As Richard Dawkins said, “[g]enetic modification, like any other kind of modification, is good if you modify in a good direction, bad if you modify in a bad direction.”1 Gene editing, with all of its accompanying fears and promise, has emerged from the realm of science fiction comfortably into contemporary reality. This article, like human germline gene editing (HGGE) itself, poses more questions than answers.
HGGE is the process of modifying the genome of cells in an embryo such that the changes are heritable, passing to future generations through reproduction and permanently altering the human gene pool.2 The technology to edit human embryos and make precise, targeted changes to specific genes has recently become feasible on a large scale through a mechanism called CRISPR-Cas9.3 The potential to create “designer babies” or eliminate certain diseases is no longer merely hypothetical, but rather is a contemporary issue that warrants urgent policy discussions and regulatory action.4
The most significant policy considerations surrounding the utilization of this technology are balancing potential medical benefits with potential social harms. Concerns are intensified due to the nature of the changes being heritable and permanently altering the greater human gene pool. It is no exaggeration to say that the effects of human gene editing technology may shape the future of society and humanity writ large, as well as the very core of what it means to be a human.
This article will introduce gene editing technology, other assisted forms of reproduction, and Dr. He’s experiment. It addresses six major ethical dilemmas and debates concerning gene editing technology and discusses the domestic and international legal landscape of gene editing regulations and proposed approaches. It then advocates for a prudent path forward following a moderate pragmatic approach in line with the World Health Organization (WHO) governance guidelines, specifically addressing the role of the United States.
Human gene editing is a broad, multifaceted, and burgeoning field. This article is concerned only with a specific type of human gene editing – modifications to the human germline. These edits alter the gametes of an organism, the sperm or egg, creating permanent, heritable changes in the organism.5 When successfully made at the embryonic stage, the future child will exhibit the selected traits and pass those modifications to the child’s offspring as well.6 Thus, edits at the embryonic stage implicate the greater human genome, not just that particular individual. In contrast, somatic cell editing can be, and is, done on specifically targeted cells in adult humans and the modifications are not passed on through reproduction.7 Consequently, somatic cell editing technology has far fewer ethical quandaries, is less controversial, and operates in a much more permissive regulatory environment.8 Somatic cell editing is at the forefront of precision medicine and innovation, and is an area of substantial investment.9
The primary catalyst for the recent boom in gene editing technology was the discovery and utilization of the CRISPR-Cas9 system in 2011.10 CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.11 The CRISPR mechanism is a natural defensive function used by bacteria that has been coopted by researchers to cut DNA at precise designated sites and substitute specific predetermined nucleic base pairs.12 The most intuitive analogy to how the CRISPR-Cas9 system functions at the molecular level is to the “cut-and-paste” or “replace” function in a word processor.13
Changing even a single nucleotide in a string of DNA could be the difference between producing normal hemoglobin instead of developing sickle cell disease, or whether a person develops a host of other monogenetic disorders, including Huntington’s disease, muscular dystrophy, cystic fibrosis, or Rett's syndrome.14 While gene editing was possible in a laboratory setting before then, this technology revolutionized the field by making the process exponentially cheaper, easier, and more accurate.15 Due to the profound effects this technology has already had on a vast range of science and technology, the Nobel Foundation awarded the 2020 Nobel Prize in chemistry to Emmanuelle Charpentier and Jennifer A. Doudna for their discovery of the CRISPR system.16 In awarding the Nobel Prize, the Nobel Foundation praised the discovery that it may “make the dream of curing inherited diseases come true.”17
Unfortunately, making genetic mutations in embryos has unavoidable risks.18 There are four main categories of technical risks: (1) off target effects, when the correct change is made, but in the wrong place; (2) when the change is made in the correct place, but it’s the wrong change; (3) mosaic organisms, when not all of the DNA in the organism is successfully changed; and (4) other unexpected changes.19 The first two of these risks, and possibly the third or fourth, not only deprive the future child of the intended benefit, but also introduce unpredictable and unknown mutations and other health risks.20 Further, these mutations have likely never been seen before in the human genome. These mutations may be passed on to future generations and allowed to proliferate, thus altering the human gene pool and shaping evolution.21 Accordingly, the technical risks set up the larger debate on HGGE, which revolves around the ethical and moral risks.
