Genome editing offers great potential to advance both fundamental science and therapeutic applications. Basic laboratory research applying genome-editing methods to human cells, tissues, germline cells, and embryos holds promise for improving understanding of normal human biology, including furthering knowledge of human fertility, reproduction, and development, as well as providing deeper understanding of disease and establishing new approaches to treatment. Such research is proceeding rapidly within existing oversight systems. Genome editing is already entering clinical testing for somatic treatment of certain genetic diseases, subject to regulatory systems designed to oversee human somatic cell gene therapy research. Furthermore, recently developed methods offer the future possibility of editing germline cells to prevent heritable transmission of genetic disease, within the limits of domestic and transnational law. At the same time, genome-editing technologies challenge regulators and the public to evaluate existing governance systems to determine whether there are some genetic alterations that are insufficiently justified, too risky, or too socially disruptive to be pursued at this time. This chapter summarizes the conclusions of the committee relating the overarching principles and conclusions to recommendations for the conduct and oversight of this burgeoning area of research and application.
Genome editing holds great promise for preventing, ameliorating, or eliminating many human diseases and conditions. Along with this promise comes the need for ethically responsible research and clinical use.
RECOMMENDATION 2-1. The following principles should undergird the oversight systems, the research on, and the clinical uses of human genome editing:
- Promoting well-being
- Due care
- Responsible science
- Respect for persons
- Transnational cooperation
In turn, these principles, detailed below, result in a number of responsibilities when devising a governance system for genome editing:
Promoting well-being: The principle of promoting well-being supports providing benefit and preventing harm to those affected, often referred to in the bioethics literature as the principles of beneficence and nonmaleficence.
Responsibilities that flow from adherence to this principle include (1) pursuing applications of human genome editing that promote the health and well-being of individuals, such as treating or preventing disease, while minimizing risk to individuals in early applications with a high degree of uncertainty; and (2) ensuring a reasonable balance of risk and benefit for any application of human genome editing.
Transparency: The principle of transparency requires openness and sharing of information in ways that are accessible and understandable to stakeholders.
Responsibilities that flow from adherence to this principle include (1) a commitment to disclosure of information to the fullest extent possible and in a timely manner, and (2) meaningful public input into the policy-making process related to human genome editing, as well as other novel and disruptive technologies.
Due care: The principle of due care for patients enrolled in research studies or receiving clinical care requires proceeding carefully and deliberately, and only when supported by sufficient and robust evidence.
Responsibilities that flow from adherence to this principle include proceeding cautiously and incrementally, under appropriate supervision and in
ways that allow for frequent reassessment in light of future advances and cultural opinions.
Responsible science: The principle of responsible science underpins adherence to the highest standards of research, from bench to bedside, in accordance with international and professional norms.
Responsibilities that flow from adherence to this principle include a commitment to (1) high-quality experimental design and analysis, (2) appropriate review and evaluation of protocols and resulting data, (3) transparency, and (4) correction of false or misleading data or analysis.
Respect for persons: The principle of respect for persons requires recognition of the personal dignity of all individuals, acknowledgment of the centrality of personal choice, and respect for individual decisions. All people have equal moral value, regardless of their genetic qualities.
Responsibilities that flow from adherence to this principle include (1) a commitment to the equal value of all individuals, (2) respect for and promotion of individual decision making, (3) a commitment to preventing recurrence of the abusive forms of eugenics practiced in the past, and (4) a commitment to destigmatizing disability.
Fairness: The principle of fairness requires that like cases be treated alike, and that risks and benefits be equitably distributed (distributive justice).
Responsibilities that flow from adherence to this principle include (1) equitable distribution of the burdens and benefits of research and (2) broad and equitable access to the benefits of resulting clinical applications of human genome editing.
Transnational cooperation: The principle of transnational cooperation supports a commitment to collaborative approaches to research and governance while respecting different cultural contexts.
