Commite. Ethics of Human Genome

ME70CH20_Coller ARI 22 December 2018 8:47
Annual Review of Medicine
Ethics of Human Genome

Editing
Barry S. Coller
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Allen and Frances Adler Laboratory of Blood and Vascular Biology, Rockefeller
Annu. Rev. Med. 2019.70:289-305. Downloaded from www.annualreviews.org
University, New York, NY 10065, USA; email: [email protected]
Annu. Rev. Med. 2019. 70:289–305 Keywords

The Annual Review of Medicine is online at human genome editing, germline (heritable) human genome editing,
med.annualreviews.org
somatic (nonheritable) human genome editing, disability, genetic, mutation
https://doi.org/10.1146/annurev-med-112717-
094629 Abstract
Copyright c 2019 by Annual Reviews. Advances in human genome editing, in particular the development of
All rights reserved
the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9
method, have led to increasing concerns about the ethics of editing the
human genome. In response, the US National Academy of Sciences and
the National Academy of Medicine constituted a multidisciplinary, interna-
tional committee to review the current status and make recommendations.
I was a member of that committee, and the core of this review reflects the
committee’s conclusions. The committee’s report, issued in February 2017,
recommends the application of current ethical and regulatory standards for
gene therapy to somatic (nonheritable) human genome editing. It also rec-
ommends allowing experimental germline genome editing to proceed if
(a) it is restricted to preventing transmission of a serious disease or con-
dition, (b) the edit is a modification to a common DNA sequence known
not to be associated with disease, and (c) the research is conducted un-
der a stringent set of ethical and regulatory requirements. Crossing the
so-called red line of germline genome editing raises important bioethical
issues, most importantly, serious concern about the potential negative im-
pact on individuals with disabilities. This review highlights some of the ma-
jor ethical considerations in human genome editing in light of the report’s
recommendations.
289
INTRODUCTION
Ethical considerations and concerns about altering human DNA extend back at least 48 years,
when, at the beginning of the revolution in molecular biology, Bernard Davis raised the prospect
of “modifying the pattern of genes of a human being” (1, p. 1279). Since then, an enormous
amount has been written on this topic from a wide breadth of viewpoints, including bioethics,
religion, anthropology, philosophy (utilitarian and deontologic), law, sociology, and medicine (1–
12). This body of commentary has been complemented by numerous attempts to sample public
opinion, including the views of the general public and of individuals with specialized scientific and
medical knowledge (13, 14).
Precedents abound regarding general acceptance of modifying a single person’s nonheritable
(somatic) DNA in order to achieve a definable medical benefit with a favorable benefit-to-risk ratio.
These include transplanting a solid organ from another individual and replacing an individual’s
bone marrow with donor cells, both of which involve a recipient whose cells contain a different
DNA sequence, as well as the addition of genes containing a DNA sequence different from that
of the recipient in gene therapy to treat serious medical disorders. Robust ethical safeguards and
regulatory policies have been developed to ensure that these procedures are conducted in accord
with societal values, including nation-specific variations to accommodate different cultural and
religious views (4, 15–19).
In contrast, the ethics of heritable (germline) gene modification lacks societal consensus and
thus has been contentious, with some countries outlawing it under any circumstances and others
placing barriers of varying heights. For example, 29 countries have signed and ratified the Euro-
pean Oviedo Convention (https://www.coe.int/en/web/bioethics/oviedo-convention), which
specifically outlaws heritable genome editing (20, 21). In the United States, the Food and Drug
Administration (FDA) requires an Investigational New Drug (IND) exemption for clinical trials
involving transfer and gestation of a DNA-edited embryo in accord with Title 21 of the Code of