Human genome editing does not operate alone, but rather is used in conjunction with other assistive reproductive technologies (ART). The two most important techniques are in vitro fertilization (IVF) and its auxiliary, pre-implantation genetic diagnosis (PGD). These procedures, used in combination, can very effectively reduce the risk of genetic diseases passing on to future generations. When these laboratory techniques are coupled with gene editing technologies, the efficacy of each procedure significantly increases.22 First, using IVF, a clinician will grow embryos in a petri dish.23 Second, using PGD, the genome of each embryo is screened and assessed for certain mutations and disorders.24 Third, the CRISPR system is utilized to modify or eliminate the target gene or genes.25 Lastly, if all goes well, the modified embryo is implanted into the uterus and an otherwise typical pregnancy follows.26
ART has been embroiled in religious, ethical, and political controversy ever since it emerged.27 At a congressional committee hearing discussing IVF in 1974, James Watson, the acclaimed molecular biologist, predicted that if embryo growth and transplantation were condoned and successful, “all hell will break loose, politically and morally, all over the world.”28 Another doctor described the procedure as “an incredible leap into the unknown.”29
Despite these predictions and controversy, the first IVF baby was born in 1978.30 The test of time, even in this relatively short period, has overwhelmingly favored the technology, with IVF achieving widespread global acceptance in medical and research settings, and more importantly, in broader culture and society.31 By 2018, over eight million babies had been born using IVF and other ART.32
PGD was first introduced in the 1990s.33 Since then, it has been used to screen embryos for genetic diseases and allowed thousands of parents to be assured that they were not passing deadly monogenic disorders on to their children.34 PGD technology has also been used for alternative purposes, such as sex selection.35 Sex selection using PGD became sufficiently widespread in China and India that, due to significant disproportionate selection of males and the resulting skewed population distribution, both countries banned the practice.36 However, since PGD screening is legal for other uses that provide the same information, it may be hard to determine when a certain embryo was chosen for implantation merely because of gender. Therefore, the bans may practically be rendered unenforceable.37
Despite the dire warnings of reproductive technologies, which are now partially supported by the ability of parents to select certain “preferred” embryos through advances in existing ART technologies, these procedures remain relatively lightly regulated.38 The U.S. Food and Drug Administration (FDA) does not directly regulate procedures, only certain devices used in these procedures.39 Therefore, IVF is unregulated as a medical product at the federal level.40 Instead, it is covered by state law and industry self-regulation.41 This leaves increased discretion and variation in the legality of ART in different jurisdictions, but most commentators describe the regulatory landscape as “‘minimally regulated,’ ‘unregulated,’ or ‘non-uniformly regulated.’”42
Notably, there is one major federal constraint on IVF. Under the Dickey-Wicker amendment, no federal funds may be allocated for the “creation of a human embryo or embryos for research purposes.”43 Effectively, this limits all IVF funding, research, and innovation to the private sector.44 The amendment has been renewed as a budget rider every year since 1996.45
In 2018, the landscape of gene editing was suddenly and unexpectedly changed forever.
Dr. He Jiankui announced to the world that, using the CRISPR system, he had edited the germline of embryos and successfully implanted them in a woman who gave birth to twin girls.46 This was the first instance of a gene edited human birth. Dr. He intended to edit the CCR5 gene, which is known to vastly decrease susceptibility to contracting HIV. However, the edits were not made as intended, and instead of producing the desired mutations, one of the babies has mosaic edits, and the edits made to the embryo of the other baby were off-target and created mutations that are entirely novel in the human genome, and thus have wholly unknown effects.47
Dr. He’s announcement of his experiment was met with overwhelming outrage and condemnation both in the scientific community and public sphere. In a surprise to many commentors and scientists, the Chinese government imposed significant repercussions on Dr. He. In December 2019 Dr. He was sentenced to three years in prison and fined three million yuan (US $430,000) for “illegal medical practice” with lesser sentences for two collaborators.48 The researchers have additionally been banned by other government ministries from conducting any further work on human reproductive technology and from applying for research funding.49 This reaction provides a strong deterrent to other researchers seeking to push the boundaries of human gene editing.50
The international community’s strong condemnation of Dr. He, backed up by the Chinese legal proceedings, may forestall similar experiments in the near future, but is not a long-term solution. Accordingly, Dr. He’s experiment sparked a marked resurgence in the policy, scientific, and ethical conversations surrounding heritable gene editing.
The moral issues surrounding genome editing are multifaceted and interwoven. There are six major areas of contention that weigh heavily on the policy debate of if or how to regulate gene editing technology. They are: (1) issues surrounding enhancement; (2) allegations and issues surrounding eugenics; (3) questions of consent and autonomy; (4) inequality, social welfare, and justice in outcomes and access; (5) the impact of permanent changes and sanctity of the human genome; and (6) if the technology is necessary to achieve its goals. Each issue will be discussed in turn.
The first important boundary question is how, or if, human enhancement can be defined.
There is a spectrum, where extreme examples may be clear. For example, it is generally undisputed that editing genes with the sole intent of increasing nonmedical traits such as height, hair color, or intelligence, all else being equal, would be deemed “enhancement.” On the other end of the spectrum, editing an embryo to prevent a genetic disorder such as Tay-Sachs disease would not be deemed an enhancement. In between, there is a vast grey area.
Humans use scientific “enhancement” constantly. Procedures such as LASIK eye surgery or implants such as stents and pacemakers are common, even though they impart unnatural enhancements that increase function and inhibit diseases.51 One example of an application of gene editing that pushes these boundaries is genetic modification that imparts disease immunities. Immunities are biological enhancements and do not prevent an inevitable disease.52 Yet vaccines for diseases such as tuberculosis and polio have the same function and purpose, but are largely uncontroversial and routinely administered. Some argue that if society views these effects as acceptable and beneficial in other cases, then there should be no issue proactively and preemptively editing genes to achieve the same end and avoid having to administer these procedures later in life.
