Introduction
In its comprehensive 2018 review, Genome Editing and Human Reproduction: Social and Ethical Issues,Footnote 1 the Nuffield Council on Bioethics concludes that while heritable genetic therapies are currently not permitted under the British Human Fertilisation and Embryology Act 1990, that U.K. regulatory bodies are adequate to the task of regulating heritable gene therapies. It cautions against a rush to ban such therapies without extensive public debate, and urges research on their safety and efficacy. Once “risks of adverse outcomes have been assessed by a national competent authority…we recommend that genome editing should be licensed for clinical use.”
This essay focuses primarily on the U.S. case to argue for a similar liberal approach to gene therapy, regulated by the National Institutes of Health and the Food and Drug Administration, rather than the creation of new bodies with expanded, illiberal mandates. While this essay addresses “gene therapy” broadly, it focuses on heritable therapies, since heritable therapies raise the most concerns, and the line between somatic and heritable therapies is now blurred by the ability to modify sperm and eggs before natural or in vitro conception.
What Should a Government Regulate?
There are two broad approaches to regulation in democratic societies. The more communitarian approach argues that all majority concerns, no matter their base in evidence or their effects on minorities, should become laws. The other approach starts from John Stuart Mill’s proposition that individuals in general know what is best for themselves better than governments and that the state should only interfere in individual freedoms when there is a clear harm to the public good. That is the classic case for “liberal democracy,” which appeals to the discourse of rights, and in the United States to constitutional protections, to assert that minorities should be protected from majorities’ unwarranted prejudices.
One way to understand changes in laws around interracial and same-sex marriage, for instance, is that the United States has been pushing back unfounded majoritarian claims that these marriages would harm society, in defense of the ideal of a liberal democracy with individual and minority rights. Rather than allowing any claim to the public welfare to trump individual rights, we increasingly insist that individual rights be balanced against claims to the public good, and that the majority’s claims be based in evidence and not prejudice.
Human genetic engineering now needs to be regulated in the context of this unfinished project of liberal democracy. I will first outline some of the reasons given by proponents of illiberal regulation of human gene therapiesFootnote 2 for creating new laws and agencies. I will then outline the existing, and generally adequate, regulatory framework around human gene editing in the United States, focused on safety and efficacy.
Nonregulatory Concerns
The history of inaccurate dystopian predictions about social and medical innovations should give us pause about calls to ban gene therapies. Opponents of interracial marriage argued that the children of such unions would never be accepted by society. In vitro fertilization was predicted to degrade the meaning of family and produce children burdened by having been produced through technology. Today similar anxieties are often expressed about gene therapies, especially if they are heritable.
In United States Supreme Court deliberations, distinguishing which concerns about human genetic engineering are best left to public debate and which are sufficiently weighty to warrant regulation turns on which concerns have a sufficiently “rational basis” to interfere with the right to control one’s own body and reproduction. The 1975 Supreme Court decision Cleveland Board of Education v. LaFleur found, for instance, that mandatory maternity leaves “needlessly, arbitrarily, or capriciously” restricted teachers’ reproductive freedoms. While the Supreme Court recognized in LaFleur that there may be some interests to be protected, the policies were so broad that they reflected “outmoded taboos” and lacked a “rational basis.” In this section we want to examine some of the arguments for regulating human genetic engineering that we believe lack this “rational basis.”
Not All Risks Can Be Anticipated
One argument frequently heard in calls for the regulation of human genetic engineering, and especially in regulating germ line genetic engineering, is that the genome is complicated and gene therapies will have some unintended risks and side effects. This is inescapably true, because it is true for every medical therapy. Approving the use of any medical therapy requires a body of animal and human testing, and a broader assessment of risks and benefits, to determine if the benefits outweigh the risks in the light of evidence available at the time. When side effects are detected, the therapy may be pulled from use, and that may not occur for decades. Unless we apply the precautionary principle so conservatively that it forbids all new therapies, there must be some level of risk permitted in all innovation and no a priori reason why gene therapies should face a higher standard than other therapies.
Preventing “Eugenics”
If eugenics means government interference in competent adult reproductive decision-making and parental decision-making for their children, then the lesson to be learned from eugenics is to set a very high bar on state regulation of reproductive and parental freedom. When Justice Oliver Wendell Holmes compared involuntary sterilization of the genetically unfit to vaccinations and the military draft in the 1927 Buck v. Bell case, the scientific basis for predicting genetic outcomes was much weaker than it is now. Yet today we have stopped regulating (or sterilizing) people to stop the spread of genetic diseases and disorders, precisely because we value reproductive freedom so highly. It would be very strange then, that in the interests of avoiding “liberal eugenics,”Footnote 3 we might prevent parents from making genomic choices that have been approved as safe and effective.