Federal Regulations, Part 313 (21 CFR Part 312). The Research Technology Subcommittee of
the US House of Representatives Committee on Science, Space, and Technology held a hearing
on this topic in June 2015 (22). Subsequently, Congress passed an omnibus spending bill that
explicitly prevented the FDA from using any of its resources to consider an IND application
involving germline DNA modification (23). As a result, while not illegal in the United States,
germline editing cannot proceed at present. Independently, National Institutes of Health (NIH)
Director Francis Collins decided in 2015 that the NIH would not fund any use of gene-editing
technologies in human embryos, thus reflecting the intent of the congressional Dickey-Wicker
Amendment (H.R. 2880, Section 128) and the policies of the NIH Recombinant DNA Advisory
Committee (24). In summarizing the subject, Dr. Collins, who had previously expressed concerns
about human enhancement to the President’s Council on Bioethics in 2002 (25), noted that in
addition to problems with informed consent, the “concept of altering the human germline in
embryos for clinical purposes has been debated over many years from many different perspectives,
and has been viewed almost universally as a line that should not be crossed.”
Dramatic technical advances in genome modification, particularly the introduction of the
CRISPR/Cas9 method (26, 27), created a sense of heightened urgency in developing regulatory
and ethical guidelines to address both somatic and germline genome editing. The nucleating event
was the first report of modifying the DNA of a nonviable human embryo using CRISPR/Cas9
by Chinese scientists in 2015 (28). Soon thereafter, in December 2015, an international group
of scientific leaders in the field joined with the Chinese Academy of Sciences and the United
Kingdom Royal Society to sponsor a summit at the US National Academies of Science (29). That
meeting culminated in a joint statement that included the following: “It would be irresponsible to
290 Coller
proceed with any clinical use of germline editing unless and until the relevant safety and efficacy
issues have been resolved . . . and there is broad societal consensus about the appropriateness of the
proposed application” (30). The statement also highlighted the need for appropriate regulatory
oversight.
In parallel, the US National Academy of Sciences (NAS) and the National Academy of Medicine
(NAM) cosponsored the creation of an international committee composed of individuals from
diverse disciplines to review the current state of the field and make recommendations about
policies and procedures governing human genome editing. The committee issued its report in
February 2017 (31). The author of this review was a member of that committee, and the core of
this review reflects the conclusions of the committee’s report (32).
OVERARCHING PRINCIPLES
As a subset of human subjects research, human genome editing performed anywhere in the world
should conform to international conventions and norms for protecting human rights as they relate
to human experimentation. This is of particular importance in human genome editing because
differences in cultural and religious values and priorities essentially foreclose the possibility of
gaining international agreement on a single set of rules and regulations. If, however, rules and
regulations are widely divergent from country to country with regard to regulatory oversight and
conformity to international bioethical standards, both scientists and patients may choose to migrate
to countries with less stringent regulations or ethical standards. To address these challenges, the
NAS/NAM committee report builds on a long tradition in developing international standards of
behavior, including the 1948 Universal Declaration of Human Rights by the United Nations (33)
and the 1979 Belmont Report by the US National Commission for the Protection of Human
Subjects in Biomedical and Behavioral Research (34). The report proposed seven overarching
principles: promoting well-being, transparency, due care, responsible science, respect for persons,
fairness, and transnational cooperation. These have all been extensively analyzed in the bioethical
literature and so are not further discussed in this review.
NONHERITABLE (SOMATIC) HUMAN GENOME EDITING

