs to set rules and collective conditions that best protect and foster values and preferences most stakeholders are willing to accept. Even though the meta-meta-game is one of steady process, values deliberation, and creative discussion, the experiments of He Jiankui show the necessity for a transformation into a meta-game in order to reach a regulatory framework excluding some experiments and applications by setting minimum standards for GGE.

A Pragmatic Approach for Rule Setting

We suggest that recognized international bodies initiate a global rule-finding process for GGE. If these bodies take ordo-responsibility seriously, they have to pay attention to institutional-level patterns of social cooperation in terms of positive and negative externalities—the so-called unintended (though predictable) effects. For example, a moratorium on all forms of genome-editing research on embryos could lead to detrimental effects on the basic game. A general GGE moratorium would suppress research momentum at institutional and personal levels and cause knock-on harm in associated research fields beyond those dealing with human reproduction. Further, such a ban would be difficult to enforce because it would not enjoy support from many scientific and nonscientific stakeholders. If some states were not willing to ratify the moratorium, this could lead to research centers moving to more regulation-friendly or regulation-less locations. ²⁸

As a result, a supranational regulatory framework must be more limited in ambitions to keep all parties committed, even though some may demand stricter rules for religious or philosophical reasons. Its rule framework would have to be carefully crafted to be internationally enforceable, as well as to be properly structured to support public goods while incentivizing compliance and punishing noncompliance. The meta-game of rule setting needs support from the sciences, industry, law, ethics, the public, and politicians willing to engage in the process of establishing the global framework of minimal standards.

In exploring a practical pathway toward international standards on the use of GGE, one might seek inspiration from other international rule-setting procedures. The Montreal Protocol helped illustrate the rationale behind ordo-responsibility. Regarding the necessary law-making techniques, within the frameworks of international organizations, the law-making procedures of the International Labor Organization Constitution ²⁹ or the Council of Europe ³⁰ could additionally serve as a blueprint for regulating GGE. It might be advisable to start off a multi-staged procedure in the form of a series of international conferences (meeting at regular intervals), the first of which would seek no more than to agree on recommendations^a for how states ought to regulate GGE. In that process, it is imperative to include stakeholders representing a vast number of people because GGE potentially affects the whole of humankind.^12,13

The Washington and Hong Kong Summits and the recently established working groups of U.S. National Academies and the Royal Society of the United Kingdom ³¹ as well as the World Health Organization ³² are helpful but not sufficient. These initiatives lack a comprehensive plan on how to translate results of their discussions into a global framework. Furthermore, the working groups have no mandate for proposing binding regulatory norms in their states. Hence, a platform is needed where single states could nominate representative members with a specific directive to develop recommendations.

A second stage would follow after further meetings. Here, political representatives would report (whether and) how they have tried to put those recommendations into practice “at home.” At this stage, an international agreement might be drafted, setting up a catalogue of rules and conditions^b for the application of GGE (the meta-game). In order to enable as many states as possible to ratify such an agreement (the act of ratification making it legally binding for them under Public International Law), the agreement could allow states to “pick and choose” from this catalogue a minimum set or, in more cautious approach, a minimum number of rules (e.g., 50%) and “subscribe” only to the rules it selects.^c This could make a broader agreement possible than a maximalist framework for governing GGE. In its act of ratification, every state would then be required to declare which of the rules it is going to adopt as binding and whether and how far it accepts more rules as binding than the required minimum.

In subsequent conferences, the states would again report on how adopted rules have been implemented in their domestic legal systems—and how these rules changed the basic game. Reporting conferences function as assessment milestones regarding rule effectiveness within states' domestic legal orders. Comparing assessments fosters best-practice principles based upon empirically substantiated experience of rule compliance and science progress. Knowledge is gained regarding what works—namely, how actors are prevented from rule evasion and laboratory emigration to nations with less burdensome rule regimens. If conference assessments reach sufficient consensus, that offers opportunities for “cranking up” minimum internationally binding requirements. Such bottom-up consensus building encourages states to accept rules as legitimate and binding, thus adding stability and confidence to the regime of GGE regulation.^d

Human Dignity and Self-Determination as Common Ground of Ordo-Responsibility

Ordo-responsibility exists in a context of legitimate pluralism of games within meta-games of rule implementation on national and subnational levels relevant for GGE. Nevertheless, it is bound to common minimum moral principles that underlie international declarations and norms. Rules at the national levels must be established in a way that is consistent with fundamental values in international declarations such as the United Nations Declaration of Human Rights and the Helsinki Declaration of the World Medical Association on the one hand and preferences of stakeholders of different economic, philosophical, theological, and political background on the other hand.

Even though the separation between state and religion is a fundamental characteristic of modern liberal democracies, religion plays an important role if the implementation of rules is to succeed. Even in liberal democracies such as the United States, the United Kingdom, and Germany, commissions and ethical bodies include representatives from different religious communities. The Catholic Church exercises an important influence on countries with a large catholic population, and Muslim countries are influenced in their rule setting by their religious bodies. If an international binding regulation on GGE is to succeed, these religious influences must be taken into account too.