Responsibilities that flow from adherence to this principle include (1) respect for differing national policies, (2) coordination of regulatory standards and procedures whenever possible, and (3) transnational collaboration and data sharing among different scientific communities and responsible regulatory authorities.
These principles and responsibilities can be fulfilled in the form of specific recommendations for regulation of genome editing, as presented below.
In the United States, existing laws and funding policies at the state and federal levels will govern human genome editing at all stages, from laboratory research through preclinical testing and clinical trials to clinical
application. The existing systems, while always having room for improvement, can be deployed to manage currently anticipated uses of human genome editing, but some future uses will require stringent criteria and further public debate.
Laboratory Research Using Genome-Editing Methods
The use of genome editing as a laboratory research tool in human somatic cells and tissues would largely be governed in the same way as other types of laboratory research, which are subject to institutional biosafety review and general standards of laboratory practice. Additional policies are also in place to govern the donation and use of human cells, tissues, or embryos for research. These take account of factors such as whether the tissue is left over from a clinical procedure or is obtained through intervention specifically for research. If tissue has information within or linked to it that makes the donor’s identity readily ascertainable, then additional human subjects protections, such as the need for some form of consent and an institutional review board (IRB) review, generally will also apply.
Additional considerations apply to the use of genome editing for laboratory research using human embryos (with no aim of establishing a pregnancy). In the United States, federal funding for research using embryos generally is prohibited by the Dickey-Wicker Amendment, but some state and private sources for such research are available. Such uses would be subject to some of the legal regimes governing human reproduction and products of conception. Recommendations of the 1994 National Institutes of Health (NIH) Human Embryo Research Panel; the National Academies of Sciences, Engineering, and Medicine’s Guidelines for Human Embryonic Stem Cell Research; and the guidelines of the International Society for Stem Cell Research guidelines continue to shape research practices in this area.
The ethical and regulatory considerations posed by genome-editing research using human embryos in the laboratory have been explored in the past: the moral status of the embryo, the acceptability of making embryos for research or using embryos that would otherwise be discarded, and legal or voluntary limits that apply to the use of embryos in research. These same ethical considerations are raised in other countries. Even with recognition of the scientific value of using human embryos in research, the practice is limited, discouraged, or even prohibited in many jurisdictions. Genome editing of human embryos purely for nonreproductive research purposes will be subject to those same ethical norms and policies. Where permitted, however, oversight procedures already in place for other forms of embryo research should provide assurance of the necessity and quality of the research.
Oversight of laboratory research using human cells and tissues is an expression of the principle of Responsible Science, which includes high-quality experimental design and protocol review. Science proceeds by rigorous peer review and publication of results, and also benefits from sharing of and access to data that can support continued development of the field. The principle of Transparency supports sharing information to the fullest extent possible consistent with applicable law. Respect for diversity among nations in domestic policy on research using human embryos should not be an obstacle to Transnational Cooperation, including data sharing, collaboration by regulatory authorities, and, where possible, harmonization of standards.
Conclusions and Recommendation: Fundamental Laboratory Research
Laboratory research involving human genome editing—that is, research that does not involve contact with patients—follows regulatory pathways that are the same as those for other basic laboratory in vitro research with human tissues, and raises issues already managed under existing ethical norms and regulatory regimes. This includes not only work with somatic cells but also the donation and use of human gametes and embryos for research purposes, where this research is permitted. While there are those who disagree with the policies embodied in some of those rules, the rules continue to be in effect. Important scientific and clinical issues relevant to human fertility and reproduction require continued laboratory research on human gametes and their progenitors, human embryos, and pluripotent stem cells. This research is necessary for medical and scientific purposes that are not directed at heritable genome editing, though it will also provide valuable information and techniques that could be applied if heritable genome editing were to be attempted in the future.
RECOMMENDATION 3-1. Existing regulatory infrastructure and processes for reviewing and evaluating basic laboratory genome-editing research with human cells and tissues should be used to evaluate future basic laboratory research on human genome editing.