There is also no easy answer to what is “normal” for a human, particularly as these standards are constantly changing. The same issue is prevalent in other medical technologies and drugs, for example the legitimate and illegitimate uses of the focus enhancing drugs Ritalin® or Adderall®.53
Genetic heterogeneity cuts both ways. Professional athletes often have body types that are quite abnormal, which allows them to excel in their discipline.54 These athletes are perceived as genetic marvels, not as freaks of nature. Despite this, when these results are manufactured in
the lab, it seems to diminish the popular appeal. For example, steroids have been almost uniformly condemned, particularly in professional sports, but recreationally as well. These attitudes go beyond the mere health effects and more directly to the ethical implications and conceptions of fairness and what is “natural.” These equitable beliefs have their root in the “genetic lottery,” a concept that would be undermined by HGGE.55
Some of the strongest objections to human enhancement come not in relation to the enhancement itself, but rather its indirect effects, such as the creation of a slippery slope that implicates eugenics, coercive effects, social justice, equality, and personal autonomy, as discussed below. Nonetheless, to some, human genetic enhancement is not a risk to be avoided, but a moral imperative. For example, Nobel Prize-winning molecular biologist Craig Mello has stated that “if [gene editing technologies] were safe, and if we have the knowledge to make improvements in the human germline, then it might be unethical not to do so.”56 In a similar vein, Julian Savulescu, a philosophy professor, has argued that creating the genetically “best children” is morally required, an imperative that follows from the principle of beneficence.57
A commonly advocated approach to this problem is to limit gene editing to treat only fatal diseases. This approach is too vague, however, as it leaves open questions such as timeframe. Almost any disease may be fatal in some sense or in some eventuality. It is not clear how to establish a justifiable cutoff timeframe that is not arbitrary. Further, implementing a standard like this leaves significant medical potential untapped and would prevent interventions such as eliminating sickle cell anemia and other single gene mutations that are not imminently deadly but may cause significant hardships. A narrower approach is to limit HGGE to deadly single gene mutations, and those disorders are the most well understood and simplest to remedy.58
A further critique, advanced by those in favor of a complete ban, is that once gene editing is allowed in any capacity, it will not remain confined to that specific use, and will inevitably become widespread practice.59 For example, while the original purpose of IVF and PGD was to facilitate healthy reproduction and address fertility problems, they are increasingly being used to facilitate non-medical preferences such as gender selection.60 Many predict that this pattern would repeat with HGGE, except with much higher stakes and unpredictability.61
The second major ethical concern of HGGE is its eugenic potential. This concern stems from the premise that, inherently, the fundamental purpose and function of HGGE is to select for or against certain traits. This process implies value judgments on which traits are “desirable” and which lives are worth living, and is reminiscent of a very dark history of the eugenics movement.62
The first distinction that must be made in this context is between positive and negative eugenics. Negative eugenics teaches “breeding out” negative or unwanted characteristics, such as the Huntington's disease mutation. On the other hand, positive eugenics promotes the selection of desirable genetic traits, such as eye color, immunities, or muscle mass.63 The second distinction is between government and private actors.64 Proponents of gene editing argue that because the decisions and selections are autonomously made by private actors, they do not implicate eugenic concerns and avoid historical resemblances to government coerced selection.
Even without the overt coercive influence of government, concerns of discrimination are not extinguished.65 Regardless of how the choice is made, HGGE facilitates a societal distinction between traits that are “desirable” and “undesirable.”66 In the United States and most parts of the world, these preferences are historically influenced and are self-perpetuating.67 Physical traits that are seen as “desirable” are often those correlated with success and privilege and thus grounded in historical discrimination.68 Following these premises to their logical conclusion on a large scale seems to suggest an ultimate result of society eliminating or disincentivizing births of historically marginalized races, people with disabilities, and other such traits, all by autonomous, uncoerced, individual choice.69 Thus, the same people advanced by the eugenics movement would be realized through corrosive societal pressure, rather than coercive government measures.70
Similar to the ambiguity of what constitutes an enhancement, it is subjective and far from clear which are positive or negative characteristics.71 This raises highly controversial questions surrounding the desirability of certain traits and what constitutes a disability.72 For example, deafness and dwarfism often have genetic markers, which makes it possible to select out those embryos in favor of “normal” sets of genes.73 Doing so makes an explicit eugenic statement of preferability of some types of humans.74 The deaf and dwarf communities are thriving communities with a proud culture and live largely normal lives, which makes this not the same situation as selecting against embryos that exhibit deadly diseases like cystic fibrosis or Tay-Sachs.75
When creating policy and regulations of HGGE that are anywhere between full admissibility and a full ban, difficult decisions and value judgments inevitably arise regarding which traits or disorders are worthy of eugenic treatment, and which are not.76 A bright line rule seems inextricably arbitrary because the spectrum of genetic conditions does not easily break down into clearly defined categories.77 This becomes increasingly apparent as the conversation gradually moves further away from targeting only diseases unanimously regarded as deadly and dreadful.78
The eugenic potential of HGGE is also evident in the prediction of geneticist Bentley Glass in 1971 that, “[n]o parents will in that future time have a right to burden society with a malformed or a mentally incompetent child.”79 In a future world, children born without the use
of genetic technology could conceivably be denied access to social support systems and public services for “preventable” diseases.80 This could occur both through government policies, such as denial of special education services in public schools, and private sector actions, such as by health insurers denying coverage or charging higher premiums.81 In the latter case, overt state coercion would not be necessary to advance “superior” traits while disincentivizing traits and types of persons perceived as undesirable.82 Thus, regardless of how eugenics is implemented, the result will inevitably be discriminatory.83
The true question is where to draw the line. How much risk of discrimination or eugenic potential is society willing to accept or able to handle?84 This must be assessed in the context of the burden that harmful and deadly genetic diseases place on individual parents and society.85 A balancing test approach to whether the significant benefits may justify or outweigh the significant risks seems inevitable.86 However, defining the equilibrium point is contentious, elusive, and surely not unanimous.
Questions of consent and autonomy begin with the question of who, specifically, is the patient when the genes of an embryo are edited?87 On one hand, the patient might be understood to be pregnant persons, as the edited embryos originated from them and are ultimately being implanted back into their bodies.88 Further, it is the pregnant person who has elected to have the procedure. On the other hand, the future legal person, the child, is the subject whose potential livelihood and genome are ultimately at stake and being modified.89 The legal rights of the unborn vary by national jurisdiction.90 Consequently, in some countries, the legality of HGGE may turn on the purpose of the edit. For example, HGGE may be legal when used to treat infertility, based on a child’s right to be born, whereas modification for preventative or enhancement purposes would be illegal.
