Introduction

Current advances in assisted reproductive technologies (ARTs) aim to promote the health and well-being of future children.1 They offer, for example, the possibility to select embryos with the greatest potential of being born healthy (eg, preimplantation genetic testing (PGT)ⁱ) and, perhaps, one day to correct genes responsible for heritable diseases in the embryo (eg, human germline genome modification (HGGM)ⁱⁱ). ARTs raise the question of what uses are ethically and socially acceptable and which should be prioritised. For PGT, for example, thresholds of acceptability are gravity, treatability, risk of occurrence of a given disease and more.2–4 Past experience with the normative analysis and governance of PGT and prenatal testing can serve as a model to guide similar debates surrounding the acceptability of HGGM.

The announcement of the ‘CRISPR babies’ in China5 6 and the Second International Summit on Human Genome Editing in Hong Kong (November 2018)7 put HGGM at the forefront of international policy debates. The general agreement remains that HGGM should not be used for reproductive purposes at this time, as many unknowns remain surrounding its safety, efficacy and transgenerational impacts. Yet, there is emerging consensus on the need for a translational pathway forward. Such a pathway requires adherence to and development of scientifically rigorous and ethically acceptable standards for future clinical research using HGGM,7 including which diseases it should be used for first.

Numerous policy discussions (both national and international) surrounding HGGM refer to the notion of ‘serious’ genetic disease as a core parameter in determining what genetic diseases should be targeted by these technologies and where the line should be drawn.8–12 For example, in their 2017 Report, the US National Academies of Sciences, Engineering, and Medicine (NASEM) lists a set of thresholds that must be met for the advancement of HGGM into clinical trials.9 These include ‘preventing a serious disease or condition’ and the need for ‘reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition’ (p. 8) (emphasis added).9 More recently, Quebec’s Commission on Ethics in Science and Technology stated that HGGM, if proven to be safe and effective, should be limited to ‘very serious , high penetrance diseases, where there are no other reproductive or therapeutic options available’ (p. 14).12 The German Ethics Council’s 2019 Report has also mentioned HGGM’s application as an ‘interventions to avoid serious monogenic hereditary diseases’.11

Wertz and Knoppers8 raised the importance of this notion back in 2002. They demonstrated through an international survey that there is insufficient consensus, even among experienced genetics professionals regarding the definition of ‘serious’ genetic disease within a strictly legal and policy context. They also highlighted that socioeconomic factors are influential in determining individual perceptions of what would be classified as ‘serious’.8 The literature suggests it would be unrealistic to expect a universal definition of ‘serious’ and that when employed it must be qualified and consider both patient and medical perspectives.8 This renders the application of this term vague and decision making subjective and perhaps arbitrary. Furthermore, public opinion also appears to converge towards acceptance of HGGM for therapeutic purposes (ie, the treatment and prevention of serious, life-threatening and debilitating diseases).13–18

This paper explores whether the notion of ‘serious’ genetic disease should be qualified by a circumscribed set of criteria (ie, objective approach to decision making limiting or characterising access to HGGM). If so, we consider who should be entrusted with qualifying this notion. We begin by presenting a brief overview of two conceptual approaches: objectivism (ie, emphasis on biological facts) and constructivism (ie, emphasis on human values), which are indispensable tools to situate and provide a basis for understanding and discussing the concepts of ‘health’ and ‘disease’. The challenge under both is sorting out whether and to what extent social and environmental factors have a role in helping to define what qualifies as a ‘serious’ disease beyond the medical criteria. Moreover, the classification of ‘serious’ should be flexible enough to include shifting socioeconomic conditions (eg, if burdens are lessened through policies or whether cost of treatment should play a role). Our focus is on how a human rights-based framework (eg, right to science and right to health) could integrate the concepts of objectivism and constructivism to provide guidance for a more actionable consideration of ‘serious’. Indeed, we would argue that a human rights framework, by way of its legally binding nature (for States having ratified the international treaties) and its globally accepted norms/values, provides a more universal foundation for discussions of the ethical, legal and social implications of emerging or disruptive technologies.19

CONCEPTIONS OF ’HEALTH' AND ’DISEASE'

The concepts of ‘health’ and ‘disease’ are pivotal in the context of healthcare. The way we define and qualify them has individual, societal and policy implications. Laws and policies employ the notion of ‘serious’ as a qualifier in determining the circumstances under which HGGM may be used and what genetic diseases it would be acceptable to target. Yet, in most countries, the notion of ‘serious’ has not been explicitly defined,ⁱⁱⁱ rendering its application rather limited, dependent on the weight it attributes to physiological, sociocultural and environmental factors.20 A brief overview of two conceptual approaches is provided below to contextualise the concepts of ‘health’ and ‘disease’ within the discussion of what is considered ‘serious’. While a comprehensive and in-depth exploration of these approaches goes beyond the scope of this paper, the interested reader can refer to a rich literature that offers such analysis.21–30