If, however, eugenics is defined more broadly as “any state action to encourage the genomic health of the population,” then it includes publicly supported prenatal counseling and screening, and even efforts to improve prenatal nutrition and remove perinatal toxins. Every government has programs aimed at improving genomic health, and few people object that they are “eugenics.” The key to preventing eugenics is not to ban government efforts to facilitate genomic choice, but to ensure that government policies provide all possible risk and benefit information for approved therapies within a context of individual and reproductive freedom.
Negative Impacts of Therapies on Those Who Cannot, Or Choose Not to, Benefit from Them
The interests of all parties should be monitored as technologies are implemented. But the speculative claim that a more able society will be more discriminatory against the disabled is not one that can or should be a basis for regulating gene therapies. It is certainly true that the modal understanding of health and ability has shifted as society became healthier and more able over the last century. Mild depression has become diagnosable and treatable. Bad teeth and other cosmetic flaws that once would have been accepted are now fixable, and less accepted.
Yet, as the proportion of the population with mental and physical disabilities has declined due to improving public safety, nutrition, health, and medicine, the rights and enablement of disabled citizens have generally improved. There does not appear to be any diminishment of society’s acceptance of, for instance, amputees since the decline of wars, infections, and industrial accidents created ever fewer of them. Arguing that we should avoid treating diabetes or creating safe workplaces because we might reduce social acceptance of amputees seems, correctly, absurd. As the methods for ensuring one’s own and our children’s health and abilities expand, this will shift the expectations of an increasingly able society, just as illiteracy became problematic in an increasingly literate society. Individual genomic choices in a free society mean that some forms of diversity may shrink, while gene therapies increase other forms of diversity. But few would argue that society’s goal should be to ensure that health and abilities always stay as is.
Changes to Meanings of Family and Humanity
Another concern often heard in debates about gene therapies is that they might change our understanding of sex and the family,Footnote 4 as with the use of “three-parent” mitochondrial replacement therapy. The structure of the family and the boundaries of human solidarity have changed radically in the last two centuries. The migration to cities, and the increasing mobility of the labor force, have broken extended families into nuclear families. Now the rates of marriage and fertility are declining for Americans facing increasing economic precarity. The movements for gender and racial equality, and the social and behavioral sciences, have changed normative ideas about what a human is and challenged us to be more expansive in our solidarity. The concern that reproductive technologies and genetic engineering might have a tangible impact on changing families or the definition of the human, compared to these broader economic, cultural and political forces, seems unlikely, at least in the coming decades. But even if human genetic engineering is widely adopted by individuals in ways that change our definitions of the family or humanity, it is not in the purview of a liberal democracy to use public policy to defend normative definitions of the family or humanity.
Another concern often heard about reproductive genetic therapies is that they will exacerbate trends towards perfectionist parenting and its illusion of control. To the extent that parents have increasingly ambitious and specific aims for their children, this is largely the result of smaller families and the increasing cost of child-rearing. Genetic therapies may be yet another way that parents ensure that their children both have the best possible opportunities in life and most closely fit their parents’ expectations for an investment of time, money, and love greater than buying a home. But it is unlikely that bans on therapies that give perfectionist parents more choices would actually reduce the trend towards perfectionism, and it would be an illiberal intervention in parental decision-making even if it did have such an effect. Rather than discouraging perfectionism, bans on extant therapies will probably increase parental and child disappointment at foregone opportunities for desired health, abilities, and other traits. Government regulation of reproductive decision-making is not the way to encourage parents to have fewer expectations.
Regulating Human Gene Therapies
In 2017, the National Academies published a report from the Committee on Human Gene Editing, Human Genome Editing: Science, Ethics, and Governance, which reviewed possible gene therapies and set out recommendations for regulating human genome editing. It concluded:
In the United States … regulatory authority tends to focus primarily on health and safety of individuals and the public, and not on issues surrounding possible effects on social mores and culture. These latter concerns are regularly addressed in other fora, such as advisory committees, but lack legal force unless reflected in legislation that is grounded in the limited powers granted to government. . . . While capable of improvement, the structure of the U.S. regulatory system is adequate for overseeing human genome-editing research and product approval.Footnote 5
This essay is a defense of this position.
International Conventions
Many have proposed that international conventions are required to prevent international competition in applying gene therapiesFootnote 6,Footnote 7 or the proliferation of gene therapy tourism to unregulated clinics. Unfortunately, the majority of the world has very different standards and normative concerns around the regulation of medicine and reproduction. In principle, international regulations on the safety and efficacy of human gene therapies would be desirable and possible. But even international harmonization of biomedical regulation around these obvious lowest common denominators has been very slow.