The concept of preserving the human dignity of the child may also be reasonably argued from both sides.91 The future edited child may have pressure to “live up to” certain expectations for which the child was “designed,” thus diminishing, to a certain extent, self-determination and autonomy.92 However, others may argue that failing to edit the genes of a future child may be unethical because it is a failure to prevent avoidable suffering and may limit the child’s potential.93
Further, parental decisions and numerous other social factors can influence a child’s traits and development in a myriad of ways.94 In fact, an argument based on principles of autonomy and much of the debate over enhancement presupposes a degree of genetic determinism.95 This is a presumption that certain genes will inevitably produce a specified trait.96 While this may be true for very basic edits like determining eye color, the theory has been heavily criticized when applied to complex traits such as intelligence and sociability. The vast majority of genes play only a probabilistic role, and traits emerge from complicated and intricate interactions and combinations of numerous genes.97 As scientific understanding of epigenetics has increased, it has become increasingly apparent that environmental and developmental factors post conception and birth play a significant role in how, or which, genes are expressed.98 Although the Human Genome Project successfully mapped out human DNA, how those genes interact when they are expressed, and how they link to non-medical traits remains largely unknown.99 For example, the CCR5 gene that Dr. He edited in order to confer immunity to HIV has been linked in other studies to an increased chance of contracting West Nile Virus.100 Further complicating the enhancement issue, preliminary studies have also associated the CCR5 gene with increased memory capacity.101
A major criticism of the utopian vision of a future world with ubiquitous human gene editing is that it would not eliminate suffering, but merely shift it elsewhere.102 While the themes and issues associated with social welfare, social justice, and inequality are implicated in enhancement and eugenic concerns, there are also direct societal issues. While each CRISPR modification is a private and individual decision and procedure, the accumulated effects undoubtedly will have significant societal ramifications, both positive and negative, particularly if the practice is widespread.103
The first question would be, if HGGE were permissible, who would have access to the technology? In all likelihood, the combined costs of IVF, PGD, and CRISPR technologies would make the procedure prohibitively expensive.104 This would limit the benefits to affluent countries, and even within those countries only to affluent individuals.105 CRISPR and HGGE are, of course, not nearly the first or only medical technologies to generate this dilemma. The effects of inequitable distribution of health technology are widely apparent. A particularly relevant example is the lack of access in the developing world to IVF and other infertility treatments.106 Recently, global inequities became particularly clear through the distribution of vaccines during the COVID-19 pandemic.107
Nonetheless, this does not mean that the issue may be ignored. One distinguishing factor between HGGE and existing medical technologies is the distribution of harms and the distinction between a harm and a lack of benefit. The effect of unequal distribution of existing technologies, such as vaccines, medical equipment, and drugs is that there are some people who do not have access to something that would otherwise help them. The fact that someone else has access, however, does not facially harm those who do not. They are, at most, indirectly affected by others’ usage. In contrast, the aggregate effect of HGGE is that it may forever alter the greater human genome, creating irreversible changes and gene drives, thereby directly affecting all humans. Thus, each individual has a vested interest in the application and global regulation of HGGE.
Similarly, HGGE has the potential to create a separate class of humans and consequently a two-tiered society – those who are enhanced, and those who are not. If allowed to run its full course uninhibited, an “arms race” of sorts may be started, and children who have not been modified may fall behind or be deemed unworthy.108 Specific laws and regulations would be necessary to prohibit stratification of society based on genetic predisposition and guard against a social order where employment, social, and economic potential are directly or indirectly attributable to genes.
In such a world, the cost of medical treatments, logistics, and accommodations for the unenhanced would presumably be diffused to the entire healthcare system.109 The most likely, and perhaps only realistic alternative would be blatant and transparent discrimination, setting up one insurance pool for unedited humans and a separate one, presumably with significantly lower premiums, for those whose genome has been curated or “corrected.” It is also unclear if insurance providers could permissibly categorize HGGE as “preventative medicine,” since it will avoid significant future costs. Doing so would provide yet another economic incentive and exert increased social pressure on future parents.110
Further, HGGE has the potential to vastly exacerbate existing types of inequality and discrimination. Even if the technology is not permitted for enhancement, the burden to conform remains at play, even with basic medical usage.111 Instead of creating a new class, it could perpetuate the elimination of certain classes or types of people and neurodiversity, such as people with disabilities or other genetic related impairments.112 Disabilities are currently seen as a product of chance, but gene editing could lead to society viewing disabled children as a product of individual parental choice, and be met with disapproval.113
An additional factor when creating policy regulating HGGE is the desire to prevent medical tourism.114 Medical tourism could exist both for patients and researchers.115 The concern is a scenario where, due to lack of international consensus, certain countries prohibit HGGE but others do not, or have much looser restrictions. It has been said that “science is a one-way train that will stop for no man's conscience.”116 Inevitably, if research is not permitted to proceed in one jurisdiction, eager researchers will set up their labs in countries with more lax or non-existent restrictions.117 This circumvention is the least desirable scenario, as the research is neither being prevented nor overseen and regulated. In fact, such a scenario effectively advantages rogue and less scrupulous researchers to the detriment of responsible researchers who wish to proceed cautiously.
Similarly, patients seeking treatment who are unable to avail themselves of the novel technology in their home country may travel elsewhere to receive treatment. This scenario is currently playing out with a different innovative fertility treatment, mitochondrial transfer.118 Patients who were unable to receive the benefits of the technology in the United States have traveled to countries such as Mexico and Korea to receive treatment.119 This situation additionally creates an even further barrier to access, as international travel likely entails, among other things, increased financial costs and time, and may remove the potential for healthcare coverage.120
One of the most intuitive challenges to HGGE is the unknown effect on future generations and the permanent impact on the human genome. However, these concerns are not novel and are easier to grapple with than the previous dilemmas on legal and policy grounds. The primary objection involves the so-called “inviolability” of the human genome.