However, one should be careful not to overemphasize any particular religious or philosophical convictions in seeking guidance for the rule-finding process at the international level. In the search for a global framework of minimal standards, it would be highly problematic to attempt to protect the embryo the same way as, for example, the German Embryonic Act does by ruling out every kind of embryo research. The legal standards of a single state should not be “forced” upon others. On the contrary, even the slightest impression that the search for a global framework could start from the most restrictive or the most liberal regulation in place ought to be avoided. Instead of a standardization of law, that is, the creation of uniform legal standards, the proposed global framework would seek convergence in common values where possible. ¹⁶

The case of the German Embryonic Act helps us to understand what common minimal values and principles are—and what they are not. Human dignity is one such common principle articulated in the Universal Declaration of Human Rights (1948), as well as in subsequent international human rights treaties and international conventions. According to that principle, all humans, as beings endowed with dignity, should be treated as ends in themselves—and not as mere instruments to achieve some other goals, including the common good. The dignity principle safeguards the fundamental right to life (including a universal right of access to adequate health care), self-determination, and liberty (including freedom of research) and the fundamental equality of all human beings.

While there is consensus on the value of human dignity, it remains an open question whether dignity has to be attributed to the early stages of the unborn life. Consequently, from a perspective of ordo-responsibility, policy-finding processes cannot reconcile such ontological or ethical questions. Instead, countries should be free to impose stricter rules as the minimal consensus that could be reached. If some stakeholders (e.g., the Catholic Church) hold the instrumental use of embryos to be intrinsically wrong and condemn any embryo research in the course of which embryos are destroyed, they may try to convince the public and states of their position. For instance, the Catholic Church had an important influence on Catholic German politicians, which was one important reason why the German Embryonic Act prohibits embryo research. However, a global framework cannot be bound by such significantly religious or ontological commitment. There exists no consensus on the ontological and hence on the moral status of the human embryo, irrespective of whether it is a human being. Therefore, a binding prohibition of embryo research is not implementable.

This legitimate pluralism is already recognized today, for example when the European Group on Ethics in Science and New Technologies states that “it is up to each Member State to forbid or authorise embryo research.” Hence, in some states “respect for human dignity requires regulation of embryo research and the provision of guarantees against risks of arbitrary experimentation and instrumentalization of human embryos.” ³³ It is crucial to notice that even stakeholders that categorically reject GGE (i.e., because of the consumption of embryos) can find reasons to agree to a global framework that allows such research and application in other states. For if such a framework allowed stricter standards or even a complete prohibition of GGE in some states, it would still be better for these stakeholders to have such a framework than to have no global rules.

That said, it is important to notice that while the question of the moral status of the early embryo is controversial, the principle of freedom of research as a fundamental right is recognized in many nations' constitutions.^34,35 Research may be restricted only on the basis of competing fundamental rights. In cases of conflict, restrictive rules (the meta-game) may limit particular forms of research activities (basic game). It is crucial to recognize, however, that authorities bear the burden of justifying restrictions upon scientific freedom.

For GGE, the guiding norm of preserving human life and physical integrity as a right connected to the dignity of all born human beings is especially crucial. While the right to life and physical integrity should direct every rule-finding process, in the meta-meta-game, the principle of human dignity may still be used to support sometimes competing rules. It is possible to argue that human dignity of future human beings demands GGE. ³⁶ It is equally possible to argue for the opposite position that interventions into the human germline violate human dignity. ³⁷ If it is believed that human biological nature or the human genome in its current form is the source of human equality or solidarity, GGE is likely to be seen as a threat to human dignity. If human dignity is associated with human freedom, a right to health or reproductive liberty, GGE may be considered in a different light. Therefore, it would be futile to aim to find a consensus on that deep metaphysical question at the global level. Instead, the rule-finding process should focus on more fundamental principles, that is, how to limit risks for the life or physical integrity of living and future human beings. This is the main reason why the experiments of He Jiankui are so contested—risking the lives of Nana and Lula and therefore, one could argue, willing to disregard their (future) human dignity.

Concluding Remarks

GGE will dramatically impact medical ethics and society more broadly. Mere national regulations, divergent as they are, lack that capacity to deal with relevant ethical challenges. An ordo-responsibility offers valuable insights for a pathway to a global framework in regulating interventions by means of CRISPR compatible with existing ethical norms and goals.

Ordo-responsibility is pragmatic in (1) accepting generally available values at the global level (e.g., human dignity, human rights) and (2) seeking achievable implementation. An effective framework must be clear, implementable, and self-sustaining in terms of enforcement, and it must enjoy broad support from the basic groups of stakeholders. Instead of blaming individuals, the challenge for the global society consists in committing to some rules restricting harmful use of GGE. This approach avoids destructive discourses of competing anthropologies and religious commitments. Instead, it focuses upon setting up implementable rules governed by established principles such as dignity and fundamental human rights providing responsible pathways to clinical applications.