We can also be certain that, with most countries less laissez-faire about medicine or reproductive decision-making than the United States, international regulations would likely reflect the speculative concerns and preconceptions discussed above. This was certainly the case with the 2005 United Nations declarationFootnote 8 calling for a ban on human cloning and “genetic engineering techniques that may be contrary to human dignity” on the grounds that no amount of regulation of human genetic therapies could “prevent the exploitation of women” or “protect adequately human life.”
Rather than suggest international declarations to restrict genomic choices, and in order to protect individual genomic choice, the 2018 Nuffield Council report argues for “an international declaration affirming that people whose genomes have been edited should be entitled to the full enjoyment of human rights.” In the long run, international regulations, not just resolutions, are inevitable. Hopefully the course set in regulating these technologies in liberal democratic countries will be a model for the international treaties to come.
Professional and Industry Self-Regulation
The self-imposed restrictions on recombinant DNA research that were adopted at the 1975 Asilomar conference are widely cited as a successful example of self-regulation by researchers. Researchers are free to refuse to work on any topic, and moral suasion from peers and professional organizations can be a very effective deterrent. It is also generally acceptable within a liberal democracy for the providers of a legal service to voluntarily withhold it, although we continue to debate the limits of service denial. Should a pharmacist be able to refuse contraception to an unmarried woman? Should a doctor be able to refuse to treat a Nazi, or to withdraw futile life-sustaining treatment? Many potential providers of human genetic therapies have strong feelings about what they should provide, and the limits of their right to refuse treatment will be decided by laws and courts.
In the meantime, professional associations are issuing opinions on how their members should behave. The Society for Developmental Biology has proposed a “voluntary moratorium by members of the scientific community on all manipulations of preimplantation human embryos by gene editing,”Footnote 9 and the American Society for Gene and Cell Therapy advocates for a “strong ban on human germ line gene editing or other germ line genetic modification” until a “societal consensus [has been] reached.”Footnote 10 But professional associations generally cannot prevent members or nonmembers from proceeding to offer these therapies. So long as professionals have a profit motive in providing a service, there will be professionals willing to weather disapproval and offer it.
National Institutes of Health
So far, the regulatory climate for somatic gene therapy has remained the same as for other forms of medicine. That is not true for heritable gene therapy. In 1996, the U.S. Congress approved a federal budget with the Dickey-Wicker amendment, which forbids federal funds from being used for research that creates, destroys, or harms human embryos, a proviso that is still in effect. In 2015, the National Institutes of Health (NIH) reaffirmed its policy that the “NIH will not fund any use of gene-editing technologies in human embryos.”Footnote 11 Then, in 2016, the U.S. Congress included language prohibiting the NIH or FDA’s use of funds “in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.”
While a temporary moratorium on heritable gene modification may be prudent, if the efficacy and safety of gene therapies is to be understood, the therapies need to be studied not only in animal models but also human trials. Bans on using public funds for this research will only slow and shape the therapies, but not stop them; the first published applications of gene-editing to embryos in the U.S. relied on private funding. Rather, we need a proactive regulatory framework for research and clinical applications that takes account of the novel nature of gene-editing,Footnote 12 but permits research on heritable therapies.
All clinical research is also subject to long-standing protections for human subjects, which the National Institutes for Health helps enforce through its oversight of institutional review boards (IRBs). While there are many criticisms of the efficacy of IRBs and human subject protections, these apply to all medical research; research on genetic therapies is subject to these constraints, which include ensuring informed consent to research. While IRBs are not allowed to deny approval for research because it is controversial (which may be the beginning of a supposed slippery slope), it can deny approval if the research poses physical or psychological harm to subjects.
To the extent that IRBs have a special regulatory role regarding gene editing, it will be in determining who the research subjects are, and whether all possible risks have been considered and mitigated. Embryos are not human subjects, and children do not have to consent to research as parents have the right to enroll them. But informing would-be parents of the possible effects of therapies on children can be required by IRBs. While somatic gene therapies may only require evidence of safety for the subjects of research, germ line and perinatal therapies might require evidence of safety from multiple generations of animal models.
Food and Drug Administration
Section 351 of the U.S. Public Health Service Act gives the Food and Drug Administration (FDA) regulatory authority to ensure the safety and efficacy of human genetic engineering, specifically through the Office of Tissues and Advanced Therapies in the FDA’s Center for Biologics Evaluation and Research.Footnote 13 Unlike restrictions on the use of public funds for gene-editing research, the FDA’s regulatory purview applies to all gene-editing on humans, public or private, and in 2015 the FDA issued an advisory to any researchers proposing gene-editing trials.Footnote 14
As with other therapies it considers, the FDA will need to continue strengthening its capacity for assessing risks and benefits and monitoring for adverse postapproval side effects. Since off-label uses of approved therapies is legal and common in the United States, these uses all require postapproval monitoring. The FDA may impose a stricter scrutiny on reproductive applications than on therapeutic applications for adult subjects, on inheritable modifications than on noninheritable, and on genetic enhancements than on therapeutic gene editing. Each of these distinctions changes the ability to understand risks and benefits. The consequences of the introduction of novel genes are less knowable than the consequences of the introduction of baseline genes, and the effects on subsequent children are less knowable than the effects on adults. For instance, Niklaus Evitt, Shamik Mascharak, and Russ AltmanFootnote 15 propose that heritable gene therapies be subject to postapproval surveillance for fifteen years. Even with extended surveillance however, the FDA would still judge gene therapies on the basis of efficacy and safety, risk and benefit.