The classical approach is represented clearly by The International Bioethics Committee of UNESCO, which advocated a complete ban on all HGGE based on the “notion of the human genome as the heritage of humanity.”121 However, the German Ethics Council, in its recommendations on gene editing, unanimously rejected the presumption that the human germline is “categorically inviolable.”122 A major factor in this decision is that through various means, the human genome is constantly being altered.123 This happens both through natural events, such as epigenetic modifications resulting from trauma, famine, and similar circumstances, as well as human action, such as selective breeding and inbreeding.124 Modern examples include the alteration of genes resulting from radiation exposure or smoking while pregnant.125 Further, the often religiously motivated argument that humans are crossing a red line by surpassing their natural place in the universe ignores the reality of the modern medical landscape.
HGGE is also readily seen as an affront to divine creation and an illicit aberration of nature and humanity’s place in the cosmos.126 There are further religious concerns with the mechanisms necessary to achieve HGGE, primarily concerns over the moral status of embryos, the creation, research, and destruction of which are critical to fertility procedures.127 Religious opposition to HGGE will likely be on the same grounds as, but even stronger than, the objections to IVF.
In many ways, however, the concept of “natural” reproduction has already been substantially displaced. With the aid of modern medicine and technology, people with severe impairments, disabilities, and congenital diseases are able to live past the age of reproduction. For the vast majority of human history, people with such traits would not have had the ability to pass their genetic mutations to future generations. This refining of the gene pool is the essence of natural selection. Currently, however, there are sperm and egg banks, fertility treatments, and many other mechanisms that override “natural” reproduction and how genetic material passes from generation to generation.
Harms to future generations are not a novel risk factor in new technologies. The most closely related and socially prevalent example is the use of genetically modified organisms (GMOs), specifically in food products.128 Genetic engineering has been used in agriculture for a variety of purposes, such as adding specific nutrients to rice grown in the developing world, adding resistance in crops to pesticides, plant viruses, and other environmental stressors, and adding mutations to increase yield size and shelf life.129 Fear of the unknown effects of GMOs has caused great controversy in domestic and international political arenas.130 Although conclusions are generally unsubstantiated, the likely effect of the controversy has been that research, planting, and distribution of lifesaving and life-enhancing GMO crops has been severely reduced.131
The law has also grappled with intergenerational harms in other medical contexts.132 There is established jurisprudence on unintended human-induced injurious effects on fetuses, including cancer and other mutations through air pollution, radiation, and other hazards.133 One example was the litigation regarding diethylstilbestrol (DES), where an FDA-approved drug prescribed to pregnant women had effects that put their unborn child, and possibly a third generation, at substantially increased risk for certain cancers, fertility problems, and several other conditions.134
A more abstract and philosophical objection to gene editing centers on the moral impact that the changes may have on human dignity and self-conception. The thrust of this argument is that harnessing power over the future of humanity through HGGE exceeds the psychological and moral place of mankind. Michael Sandel, a prominent political philosopher, and others have passionately argued that the most concerning problem with HGGE is the corrosive effect of the “drive to mastery” over all facets of human existence.135 Sandel focuses on the psychological necessity of randomness and indeterminacy in who we are or become.136 He writes, “[t]he more we become masters of our genetic endowments, the greater the burden we bear for the talents we have and the way we perform.”137
Similarly, increased importance and determination based on genetic material may alter societal values and individual opportunities. It is not hard to imagine a world in which humans would “redefin[e] ourselves as biological, rather than cultural and moral beings.”138
The application of HGGE clearly has profound potential to positively influence health outcomes. It is a separate question, however, if HGGE is necessary to achieve these goals. In many cases, the same ends may be achieved through separate, less risky means.139 Other fertility treatments, such as IVF, PGD, and sperm washing are already able to eliminate the vast majority of monogenic diseases without implicating the web of ethical and legal issues of HGGE.140 On the flip side of the coin, if these other technologies can produce essentially the same outcomes, then many of the ethical and moral issues of HGGE are not exceptional.141 Thus, if IVF, PGD, sperm washing, and mitochondrial transfer are currently accepted in society, then HGGE largely should be as well.142
The technological capabilities of PGD have advanced as to enable affirmative selection of traits and opens the door to the creation of “designer babies.”143 PGD has been widely used to ensure gender selection and clinics have even openly advertised services to preselect a baby’s eye color.144 While gender selection has been banned in many countries, the practice remains legal in the United States.145 Using PGD in this context, “designer babies” would still be comprised wholly of DNA from their biological parents (as opposed to genetically modified), but the technology may be ensuring implementation exclusively of embryos containing “ideal” genetic combinations that likely have a vanishingly small probability of natural occurrence. This invokes similar notions to many of the risks described above, such as eugenic potential, “playing God,” and social stratification.
There is also the promise of in-vivo somatic cell editing that may overlap with the purposes of HGGE, such as addressing immunities and deteriorations. For example, as of November 2021, at least two CRISPR-based somatic cell editing therapies designed to eliminate HIV in human cells are underway and showing promising preclinical results.146 Similar research for other prominent diseases, including cancer, inherited blindness, deafness, and neuromuscular disorders are underway and likely to continue proliferating.147 If this approach is successful, the type of germline gene editing done by Dr. He would be largely obviated. The regulatory framework for HGGE in this context would justifiably become increasingly narrow, permissible in only the most extreme cases where no alternative is deemed satisfactory.
