Translational Justice in Human Gene Editing: Bringing end user engagement and policy together

In their target article, Conley and colleagues (2023) appropriately highlight the ongoing conceptual and practical opacity of public engagement (PE) in the translation of human gene editing (HGE).(1) The increasing speed of translation makes it more crucial than ever to balance social and technical priorities. However, existing calls for PE most often take place in the context of a thin discourse of what constitutes “publics" and/or “engagement.” We should not conflate the authors’ concerns regarding the uncertainty produced by vague calls for PE with uncertainty that can result from heterogeneity in PE approaches. Unsurprisingly, pluralist societies may have many ways to enact and reform PE. HGE needs approaches that recognize the importance of pluralism without abandoning individual experts, patients, and their families to navigate complex moral terrain on their own. As with much policymaking, there is a tricky balance to strike between collective governance and supporting individual judgment. Having access to a variety of gene editing PE approaches suggests lively innovation in re-envisioning how science is done and how social values are operationalized, which is a service to more democratic and value-based science and technology policy.

We argue that only the active and integrative involvement of end user groups can achieve what we refer to as translational justice in HGE. Translational justice points to procedural and outcomes-based attention to how clinical technologies move from bench to bedside in a manner that equitably addresses the values and practical needs of affected stakeholders, with attention to the needs of the most morally impacted. Historically, translational pathways in the United States (U.S.) have been shaped primarily by economic forces. We have previously suggested that focusing engagement efforts on critical end-user groups who will enact and/or be affected by future uses of HGE — clinicians, scientists, and patient communities—provides essential inputs into policy development that prioritizes broader social priorities.(2) Here, we lay out a conceptual and practical vision of one mechanism for operationalizing PE around HGE, including pursuit of explicit ethical engagement goals.

The Need for End Users’ Engagement

Our work currently focuses on prenatal HGE in the United States (U.S.). We argue that additional moral weight should be given to the voices of those immediately affected by genetic targets of HGE because they will ultimately develop its applications and/or actively accept or refuse to use them. Families with genetic conditions that have significant medical burden or mortality may reasonably calculate that the potential benefits of prenatally removing the mutation responsible for the disorder are worth the risks of unknown procedures.(3) Others might view HGE as posing an unacceptable risk/reward calculus, especially when genetic conditions exhibit highly variable phenotypes.(4) Because the U.S. is one of the few high-income countries that has no central policymaker for reproductive technologies, these clinical decisions will constitute de facto policymaking. Indeed, past applications of emerging reproductive technologies by end users, including physicians and families, have engendered some negative media attention but ultimately nominal sanctions for individuals departing from scientifically and ethically established best practices. Families and clinicians make their own moral calculus of acceptable applications of emerging clinical technologies on a case-by-case basis with little, if any, governance or accountability.

This kind of clinical translational process is unjust in its ability to reflect consistent societal values and equitably benefit intended end users. It can be arbitrary and lead to significant inequities, inconsistent translation, and harms to individuals, families, and future children. Potential failures include prohibitive costs of therapies; a lack of intensive medical care surrounding therapies; mutation-specific therapies that increasingly divide rare disease communities; predatory marketing of unproven interventions; and complex webs of intellectual property that may hinder or prevent innovation and patient-centered treatment paradigms.(5)

Who Are End Users?

The need to involve end users in just translation raises the crucial question of how to select who gets a seat at the table and ensure that all voices are heard and respected.(6) This reflects concerns about the implicit ethical goals of engagement, which include empowering and increasing the influence of public/community perspectives in key scientific decision points.(7) Choices about how to include stakeholders in engagement are also pragmatic questions about how these activities can be said to be appropriate representations of a population, and directly connect to the socio-political legitimacy of the outcomes.(1)

Our team has pursued a vision of engagement that elicits the views of diverse affected stakeholders with lived experiences of genetic conditions who may benefit from prenatal interventions. Partnering with trusted patient advocate organizations, our team is applying the Family System Genetic Illness (FSGI) framework, which considers key features including symptom severity, penetrance, age of onset and treatment options across a wide variety of conditions to conceive of perspectives especially necessary to inform the future of advances in gene editing.(8) Diversity of experiences, both across and within conditions, avoids oversimplification while validating the experiential knowledge provided by those who live and care for those with genetic conditions.

In addition, we are engaging with scientists/clinicians, recognizing that science policy and self-governance are the result of many contextual factors. Policy and governance supporting responsible clinical translation are built not only on “value-neutral” technical criteria of safety and efficacy but the social values and political choices underlying such determinations. In crafting policies, clinical/scientific stakeholders respond to advances in science, changes in social and political values, and negative publicity around events that are seen to damage moral credibility or scientific progress.(9) Historically, this has been particularly true in areas where genetics and reproductive medicine overlap. Within this framework, groups are influenced by their clinical knowledge and skills as well as the broader social, moral, and political environments in which they are embedded. As such, understanding individual convictions regarding risk-benefit assessments and ethical values is central to understanding how policy-making ‘works’ in the real world and how peer attitudes could shape the direction of governance.(10) This knowledge will ultimately contribute to informed debate about the direction of policy and governance that underpins the clinical translation of HGE.

How to Engage

As recognized by Conley et al., deliberative democracy differs from other PE approaches in its attempt to inform policy. It is important to note that the meaning of “democratic” can be practically realized in different ways, including involvement of deliberants whose demographics are in some way reflective of the broader population. While the “deliberative” in deliberative democracy provides guidance on how to conduct engagement, “democratic” is only partly about who deliberates.(7) Democracy can also be interpreted in terms of its constraints on the output of deliberation, including substantive normative commitment to self-governance and fairness. In our work, it has been particularly important to prioritize the inclusion of those with lived experience of the genetic conditions most likely to be the target of early gene-editing clinical trials.(6) Disability studies have appropriately critiqued bioethics, among other fields, for sidelining these communities, citing a “nothing about us without us” ethos. Extensive evidence reflects the tendency of those without lived experience to discount the quality of life of those with genetic conditions. Our team sought to lead with the perspectives of those who have the most to gain and lose from inadequately inclusive HGE policies.(8) We are also deliberate in engaging scientists/clinicians. In a context where decisions would be made within the close confines of the doctor-patient relationship, it is important to understand the reasoning, social values and notions of responsible innovation underpinning their actions. Moreover, in a society where self-regulation with limited accountability prevails, identifying the attitudes towards scientific innovation, governance, risk tolerance, and considerations for protection of societal values pertaining to the clinical translation of HGE of these communities, and their eventual or proposed policy, is equally vital. Our approach is in keeping with political theories that challenge us to critically examine our interpretations of representative democracy.(7)

A Path Forward for Heterogeneous Engagement

The importance of Conley and colleagues’ questions cannot be ignored.(1) At a time when democratic institutions and norms are under intense political pressure, it is unrealistic to expect the scientific and bioethics communities to provide actionable specification of substantive, legitimate, and just forms of PE. Here, we have provided a brief overview of our team’s approach and its preliminary answers to which “publics” to include, how to engage them, and what that engagement seeks to achieve. Our answers flesh out only one set of possibilities in a highly consequential social and political debate. We hope that in specifying our approach, others can build upon, compare, and contrast their own PE practices and ideals in the service of maximizing translational justice in HGE.