Somatic Cell Genome Editing for Treatment or Prevention of Disease and Disability
The most immediate clinical applications of genome editing will be in human somatic cells for the treatment or prevention of disease and disability. Indeed such research is already in clinical trials. In the United States, clinical applications that use somatic cell genome editing fall under the jurisdiction of the U.S. Food and Drug Administration (FDA), which regulates human tissue- and cell-based therapies. Initiation of any genome-
editing clinical trial requires prior approval by the FDA, and IRBs will also oversee aspects of these trials such as recruitment, counseling, and adverse-event monitoring for trial participants. Regulatory assessments associated with clinical trials of somatic cell genome editing will be similar to those associated with other medical therapies, including minimization of risk, analysis of whether risks to participants are reasonable in light of potential benefits, and whether participants are recruited and enrolled with appropriate voluntary and informed consent. Additional oversight in the United States includes local safety reviews by institutional biosafety committees and national-level review opportunities under the auspices of the NIH Recombinant DNA Advisory Committee (RAC), for both specific, novel protocols and for general approaches.
The ethical norms and regulatory regimes already developed for other forms of gene therapy are adequate for managing new applications involving somatic genome editing with the purpose of treating or preventing disease and disability. But regulatory oversight should also emphasize prevention of unauthorized or premature applications of genome editing.
In some circumstances, it may also be desirable to consider undertaking genome editing in the somatic cells of a fetus in utero, for example, where fetal editing could be significantly more effective than postnatal intervention for genetic diseases with devastating effects early in development. The potential benefit to the resulting child would be key. But in utero genome editing would also require special attention to issues surrounding consent and to any increased risk of on-target or off-target modifications to fetal germ cells or germ cell progenitors.
Recommendations for regulating somatic cell genome editing are informed by several of the overarching principles. An important goal in both the research and clinical uses of somatic genome editing is promoting well-being. Transparency and responsible science are necessary for advancing the research with confidence in the quality of the work, while due care ensures that the applications proceed incrementally with careful attention to risks and benefits, as well as reassessments that allow timely response to changing scientific and clinical information. As therapeutic and preventive medical technologies are developed, fairness and respect for persons call for attention to equitable access to the benefits of these advances, protection of individual choice to pursue or decline use of these therapies, and respect for the dignity of all persons regardless of that choice.
Conclusions and Recommendations: Somatic Therapy
In general, there is substantial public support for the use of gene therapy (and by extension, gene therapy that uses genome editing) for the
treatment and prevention of disease and disability. Human genome editing in somatic cells holds great promise for treating or preventing many diseases and for improving the safety, effectiveness, and efficiency of existing gene therapy techniques now in use or in clinical trials. While genome-editing techniques continue to be optimized, however, they are best suited only to treatment or prevention of disease and disability and not to other, less pressing purposes.
The ethical norms and regulatory regimes already developed for gene therapy can be applied for these applications. Regulatory assessments associated with clinical trials of somatic cell genome editing will be similar to those associated with other medical therapies, encompassing minimization of risk, analysis of whether risks to participants are reasonable in light of potential benefits, and determining whether participants are recruited and enrolled with appropriate voluntary and informed consent. Regulatory oversight also will need to include legal authority and enforcement capacity to prevent unauthorized or premature applications of genome editing, and regulatory authorities will need to continually update their knowledge of specific technical aspects of the technologies being applied. At a minimum, their assessments will need to consider not only the technical context of the genome-editing system but also the proposed clinical application so that anticipated risks and benefits can be weighed. Because off-target events will vary with the platform technology, cell type, target genome sequence, and other factors, no single standard for somatic genome-editing specificity (e.g., acceptable off-target event rate) can be set at this time.
RECOMMENDATION 4-1. Existing regulatory infrastructure and processes for reviewing and evaluating somatic gene therapy to treat or prevent disease and disability should be used to evaluate somatic gene therapy that uses genome editing.