Until recently, there was almost a unanimous international ban or moratorium on all forms of HGGE.148 However, there has been a growing shift in scientific and political communities toward a more flexible and permissive legal approach.149
The first binding international agreement on this topic was the so-called Oviedo Convention,150 signed by 29 European countries in 1997.151 The Convention outlined a categorical ban on HGGE used for reproductive purposes, or the creation of embryos for research purposes.152 The primary reasoning was that it “may endanger not only the individual but also the species itself.”153 There are additional explicit and arguably implicit restrictions and bans on HGGE in other European Union conventions, such as the Biotech Directive, the Charter of Fundamental Rights, and the Clinical Trials Regulation.154
The Nuffield Council on Bioethics’ 2018 report Genome Editing and Human Reproduction began to challenge this consensus and has been very influential.155 The report outlined eight recommendations and ultimately concluded that under current circumstances, HGGE for reproductive purposes should be banned.156 However, a major shift was the provision that “the potential use of heritable genome editing interventions to influence the characteristics of future generations could be ethically acceptable in some circumstances.”157 Anticipating continued development in the field, the report calls for restrictions to be periodically reevaluated.158 Further, the Nuffield principles, as well as the actual law in the United Kingdom under The Human Fertilisation and Embryology Act of 1990, apply only to embryos actually intended for human implantation.159 This qualification legalizes medical research using germline gene editing techniques on human embryos so long as they are not intended for reproduction.160 It remains to be seen whether, or how, the Nuffield principles will affect policy now that has Great Britain left the European Union.161
The two most recent major reports have continued this trend. In September 2020, the International Commission on the Clinical Use of Human Germline Genome Editing released its report, Heritable Human Genome Editing.162 The Commission is primarily comprised of the U.S. National Academy of Medicine, the U.S. National Academy of Sciences, and the U.K.’s Royal Society.163 The Commission sought to create a “responsible clinical translational pathway” for the application of HGGE technology.164 The report’s recommendations include efficacy thresholds, guidelines, and oversight mechanisms designed to ensure ethical and safe applications of HGGE.165 Finding that these measures are not currently in place, the report suggests that clinical application and legalization would be irresponsible without significant technological advancements and societal dialogue.166
However, the report recognizes the substantial benefits that HGGE may provide in preventing monogenetic disorders that are untreatable by current medical technology.167 The report advocates a restrained approach designed to “proceed incrementally and cautiously, and to provide the most favorable balance of potential benefits and harms.” For example, in a future scenario where scientific, ethical, and moral issues have been satisfied and domestic law permits
HGGE, it should nonetheless be considered only when there is a known risk of a serious monogenetic disease and no other reasonable options are available to have a healthy biologically related child.168
The second major report is WHO’s Human Genome Editing: recommendations, released in July 2021.169 The multinational and interdisciplinary advisory committee was convened in 2018 in the aftermath of the announcement of Dr. He’s experiment with the goal of providing the first comprehensive global recommendations to “establish human genome editing as a tool for public health, with an emphasis on safety, effectiveness and ethics.”170 The report addresses both somatic and germline gene editing and was heavily informed by a 2020 report published by the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K.’s Royal Society171 The report reiterates WHO’s position that proceeding with any clinical applications of HGGE would be irresponsible under the current conditions.172 However, the purpose of the project was to develop a governance framework to not only prevent the premature use of gene editing technologies, but also to provide tools, mechanisms, and structures to support the use of HGGE in the future.173
The resulting recommendations contain eight key areas of regulatory focus.174 They are: (1) “Leadership by WHO and its Director-General,” which includes both scientific and moral leadership, with open eyes to both the opportunities and challenges of gene editing; (2) “International collaboration for effective governance and oversight,” seeking to facilitate a shared international development model for the technology and supporting cross-institutional efforts; (3) “Human genome editing registries” to collate all ongoing and proposed clinical trials to ensure that they are reviewed, assessed, and approved under shared international standards; (4) “International research and medical travel,” which seeks to address and prevent the risk of tourism to less regulated jurisdictions to conduct research; (5) “Illegal, unregistered, unethical or unsafe research and other activities,” which proposes essentially a whistle-blower mechanism for confidential reporting of illicit research; (6) “Intellectual property,” promoting rights and equitable access, particularly to less developed nations, and developing ethical licensing systems; (7) “Education, engagement, and empowerment” to promote an inclusive, informed, interdisciplinary, and international discourse on the future of gene editing; and (8) “Ethical values and principles for use by WHO” that are unambiguous and officially endorsed.175 Finally, the recommendations advise that the WHO Science Division undertake an extensive review of these recommendations within three years to assess their adequacy and effect, and address new and future concerns.176
A global framework, such as the one provided by WHO, is important because the ramifications of gene editing will extend beyond any one nation.177 The WHO recommendations do not have the force of law and WHO cannot obligate countries to follow a standardized global approach.178 Accordingly, WHO does not provide model legislation or didactic regulations. Instead, it is a governance framework that poses questions, considerations, and hypothetical scenarios designed to guide each individual country in assessing how to structure domestic policy.179
This flexibility is what makes the framework particularly attractive and advantageous.
Unlike most conventions and treaties, it is neither dogmatic nor prescriptive. There are no mandatory positions or provisions. For example, the hypothetical scenarios that supplement the guiding principles outline potential stakeholders and competing motivations, and provide suggested questions and considerations for policymakers to create regulations appropriate within their country’s cultural and economic context. It is presumed that governance content and structure will vary from country to country based on factors such as social norms and values and a nation’s ability to establish or enforce oversight and regulatory mechanisms.180 The process is designed to be flexible and ongoing, and attentive to evolving societal views and technological developments.181 Ideally, the framework would promote governance that is not only reactive, but proactive.182
Despite the position advanced by the American Academies’ report, the United States has not adopted a permissible approach to HGGE research. Formally, HGGE is not legally banned.183 However, through a matrix of regulatory and informal political restraints, the practice is effectively prohibited.184
Clinical trials in the United States are governed by the FDA, and thus any research involving the implementation of a genetically modified human embryo is illegal without FDA approval. Specifically, what is known as the “Common Rule” governs human subject research.185 It is reasonable to infer that the rules of subpart D of the Common Rule, which apply increased requirements and scrutiny to research involving children, would be equally applicable, if not even more stringent, in the context of experiments on unborn children.186 Currently, considering the novelty of the technology and relative lack of information, there is no reason to believe that the FDA would allow research to progress to trials without substantially more information on the safety, effectiveness, and necessity of the procedure.187
Since clinical trials are an indispensable stage in the approval process of any medical device, drug, or product, this restriction is a major hurdle.188 For HGGE to proceed to commercial usage, it must demonstrate sufficient safety and efficacy guarantees. Such information, as expressly required to begin lifting domestic and international bans and restrictions, necessarily may be gained only through clinical trials. There would likely be further difficulties in obtaining clinical trial approval, such as if there truly can be informed consent.189 A full exploration of these issues is beyond the scope of this article.