The bioethical and regulatory framework developed for gene therapy (which involves adding
genetic information to a person’s cells) in many countries is largely applicable to nonheritable
human genome editing. In the United States, this framework includes review by an Institutional
Review Board, the FDA via an IND, and, under certain circumstances, the Recombinant DNA
Advisory Committee (17–19, 35). The central issues are the likely benefit-to-risk ratio and potential
alternative therapies (36). In addition, when the gene therapy procedure involves novel aspects,
the FDA requires long-term follow-up observations extending out as far as 15 years to mitigate
potential risks (17, 31). Agreement to such long-term follow-up is included in the informed consent
document signed by the participant, but of course participants are free to withdraw from the study
at any time. The FDA approved the first human gene therapy product in 2017 to treat Leber’s
hereditary blindness (37).
Even after FDA approval, postmarket requirements of approved gene therapy and genome
editing products are likely to be rigorous, including documentation of the proficiency of physicians
in the proper use of the technology and entry of data into patient registries. The potential for
less-well-regulated off-label uses of these products is of considerable concern, especially uses other
than treating or preventing a serious illness. However, the specificity of the approved product may
www.annualreviews.org • Ethics of Human Genome Editing 291

limit the risks (31). Special requirements are in place to insure that gene therapy products do
not inadvertently integrate into germline DNA (16), and these requirements will also likely be
applicable to nonheritable human genome editing studies.
The current jurisdictional uncertainty about the FDA’s authority to regulate some stem cell
therapies, especially when cells are taken from a person, altered, and returned to the same person,
is a potential vulnerability if extended to nonheritable human genome editing (31). Consequently,
the FDA’s authority and its willingness to enforce its authority in human genome editing are issues
highlighted by the NAS/NAM report.
Editing of somatic cells of fetuses in utero may be medically justified when a disease has
early onset and irreversible effects. Moreover, the plasticity of fetal cells may provide important
scientific benefits when genome editing is performed in utero (38). Such use would, however, raise
the ethical issue of being unable to obtain consent from the fetus. Under NIH guidelines (45 CFR
Part 46, Subpart B), fetal research must hold the prospect of direct benefit to the fetus, and both
maternal and paternal (if available) consent is required. For comparison, in some cases of fetal
surgery, or when maternal health is involved, maternal consent is sufficient. Editing the cells of
a fetus in utero may, however, increase the risks of unintended germline editing, especially if the
editing occurs before germ cells are sequestered from somatic cells (31).
In summary, the NAS/NAM report (31) identified a number of diseases that might benefit from
somatic genome editing (see table 4-1, p. 92) and recommended that (a) the current ethical and
regulatory mechanisms for reviewing and approving gene therapy protocols are also appropriate
for somatic gene therapy protocols that involve human genome editing and for somatic genome
editing protocols that do not involve gene therapy, and (b) such protocols should currently be
limited to those that are designed to “treat or prevent disease and disability.” Any expansion of
the use of somatic cell genome editing for other purposes should be based on “inclusive public
policy debates” (31, p. 110).
HERITABLE (GERMLINE) HUMAN GENOME EDITING

Heritable human genome editing has the potential to (a) prevent the transmission of genetic
variants unequivocally known to be associated with a serious illness or condition, (b) lessen the
likelihood of developing a serious illness or condition, and (c) enhance a human’s function beyond
typical human capabilities.
In the first category, when preimplantation genetic diagnosis is not applicable (39), a couple may
face the difficult choice of either not having biologically related children or knowing unequivocally
that they will pass along a genetic variant responsible for a disorder such as sickle cell disease or
Huntington disease. Germline genome editing thus has the potential to give this couple another
option. The second category applies to couples who are predicted to pass along a genetic variant
that would substantially increase the risk of a disease, such as BRCA1 variants associated with
an increased risk of developing breast cancer. The second category also potentially encompasses
population-based public health efforts to reduce the risks of future diseases or disabilities. For
example, inactivation of a particular gene, which can be readily accomplished with CRISPR/Cas9,
can lower cholesterol levels (40), blood pressure (41), or the likelihood that an individual will
be infected by HIV (42). The third category of germline genome edits includes those designed
to enhance human function, for example, increasing muscle mass to increase strength (43, 44).
Table 1 contains a partial list of the various objections that have been raised to performing
germline genome editing, divided into those that are relevant to all three categories of potential
applications and those that are only relevant to applications other than preventing the transmission
of a variant known to be associated with a serious illness or condition.
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Table 1 Concerns about heritable (germline) human genome editing