A HUMAN RIGHTS-BASED FRAMEWORK

At the international level, fundamental human rights are framed by the Universal Declaration of Human Rights (UDHR, 1948)37 followed by binding international treaties such as the International Covenant on Economic, Social and Cultural Rights (ICESCR, 1966).38 Despite its foundational status for international human rights, the 1948 UDHR itself is not legally binding, but today could be considered to be part of customary law.39 The ICESCR, however, as a legally binding instrument in all 169 nations that have signed and ratified the treaty, has an enforceable ‘duty to respect, protect and fulfill the rights articulated [therein]’ (p. 899).40

An international human rights-based framework, we argue, is a useful way of addressing the ethical, legal and social issues arising in the context of novel technologies. It may be preferable to national legislation that addresses each scientific advance, which often becomes outdated. Human rights are both individual and collective, and they encompass both positive duties (ie, urging for governmental action) and negative duties (ie, to refrain from interference).40 They serve as principled and practical guides to action and promote responsible translational research.40 This can be a promising approach to addressing the proposed translational path forward for HGGM, as there is great uncertainty surrounding what might be the best ethical framework to consider HGGM.

The rationale for such a framework hinges on two main concerns: (1) the limitations of ethical frameworks (as a sole mechanism) to govern and guide healthcare professionals and (2) the ‘need to integrate stronger human rights language if professional self-regulation is to be more effective’ (p. 69).41 A human rights framework allows for the effective regulation of behaviour and the establishment of common norms as a result of its legally enforceable mechanisms and universal scope (ie, not imposing one cultural standard).40 It sets a baseline standard that can be invoked to ensure the respect of human dignity and to promote the harmonisation of governance.40–42 This approach is expanding to influence and shape both the right to science and the right to health as a result of increased knowledge and experience, as well as evolving societal perceptions and challenges.40

DISCUSSION

The undefined nature of ‘serious’ renders its application vague and decision making surrounding what diseases should be targeted for treatment or prevention potentially arbitrary. Two approaches to addressing the notion of ‘serious’ have been proposed: (1) the creation of lists of serious genetic diseases and (2) the development of criteria that guide case-by-case determinations of what is considered to be ‘serious’. It is unrealistic to expect policy makers ‘to develop a universally respected definition of serious genetic disorders’, and any such definition ‘must be qualified to include the judgment of the patient and physician, with the patient making the final, and one hopes, informed, decision’ (p. 35).8 The NASEM Report (2017) recognises the social relativity of qualifying this concept in that ‘different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities’ (p. 8).9

The literature shows that when polled, there is overlap and difficulty in drawing clear lines between what genetics professionals consider to be serious versus non-serious genetic diseases.8 This variability can be attributed to several factors, for example, the way genetic diseases are expressed in different individuals; individual, familial and societal perceptions of the disease; professional or legal definitions of the genetic disease that may be too narrow; and lack of definitional flexibility once enshrined in laws and policies.8 Today, parallels can be drawn with the ever-changing interpretations of ‘pathogenic’ variants with the advent of whole genome sequencing.54 55 Indeed, the American College of Medical Genetics and Genomics has published a revised list of 59 medically actionable genes that they recommend should be reported as incidental or secondary findings in the context of clinical genomic sequencing, testifying to the ongoing nature of this debate.56

Furthermore, the literature highlights that lists of serious genetic diseases—and the possibility of limiting access to services based on a definition of ‘serious’—would be highly discriminatory, as it ‘place[s] value labels on the lives of people with various kinds of genetic disorders and could lead to further stigmatization of people with disabilities’ (p. 35).8 Concepts such as ‘health’, ‘disease’ and ‘serious’ should not be defined without considering the adaptation of an individual to a given environment.31 Moreover, the distinction between the definitions of ‘disease’ and ‘illness’—whereby the latter considers the subjective reality of human experience—may be useful, as the concept of ‘illness’ aligns with the constructivist approach and broadens the scope to include both physiological and social aspects.34

Against the backdrop of powerful voices that perceive ‘precaution’ and ‘responsible implementation’ of emerging genomics technologies as necessitating slower progress or moratoria to address panic and resistance to HGGM,57 58 a human rights framework can offer a more balanced view. By introducing elements of ‘opportunity cost’ and the freedom to pursue interventions, it can hence foster a more balanced debate that accounts for the value of progress and of implementing technologies that have been deemed safe and effective.

Rather than relying solely on a biomedical objectivist approach for understanding the concepts of ‘health’ and ‘disease’, socioeconomic and cultural contexts should be considered, as suggested by the constructivist approach, since they provide a more appropriate basis on which the notion of ‘serious’ can be framed and elaborated. The integration of these two approaches would be more nuanced and culturally sensitive and would also align with the goals of human rights. We have focused on both the promotion of the right to science and the right to the highest attainable health. These rights provide a legally actionable focus and represent common, internationally agreed on values that can in turn help guide the development of national regulatory approaches.19 Thus, human rights may provide a more universal and legitimate foundation on which the governance of ‘serious’, ‘health’ and ‘disease’, as well as HGGM can be built. As suggested by Boggio et al,19 this would offer ‘an ideal starting point for building international consensus on governing principles that promote responsible scientific and technological advancements’.