Even if these conditions were satisfied, the FDA would be unable to consider or approve HGGE clinical research due to constraints imposed directly by Congress. In 2015, Congress added a budgetary rider to the national budget which has since been renewed every year.190 The rider restricts any public funds directed toward research “in which a human embryo is intentionally created or modified to include a heritable genetic modification.”191 This is similar but distinct from the Dickey-Wicker Amendment, discussed above, which is a separate budget rider that prohibits federal funding of research that creates or destroys human embryos.192
The practical effect of these restrictions is that HGGE for purely research purposes is permitted. However, such research would have to be strictly privately funded and not use embryos that are viable for human implementation.193 Beyond this limited research, the regulatory web creates a de facto ban on clinical trials or application of HGGE.
Supporters of the budgetary riders and political restrictions point to flaws in the regulatory system that would govern HGGE. These include the FDA’s limited scope of consideration and enforcement. The FDA’s mandate is limited to assessing risks related only to safety and effectiveness.194 This is problematic in the context of regulating a technology like HGGE, which has extensive social and moral consequences that fall outside of the FDA’s scope of review.195 Another limitation is the permissibility of off-label uses of FDA approved drugs and technologies.196 Even if the FDA approves a form of HGGE technology for a discrete purpose, once on the market, it may be used by doctors for different purposes.197
Lastly, there are existing federal laws and a growing movement at the state level to enact genetic privacy laws that provide protection to citizens and residents.198 The most relevant federal law is the Genetic Information Nondiscrimination Act of 2008 (GINA).199 GINA prevents certain group health insurance plans from discriminating based on genetic data and
prohibits companies or the government from collecting or using genetic data in any employment decisions.200 Additionally, the Health Insurance Portability and Accountability Act (HIPAA) regulations were amended in 2013 to include genetic information under the definition of Protected Health Information, which carries increased protections and burdens.201 These laws, however, are not comprehensive in their protections on their own, as they do not cover insurance for life, disability, or longer-term care. These exclusions and other loopholes effectively allow for discrimination against a person who has a known genetic predisposition for a certain disease.202
Some states have enacted legislation that expands on the protections provided by GINA. For example, in California, CalGena puts genetic discrimination on par with race and sex discrimination, ensuring equal rights and access in areas such as housing, financing, and education.203 With the rise and popularity of direct-to-consumer genetic testing companies, states have increasingly been passing legislation that creates additional duties on private companies collecting genetic data, such as to provide information to consumers on the collection and use of their data, to obtain consent before collecting genetic data, and to destroy data and samples upon request.204 Such laws are an important step toward protecting genetic rights and privacy and addressing concerns about emerging genetic technology. It is an optimistic sign of proactive legislating, yet there is a long way to go before comprehensive protections are in place to address widespread genetic engineering at the embryonic stage, specifically for germline modifications.
Clinical use of human germline gene editing is on the horizon. In many ways, it has already arrived. What is clear is that there will not be a global consensus over how and when to ban or regulate the technology. In today’s hyper-globalized and fluid economy, no country is isolated from the decisions of other nations. Regardless of the moral disposition of the United States or the stringency of its regulatory regime, the technology will continue developing. The questions are where, and with how much oversight.205
So far, gene editing has been a seemingly rare circumstance where the law has not lagged behind the technology it is governing.206 The meteoric rise of CRISPR technology in the past decade is now threatening to change that dynamic.207 Given the rapid evolution of gene editing technology as well as increased access and expertise, laws and regulations must not be drafted too narrowly or specifically, lest they become quickly obsolete and serve only to restrain innovation and efficiency.208 They must also not be written too broadly so as to have a chilling effect on less controversial technologies, such as somatic cell editing.209 Flexible and easily adaptable provisions will best serve the regulation of complex and dynamic technologies like HGGE.210
History tends to repeat itself, and the more that is learned from the past, the more practical and effective regulations will be. Gene editing technology has been following an arc that is closely analogous to multiple, once-controversial medical technologies in the past half century.211 IVF, recombinant DNA (rDNA), and retroviral gene therapy all initially caused great moral and political panic when they emerged on the medical scene.212 Like HGGE with Dr. He’s experiments, these innovations each experienced early setbacks that led to calls for bans and greatly delayed their development.213 All three, however, are no longer controversial, became standard medical practice, and have been immensely successful in attaining medical benefits for society.214 IVF has proven to be a safe and effective form of ART with efficacy rates that continue to improve and has led to millions of successful pregnancies worldwide.215 rDNA technology has produced immeasurable lifesaving medical breakthroughs, such as synthetic insulin, interferon, various antibiotics, and numerous vaccines.216 Gene therapy, while still used only in clinical trials and research contexts in the United States, has shown success in treating patients with diseases and disorders such as hemophilia and certain types of cancer.217 While HGGE undeniably poses novel and serious risks, it just as undeniably carries great potential benefits and the potential effects are not unique to the political, moral, or medical context.