Concerns specific to applications other than
preventing transmission of genetic variants known
Concerns common to all applications to be associated with serious illness or disability
Disrespect of DNA as human heritage Commodification of children
Challenging God’s role in creation Creation of social pressure to modify children to
Lack of informed consent by the child and maintain a level playing field with children modified
future generations affected by the editing by other parents
Negative impact on individuals with disabilities Exacerbation of social inequality based on access to the
related to genetic variants technology
Perceptions of parental negligence for deciding Unknown and unpredictable risks of creating novel
against performing genome editing genome modifications
Potential to create harm that will extend to multiple

generations
Potential for state-imposed eugenic applications
Potential for criminal applications
OBJECTIONS COMMON TO ALL FORMS OF HUMAN GERMLINE

GENOME EDITING
Disrespect of Human DNA as a Human Heritage

The idea has been advanced that humans have an obligation to preserve and protect human
DNA from any alteration because it reflects our uniquely human collective heritage (45), perhaps
analogous to our obligation to protect other common goods, like public lands, as heritages. In
assessing this objection, it is important to appreciate the intrinsic dynamism of human DNA.
The overall intergenerational mutation rate of human DNA, that is, the frequency with which a
germline DNA base is different in a child relative to a parent, is approximately 12 times per billion
(46). This is a net rate that reflects both inaccurate replication and nonreplicative DNA alterations,
for example, from exposure to a toxic chemical or spontaneous deamination of 5-methylcytosine
at CpG sites (47), as well as the effectiveness of the cell’s elaborate mechanisms to repair DNA
that has not been accurately replicated. Since humans have approximately three billion base pairs
in their genome, it is likely that every time a cell divides, the new cell’s DNA differs in sequence
from that of the parent cell.
While our medical orientation predisposes us to consider DNA mutations as threats to health,
from the standpoint of evolutionary biology, it is vital for humans to have mutable DNA so that
our species can improve its fitness to survive in the current environment or adapt to changing
environments. Indeed, from this perspective, mutations are not errors or a reflection of the infi-
delity of the replicating molecular machinery but rather an intrinsic and important aspect of our
species’ evolutionary success. The mutation rate is perhaps better characterized as an exploration
rate than as an error rate. As Lewis Thomas wrote (48, p. 23), “The capacity to blunder slightly is
the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and
there would be no music.”
If we consider our DNA a human heritage, modifying a variant associated with a serious illness
or condition to a sequence that is present in many other individuals in the same group and is
not associated with a disease or disability (that is, a reference sequence) would not introduce
a novel DNA sequence, and thus would not alter humankind’s DNA. It is not clear whether
individuals who express concern about DNA as heritage view disease-associated variants as part
of that heritage. If they do, then any modification would trigger this objection.