Decisions about what constitutes a ‘serious’ disease should similarly consider the limitations imposed on the ability of individuals to partake in daily activities as a result of the individual biological and contextual factors involved.59 As such, proportional policy making based on a clear assessment and delineation of realistic levels of risk or severity of a disease is important.40 Criteria currently considered in the determination of possible applications of PGT can be useful and offer a foundation on which further considerations can be extrapolated within the context of HGGM (see box 1).

For example, take the case of phenylketonuria (PKU), a rare, heritable metabolic disorder in which affected individuals cannot metabolise the amino acid phenylalanine.50 PKU is currently part of the newborn screening panel in most industrialised countries to ensure early detection and subsequent intervention.60 Infants diagnosed with PKU are placed on a special diet (eg, low phenylalanine diet) that they must maintain throughout their lives to prevent the development of severe intellectual disability resulting from their condition.50 61 Such a postnatal (and lifelong) intervention is demanding and burdensome on the individual (ie, restrictive diet, costly, may not be accessible to all).50 In such a context, could the application of HGGM be acceptable if safe and effective?

Based on considerations of the right to health and the right to science, one could argue that we have a moral imperative to pursue basic research that may eventually lead to treatment using HGGM. The goal would be to decrease human suffering and/or improve quality of life, as well as to reduce the burden placed on families and the cost to the healthcare system. Indeed, as has been argued in the literature, HGGM will initially be a costly intervention, which may create barriers to access.62 63 It will thus be essential to ensure equitable access for those who would benefit from it most. Here again, the notion of ‘serious’ may be useful in determining who has the most urgent claim to HGGM (eg, families suffering from serious genetic diseases) and therefore should be assisted or favoured to enable equitable access.

Determining what is considered a ‘serious’ condition provides two different types of policy rationales. First, it provides justified limits of acceptability and helps to delineate what uses of this technology should be deemed permissible versus impermissible.50 The justified goal being the promotion of health and improvement of quality of life of future generations, where possible. Second, it provides justifications for potential public funding for the use of the technology to facilitate access to those most in need based on the goal of trying to prevent the most serious conditions. Clarifying the notion of ‘serious’ can thus foster an equitable and inclusive approach to HGGM while ruling out its most contentious applications.64

Finally, when considering a rights-based framework, we must look beyond individual State parties and recognise the joint interests of the State, the users and the public at large to ensure the realisation of the right to science and the right to health (ie, to engage with the public on matters of scientific freedom and innovation, as well as health and the prioritisation of public health issues).41 A key aspect of the right to science relates to ‘the opportunities given to individuals and peoples to make informed decisions after considering both the possible improvements offered by scientific advances and their potential side effects or dangerous usages’ (p. 899).40 This aligns with the global call for public engagement and deliberation to bring to light societal values and attitudes concerning HGGM and to delineate what society considers to be a scientific ‘benefit’.45 65 In turn, results from such deliberations can be integrated into assessments of the risks and benefits to inform future policy making.66

CONCLUSION

The notion of ‘serious’ genetic disease has been broadly used within the legal and policy spheres, notably in the context of HGGM; yet, it remains undefined. There is a clear need to continue to discuss what we mean by ‘serious’ today across different countries, on the basis of universal human rights, so that policy applications are clearer and more practicable. Biological and contextual factors should be given consideration to fully comprehend the notion of ‘serious’. An integrated approach could thus operationalise the human rights to science and to health by helping determine their scope and content.

The evolving qualification of ‘serious’ will depend on elements that are constant and objective (eg, morbidity/mortality),4 as well as elements that are flexible and evolving (eg, disability as impacted by social arrangements or treatability as impacted by effectiveness and cost of treatment). Furthermore, the responsibility of qualifying this notion does not fall on the shoulders of any one given group but rather merits input from various stakeholders, including physicians, genetic counsellors, patients and their families.8 48 This acknowledges the complexity associated with genetic disease and will help account for the burden experienced from multiple angles (medical, emotional, economic and so on).

Framing scientific progress within a novel human rights-based approach would ‘reorient our conversation from policing science to governing society and would shift our focus from avoiding risks to protecting opportunities’ (p. 21).66 Indeed, this would foster advancements in our ability to treat and prevent disease, while remaining mindful of the need to establish anticipatory governance that provides the necessary flexibility to frame the preventive or therapeutic applications but also adapt to potentially legitimate ‘off-label’ ones.67 Finally, addressing the notion of ‘serious’ could also profit from future discussion of another human right, that of ‘future generations’,^iv as the need for intergenerational monitoring will undoubtedly lead to safety, privacy, and consent issues for children not yet born.51