Accordingly, the United States should adopt a moderate pragmatic approach to HGGE regulation. The term “moderate” distinguishes the approach from what may be labeled an “extreme,” pragmatic approach that disregards any moral quandaries associated with HGGE. It is also distinct from a “non-pragmatic” approach, which disregards the inevitability of HGGE development and seeks a comprehensive ban. The former is typified by James Watson, who once remarked that, “we can talk principles forever, but what the public actually wants is not to be sick. And if we help them not be sick they’ll be on our side.”218 This approach is shortsighted and overly narrow in its consideration of the context and breadth of potential harms as compared to benefits. The latter approach is also shortsighted in that an outright ban will never be able to perpetually halt technological development and possibility.219 Like the extreme view disregarding potential harms, the nonpragmatic view is additionally overly narrow in its consideration of the context and breadth of the potential benefits to society.
A moderate pragmatic view should be informed by, and build upon, the principles and guidelines laid out in the WHO good governance framework.220 The United States should assume a leadership role, allowing it to carefully craft and nurture the global development of HGGE technology and regulations in a way that is appropriately cautious, safe, equitable, and future oriented.221 Mechanisms for ensuring compliance include oversight boards, mandatory standards for accreditation, licensing, and quality standards, and cooperation from academic and professional journals on publishing criteria. These mechanisms should draw on the WHO governance framework, as well as the practical experience of the Human Fertilisation and Embryology Authority in the United Kingdom, which plays a comparable domestic regulatory role.222
The United States should both permit and fund HGGE research, but only in highly limited and specific contexts. A regulatory model will be more effective at preventing and
controlling certain types of harms than a prohibitive model.223 The alternative leads to risks of unscrupulous research tourism and rogue actors that would undermine the very purpose of nonengagement.224 Similarly, prohibiting public funding domestically, as is currently the case under the budget riders, skews the purposes for which research is conducted and its consequent outcomes.225 The ban effectively excludes all public universities, non-profits, and public research institutions, such as the National Institutes of Health, from conducting any research on HGGE.226 When only privately funded research is allowed, it will control the market and fears of commercialization and inequality, particularly for enhancement purposes, are substantial.227
Research, at least for the time being, should be limited strictly to monogenetic disorders and only for the purpose of eliminating imminently deadly or severely debilitating disease. This does not wholly solve the ambiguity problem, as it may still be a judgment call on what is “severely debilitating” or “imminently deadly.” There has similarly been trouble defining the “serious disease or condition” standard used by the FDA.228 However, this standard will mitigate the toughest ethical issues, and ambiguous borderline cases may be determined on a case-by-case basis through a government regulator or agency. Similarly, although the parameters of this definition might also be interpreted differently by culture and region, the good-faith degree of difference will likely be relatively low. While research should be permitted to advance, the United States and global community should incorporate the WHO guidance to prohibit all clinical applications of HGGE until certain technical, safety, and public opinion thresholds are met.
Transparency and education will be critical components in creating sound public policy around HGGE. Surveys have shown a substantial difference in public support for gene editing based on a person’s education level.229 This finding has multiple implications. First, in order for the technology to succeed, it must avoid a “Monsanto problem.”230 This problem arose with GMO foods generally, and specifically when GMO seeds were planted in communities that were left uninformed about the science, process, or safety of GMOs.231 Consequently, skepticism and resentment have prevailed, even after the safety and benefits of GMOs have been demonstrated. It is likely that many experiments and investments have been eschewed due to this public perception, thus preventing significant health and social benefits, such as climate change resistant crops.232
The education-perception gap also warns against an industry self-regulation standard and illuminates the importance of public input generally. Since the benefits and effects accrue to society as a whole, the political process must be inclusive and democratic. A regulatory model that is designed and implemented only by highly educated scientists and insiders would be wholly inadequate.233 But while public input is necessary, it is also not sufficient.234 Public opinion alone may marginalize certain groups and constituencies by presuming ethical “universalism,” a view that judgments and preferences on ethical issues are consistent across socially and culturally diverse societies.235 On the other hand, public opinion may work to marginalize certain groups and constituencies, particularly in the international arena by prioritizing domestic benefits at the expense of other countries or making decisions motivated by political and religious preferences rather than being guided by science and facts.236
Incentive structures are an additional reason why professional self-regulation is problematic. There is an inherent risk of conflicted interests among physicians, as researchers and clinicians would benefit greatly from gene editing technology being authorized.237 The soft-law standards and mechanisms of professional regulation have already proven ineffectual, as they failed to deter Dr. He, and arguably facilitated a permissive environment that emboldened and encouraged him.238 One researcher, in the wake of Dr. He’s announcement of the gene-edited twins, sharply criticized this environment, writing that “it’s wrong to call him a rogue when he’s acting in line with [a scientific culture] that puts a premium on provocative research, celebrity, national scientific competitiveness, and firsts.”239 This statement is in accord with Dr. He’s eventual indictment by Chinese authorities, who denounced the research Dr. He conducted, “in the pursuit of personal fame and gain.”240 Consequently, in the United States, adoption of a moderate pragmatic regulatory model is best suited to address both the moral and practical challenges that HGGE presents.
HGGE presents very real possibilities of both promise and peril. The benefits and the risks could change society forever. The best way to control the progress of HGGE is not to ban it completely, abdicating regulatory and moral responsibility. Instead, the United States should accept the scientific and technological inevitability of gene editing technology and foster a responsible, prudent environment for its gradual development.
Appropriate oversight mechanisms, public input, and regulations are the most pragmatic path forward, both domestically and internationally. The United States should follow the WHO Recommendations and Framework for Governance, take a leadership position in defining global norms, and collaborate with the international community to harness the immense prospective benefits of HGGE while minimizing potential risks, harms, and unscrupulous actors. Establishing and enforcing prudent and pragmatic ethical and legal principles will best protect all members of society while promoting an equitable distribution of benefits.