RECOMMENDATION 4-2. At this time, regulatory authorities should authorize clinical trials or approve cell therapies only for indications related to the treatment or prevention of disease or disability.
RECOMMENDATION 4-3. Oversight authorities should evaluate the safety and efficacy of proposed human somatic cell genome-editing applications in the context of the risks and benefits of intended use, recognizing that off-target events may vary with the platform technology, cell type, target genomic location, and other factors.
RECOMMENDATION 4-4. Transparent and inclusive public policy debates should precede any consideration of whether to authorize clinical trials of somatic cell genome editing for indications that go beyond treatment or prevention of disease or disability.
Heritable Genome Editing
Heritable genome editing, which creates genetic changes heritable by future generations, has the potential to alleviate the suffering caused by genetically inherited diseases. However, it also raises concerns that extend beyond consideration of individual risks and benefits. Although heritable editing would not currently be approved given the uncertainty about safety and efficacy, the technology is advancing rapidly, such that it may, in the not-so-distant future, become a realistic possibility that needs serious consideration. There are circumstances in which genome editing in germline cells or embryos might be the only or most acceptable option for prospective parents who wish to have a genetically related child while minimizing the risk of transmitting a serious disease or disability.
There is a history of debate around the possibility of making heritable changes to the human genome. Because the effects of such changes could be multigenerational, both the potential benefits and the potential harms could be multiplied. Benefits from such editing would accrue to any future child born with reduced burden from genetically inherited disease, and to the prospective parents seeking to have a genetically related child without fear of passing along a disease. On the other hand, concerns have been raised about the wisdom and appropriateness of this form of human intervention. The intended genome edits themselves might have unintended consequences which, if inherited, would also affect descendants. As with other forms of advanced medical technologies, questions of equality of access arise. The prospect of heritable genome editing also triggers concerns similar to those raised earlier by preimplantation and prenatal genetic screening, that is to say that purely voluntary, individual decisions might collectively change social norms about the acceptance of disabilities.
Conclusions and Recommendations: Heritable Genome Editing
In some situations, heritable genome editing would provide the only or the most acceptable option for parents who desire to have genetically related children while minimizing the risk of serious disease or disability in a prospective child. Yet while relief from inherited diseases could accrue from its use, there is significant public discomfort with heritable genome editing, particularly for less serious conditions and for situations in which
alternatives exist. These concerns range from a view that it is inappropriate for humans to intervene in their own evolution to anxiety about unintended consequences for the individuals affected and for society as a whole. More research is needed before any germline intervention could meet the risk/benefit standard for authorizing clinical trials. But as the technical hurdles facing genome editing of progenitors of eggs and sperm are overcome, editing to prevent transmission of genetically inherited diseases may become a realistic possibility.
The primary U.S. entity with authority for the regulation of heritable genome editing—the FDA—does incorporate value judgments about risks and benefits in its decision making. A robust public discussion about the values to be placed on the benefits and risks of heritable genome editing is needed now so that these values can be incorporated as appropriate into the risk/benefit assessments that will precede any decision about whether to authorize clinical trials. But the FDA does not have a statutory mandate to consider public views on the intrinsic morality of a technology when deciding whether to authorize clinical trials. That level of discussion takes place at the RAC, in legislatures, and at other venues for public engagement, discussed in Chapter 7.
Heritable germline genome-editing trials must be approached with caution, but caution does not mean they must be prohibited. If the technical challenges are overcome and potential benefits are reasonable in light of the risks, clinical trials could be initiated, limited to only the most compelling circumstances and subject to a comprehensive oversight framework that would protect the research subjects and their descendants; and have sufficient safeguards in place to protect against inappropriate expansion to uses that are less compelling or less well understood.
RECOMMENDATION 5-1. Clinical trials using heritable genome editing should be permitted only within a robust and effective regulatory framework that encompasses
- the absence of reasonable alternatives;
- restriction to preventing a serious disease or condition;
- restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to that disease or condition;
- restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects;
- the availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures;
- ongoing, rigorous oversight during clinical trials of the effects of the procedure on the health and safety of the research participants;
- comprehensive plans for long-term, multigenerational followup that still respect personal autonomy;
- maximum transparency consistent with patient privacy;
- continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public; and
- reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition.