Challenging God’s Role in Creation

The NAS/NAM committee heard presentations from a broad range of religious leaders who
provided diverse views about human germline genome editing (31). Since one possible method
of germline genome editing involves editing an embryo’s DNA prior to implantation, and since
this would almost certainly result in some embryos not being implanted, religions that reject all
research or artificial reproductive methods that may result in the nonimplantation or destruction
of an embryo oppose such germline genome editing. It is possible, however, that in the future
human germline genome editing may be performed on human gametes produced by in vitro
gametogenesis from induced pluripotent stem cells derived from human somatic cells, such as
those from the skin (48–51). In fact, this approach may be preferable from both a scientific and
a regulatory standpoint because editing of the cells in an embryo may result in only some of the
embryo’s cells being successfully edited (mosaicism), and it is difficult or impossible to be sure
that all of the cells in the embryo are successfully edited (52). In contrast, editing sperm precursor
cells in vitro, followed by in vitro expansion, allows for the testing of large numbers of sperm
precursors after editing and affords a more robust assessment of the success of the edit. Gamete
precursor editing has already been successfully performed in mice, but many obstacles remain in
translating this technology to humans (48–51). If these are overcome, however, it could obviate
the religious objections related to embryo destruction.
The mainstream western Judeo-Christian tradition recognizes the legitimacy and importance
of medical interventions to protect human health based on the belief that humans are made in God’s
image and therefore humans have an obligation to protect God’s creation. Similarly, religions in
this tradition tend to emphasize the importance of having children, in some cases even making it
an obligation (53–56). Thus, with the exception of those religions that oppose embryo editing or
in vitro fertilization, they are unlikely to oppose human germline genome editing performed to
prevent the transmission of a serious disease or disability, especially when the disability results in
infertility.
Religious concerns are likely to be much more intense if human germline genome editing is
used to enhance human performance or even reduce the risk of developing a disease by making
novel changes in the DNA sequence. Polls of public opinion on genome editing have repeatedly
identified a substantial percentage of people who express serious concern about such edits (13, 14,
57). For example, a Pew Research Center poll of US adults in 2016 found that 46% of individuals
felt that genome editing to give babies a much-reduced disease risk “crosses a line, is meddling with
nature,” and an even higher percentage of religious respondents expressed this view (13, 14, 57).
Lack of Informed Consent by the Child and Future Generations

Affected by the Edits
Informed consent by the individual agreeing to participate in a research study is the cornerstone
principle of human experimentation, since that individual has to accept the potential risks in order
to have the opportunity to enjoy the potential benefits (58). This principle cannot be fully met
when the research participant is a child below the age of decision-making capacity. In the United
States, the decision is left to one or preferably both parents, and added safeguards are introduced.
These include the requirement for a chance of direct benefit to the child from participating if the
research involves more than minimal risk and, with few exceptions, obtaining the child’s assent
to participate if the child is old enough to have an understanding of the procedures involved (21
CFR 46, Subpart D). When the research involves a fetus, assent is not possible, and there is a
requirement to try to obtain consent from both parents (45 CFR 46, Subpart B).
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Heritable human genome editing has similarities to fetal research, but it differs in that there
is a potential for all future generations of the offspring of the individual whose genome is edited
to be affected by the edit, without their consent or the consent of their parents. Once again, if
the edit is performed to prevent the transmission of a serious disease or disability by changing a
DNA sequence to one known to be common and not associated with a disease, the concern may
be mitigated. However, it is not eliminated, since this is striking new bioethical grounds without
precedent. These concerns are likely to be more intense if the goal is to enhance human capabilities
and/or introduce novel DNA sequences. Thus, there is an immediate need to develop an ethical
framework, policies, and procedures for multigenerational consent for experimental procedures
that may alter germline DNA.
Negative Impact on Individuals with Disabilities Related to Genetic Variants