Public Health Agencies and Laws
Governments may additionally adopt policies to encourage or discourage the use of emerging technologies that have been approved for public use. For instance, since the 1950s the U.S. federal government has encouraged physical fitness and good nutrition without banning sloth or junk food. Within a liberal democracy it is acceptable to require that children be taught the virtue of voting, while (outside of Australia) we have not made voting obligatory. Likewise, while the norm in publicly funded genetic counseling is to remain scrupulously nondirective, nonetheless counselors provide information about risks and benefits in ways that influence choices. Governments may also restrict the conditions under which therapies may be used, as the U.S. Supreme Court has done in upholding states’ laws regulating abortion, such as mandatory waiting periods and informed consent materials, until these regulations become unreasonable or discriminatory.
Health Insurance Regulations and Policies
Condemning the 2018 Nuffield Council report on heritable gene therapy, Marcy Darnovsky cautions that they “could be leveraged by privileged elites seeking purported genetic improvements to ensure that their children are treated as superior to the rest of us.”Footnote 16 It is a legitimate regulatory concern that all the citizens have an equal opportunity to benefit from new therapies, and there is certainly a political and regulatory case for ensuring that future generations not become unsustainably unequal as a result of unequal access to medical therapies. But with all the social and economic forces driving inequality today, it seems strange to focus on restricting genetic therapies in order to ameliorate inequality when regulatory efforts could instead ensure widespread access to the therapies. In fact, focusing on the aftereffects of inequality, such as unequal access to medicine, rather that its causes, such as wages, taxation, and unequal health insurance, could be seen as counterproductive.
Currently, all U.S. health agencies have programs in place to study and ameliorate health inequalities, and these should also study and attempt to ameliorate unequal access to gene-editing. If there are gene therapies that promise radical improvements in health, cognition, or longevity, and these are only accessible to the rich, there may be a case for a temporary moratorium until they can be made available to all. But we are unlikely to see gene therapies in the near future that have such dramatic effects, and broad applicability, that they would be in this category.
In most countries, ensuring equitable access to genetic therapies resolves to a debate about whether to include them in the national health system. If therapies are too expensive or have too low a risk/benefit ratio to be provided to everyone, then they may be left to individual out-of-pocket choice, or banned if they pose risks to equality. Ensuring equitable access in the United States, which lacks universal health insurance and instead contends with dozens of private and public insurance providers, is a greater regulatory challenge. Nonetheless, we have gradually expanded access to many therapies through mandating that public and private insurance cover them. For instance fifteen U.S. states require that insurers cover infertility testing and fertility therapies. As human gene therapies are approved by the FDA, universal access can be ensured by requiring that those that are affordable, high benefit, and low risk also be covered.
Final Thoughts
The struggle for a liberal regulatory environment for gene therapies is an extension of the struggle for a more liberal democracy, one that maximally respects cognitive, bodily, and reproductive freedom. Largely as a result of the incapacity of the Christian right and other critics of gene therapy to overcome the political influence of the American medical-industrial complex, the U.S. still has relatively liberal regulations around gene therapy. In result if not in process, U.S. gene therapy regulation is a model. One glaring exception is the Congressional ban on heritable gene therapy, which should be lifted, so that the safety and efficacy of these therapies can be determined. Future work will also be required to establish protocols for research on genetic enhancements.
Given the myriad social and ethical issues that gene therapies raise, we do also need agencies with a mandate to address them, albeit only in an advisory capacity and not with regulatory powers. The 2018 Nuffield Council report recommends the creation of a nonregulatory body to “identify and produce an understanding of public interest(s) through promotion of public debate, engagement with publics and monitoring the effects of relevant technological developments on the interests of potentially marginalized subjects and on social norms.” The sterling example of such an agency in the United States was the Office of Technology Assessment (OTA), created by Congress in the 1970s to assess a broad range of issues around emerging technologies. The OTA issued hundreds of important research reviews and was then disbanded by the Republican Congress in 1995 in an excess of antiregulatory zeal. Today, we need advisory bodies like the OTA more than ever, to provide nonpartisan reviews of everything from quantum computing and artificial intelligence to genetic engineering. Given the politicization of science in the United States a re-embrace of impartial technology assessment will likely require political change in the U.S. Congress.