Given how long modifying the germline has been at the center of debates about moral boundaries, as well as the pluralism of values in society, it would be surprising if everyone were to agree with this recommendation. Even for those who do agree, it would be surprising if they all shared identical reasoning for doing so. There are also those who think the final criterion of Recommendation 5-1 cannot be met, and that once germline modification had begun, the regulatory mechanisms instituted could not limit the technology to the uses identified in the recommendation. If, indeed, it is not possible to satisfy the criteria in the recommendation, the committee’s view is that heritable genome editing would not be permissible. The committee calls for continued public engagement and input while the basic science evolves and regulatory safeguards are developed to satisfy the criteria set forth here.
Heritable genome editing also raises concerns about premature or unproven uses of the technology, and it is possible that the criteria outlined here for responsible oversight would be achievable in some but not all jurisdictions. This possibility raises the concern that “regulatory havens” could emerge that would tempt providers or consumers to travel to jurisdictions with more lenient or nonexistent regulations to undergo the restricted procedures. The phenomenon of medical tourism, which encompasses the search for faster and cheaper therapeutic options, as well as newer or less regulated interventions, will be impossible to control completely if the technical capabilities exist in more permissive jurisdictions. Thus, it is important to highlight the need for comprehensive regulation.
As of late 2015, the United States is unable to consider whether to begin heritable genome-editing trials, regardless of whether the criteria laid out above could be met. A provision (in effect until at least April 2017)
was passed in a congressional budget bill,1 in which Congress included the following language:
None of the funds made available by this Act may be used to notify a sponsor or otherwise acknowledge receipt of a submission for an exemption for investigational use of a drug or biological product under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) or section 351(a)(3) of the Public Health Service Act (42 U.S.C. 262(a)(3)) in research in which a human embryo is intentionally created or modified to include a heritable genetic modification. Any such submission shall be deemed to have not been received by the Secretary, and the exemption may not go into effect.
The current effect of this provision is to make it impossible for U.S. authorities to review proposals for clinical trials of heritable genome editing, and therefore to drive development of this technology to other jurisdictions, some regulated and others not.
Genome Editing for Purposes Other Than Treating or Preventing Disease or Disability
Both the ongoing development of therapeutic uses of somatic genome editing, and possible future development of therapeutic uses of heritable genome editing, raise the issue of defining disease and disability, and the question of how and where to set appropriate boundaries for treatment and prevention of these conditions. Like other technologies, human genome-editing methods may be applied for a wide range of purposes, including to enhance human capacities beyond the normal range. It is difficult to define the concept of enhancement. The lines between what are considered therapy, prevention, and enhancement are not rigid or easily discernible in all cases, and even the definition of what is considered a disease can be open to debate. For this reason, distinguishing between treating or preventing disease and disability on the one hand, and a notion of enhancement on the other, is challenging. Possible uses of genome editing thus fall along a continuum of acceptability. Addressing serious genetic disorders by converting causative genetic variants to nondeleterious variants generally falls at the most acceptable end of this spectrum, while editing to produce enhancements unrelated to disease typically falls at the least acceptable end. The report draws a distinction between genome editing for the purpose of treating or preventing disease or disability and for other purposes, without
1 Consolidated Appropriations Act of 2016, HR 2029, 114 Cong., 1st sess. (January 6, 2015) (https://www.congress.gov/114/bills/hr2029/BILLS-114hr2029enr.pdf [accessed January 4, 2017]).
concluding that there is, as yet, any general consensus as to how to define the blurry boundaries of enhancement more clearly.
Editing to create a genetic enhancement could, in principle, be undertaken in the context of somatic cell or heritable editing. As with other potential applications of genome editing, individual risks and benefits would be associated with the assessment of such editing. But the possibility of genetic enhancement raises a number of additional ethical and social concerns for which easy answers are not available, and differences of opinion are likely.
Conclusions and Recommendations:
Genome Editing for Purposes Other Than Treatment or Prevention of Disease
Significant scientific progress will be necessary before any genome-editing intervention for indications other than the treatment or prevention of disease or disability can satisfy the risk/benefit standards for initiating a clinical trial. This conclusion holds for both somatic and heritable genome-editing interventions. There is significant public discomfort with the use of genome editing for so-called enhancement of human traits and capacities beyond those typical of adequate health. Therefore, a robust public discussion is needed concerning the values to be placed upon the individual and societal benefits and risks of genome editing for purposes other than treatment or prevention of disease or disability. These discussions would include consideration of the potential for introducing or exacerbating societal inequities, so that these values can be incorporated as appropriate into the risk/benefit assessments that will precede any decision about whether to authorize clinical trials.
RECOMMENDATION 6-1. Regulatory agencies should not at this time authorize clinical trials of somatic or germline genome editing for purposes other than treatment or prevention of disease or disability.
RECOMMENDATION 6-2. Government bodies should encourage public discussion and policy debate regarding governance of somatic human genome editing for purposes other than treatment or prevention of disease or disability.
The Role of Public Engagement in Governance of Human Genome Editing
Efforts to advance human medicine through genome editing will be strengthened by public engagement, and this engagement will be particularly critical for the potential uses that are not captured effectively by current regulatory frameworks. In the United States in particular, 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. Other countries have systems that more explicitly account for public attitudes in deciding whether and how to permit new technologies to be developed, with widely varying degrees of legal constraint on governmental authority.
Conclusions and Recommendations: Public Engagement
Efforts to advance human medicine through genome editing will be strengthened by public engagement informed by technical experts and by social scientists who undertake systematic public opinion research, develop appropriate communication materials, and minimize artificial biases or constraints that would hinder discussion and debate.
Existing public communication and engagement infrastructures in the United States are sufficient to address oversight of basic science and laboratory research on human genome editing. Similarly, mechanisms for public communication and consultation that are part of the current U.S. regulatory infrastructures are also available to address public communication around development of human somatic cell genome editing.
Weighing the technical and societal benefits and risks of applications of future uses of heritable genome editing will require more formalized efforts to solicit broad public input and encourage public debate than are currently in place. Furthermore, the complex issues surrounding enhancement will require an ongoing public debate to inform regulators and policy makers about the individual and societal values to be placed on the benefits and risks before clinical trials for such enhancement interventions could be authorized.
The practices and principles developed for effective and inclusive public engagement in other emerging areas of science and technology provide a valuable base to inform public engagement on genome editing.
RECOMMENDATION 7-1. Extensive and inclusive public participation should precede clinical trials for any extension of human genome editing beyond treatment or prevention of disease or disability.
RECOMMENDATION 7-2. Ongoing reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public, should precede consideration of any clinical trials of heritable germline genome editing.
RECOMMENDATION 7-3. Public participation should be incorporated into the policy-making process for human genome editing and should include ongoing monitoring of public attitudes, informational deficits, and emerging concerns about issues surrounding “enhancement.”
RECOMMENDATION 7-4. When funding human genome-editing research, federal agencies should consider including funding to support near-term research and strategies for
- identifying areas that require systematic and early efforts to solicit public participation,
- developing the necessary content and communicating it effectively, and
- improving public engagement within the context of existing infrastructure.
RECOMMENDATION 7-5. When funding human genome-editing research, federal agencies should consider including funding for research aimed at
- understanding the sociopolitical, ethical, and legal aspects of editing the human germline;
- understanding the sociopolitical, ethical, and legal aspects of uses for genome editing that go beyond treatment or prevention of disease or disability; and
- evaluating the efficacy of efforts to build public communication and engagement on these issues into regulatory or policy-making infrastructures.