Historically, individuals with genetic disorders that produce phenotypes identifiable as abnormal
by the general public have been stigmatized, bullied, discriminated against, and even physically as-
saulted. Such treatment can have a serious psychological impact on individuals with the disorders,
especially children, arousing feelings of insecurity and anxiety about self-image and self-worth
that often lead to social isolation. Great advances have been made in the United States in coun-
tering the stigmatization and unfair treatment of individuals with genetic disorders, including the
passage of the Americans with Disabilities Act in 1990 and the growth of both disease-specific pa-
tient advocacy groups and umbrella organizations representing large numbers of patient advocacy
groups (59, 60). Advocates for individuals with these disorders also have changed the fundamental
discourse on disabilities, with some members of the deaf community, for example, contending that
deafness is not a disability but rather a manifestation of human diversity and that it is important
to protect and preserve the deaf community’s culture. This view is manifested by documented
examples of couples’ use of preimplantation genetic diagnosis to insure that they had a deaf child
to carry on the culture (61). It is thus vital to develop and sustain a dialogue between healthcare
professionals and advocates for individuals with disabilities, especially since studies indicate that
healthcare professionals tend to overestimate the impact of some disabilities on life satisfaction of
children and their families (62).
Public accommodations and public education have dramatically improved conditions for in-
dividuals with genetic disorders that compromise ordinary function, both in schools and in the
workplace (63, 64). Nonetheless, residual stigmatization remains, and given people’s innate fear of
those who are different from themselves, the advances are fragile. Thus, the emphasis that human
genome editing places on “correcting” mutations has the potential for the unintended conse-
quence of stigmatizing and marginalizing individuals with genetic disorders. It is vital, therefore,
to redouble our efforts to protect against such stigmatization.
One place to start is with careful attention to the language used to describe human genome
editing. The word “editing” itself is value laden, implying correction or improvement in a text,
whereas a dispassionate analysis of the science is much more nuanced. For example, the prevalence
of the gene for hemoglobin S is considerably higher in regions of the world where malaria is en-
demic because heterozygosity for hemoglobin S and hemoglobin A confers protection from death
from malaria, although homozygosity for hemoglobin S dramatically reduces life span without
modern therapy (65, 66). Thus, in a region where malaria is prevalent, making the single DNA
base pair conversion from hemoglobin S to hemoglobin A in a heterozygous person would not be
“correcting” a mutation; rather, it would be eliminating a potentially important genetic adaptation.
Whenever possible, therefore, it is important to consider the impact of language on those with
genetic disorders and select terms that are as value free as possible. In our hemoglobin example,

modifying the single base pair from encoding hemoglobin S to encoding hemoglobin A could be
termed “converting to a reference sequence.” The word “mutation” itself, while value free when
used in scientific writing, has a negative connotation for much of the lay public. Use of the term
“variant,” which has much less of a negative connotation, coupled with education to inform the
public that all human beings have some genetic variants relative to even group-specific reference
sequences as part of human evolution, may provide a more appropriate and supportive context for
avoiding stigmatization of individuals with genetic disorders.
Perceptions of Parental Negligence for Deciding Against Performing

Genome Editing
Once heritable genome editing becomes available, parents who choose not to have their progeny
undergo the procedure may be viewed as being negligent for failing to perform the editing if they
have a child with a genetic disorder (67). This may have serious social and psychological effects
and may even have legal implications.
OBJECTIONS SPECIFIC FOR APPLICATIONS OTHER THAN

PREVENTING TRANSMISSION OF GENETIC VARIANTS KNOWN
TO BE ASSOCIATED WITH A SERIOUS DISEASE OR CONDITION
Traditional bioethical formulations of genome modification have separated interventions designed
to treat an illness from those designed to enhance human function, placing these along one axis,
and separated somatic (nonheritable) from germline (heritable) modifications on the other axis
(Figure 1a) (67–68b). The binary division into treatment versus enhancement, however, omits
the application of genome editing for the prevention of illness via risk reduction. In fact, the iden-
tification of risk factors for disease, many of which are under genetic control, and the design of
interventions to lower those risks have been major contributors to improved human life expectancy
over the past half century, with better control of hypertension and hypercholesterolemia being two
vivid examples (69, 70). Moreover, as associations between genetic variants and disease risk have
been identified, measures to prevent the development of the disease despite the genetic predispo-
sition have been devised, such as prophylactic bilateral mastectomy to prevent the development of
breast cancer in women with deleterious BRCA1 variants (71). What distinguishes these preven-
tive efforts from those related to genetic variants with large phenotypic effects and near-complete
penetrance (i.e., Mendelian disorders), such as sickle cell disease and Huntington disease, is that
a Traditional ethical formulation b Modern reality
Somatic Germline
Treatment Somatic therapy Germline therapy Treatment Prevention Enhancement

of disease
Enhancement Somatic Germline

of capabilities enhancement enhancement
Figure 1
Ethical formulations of human genome editing. (a) Traditional ethical formulation (adapted from 67a and 68b with permission) with
treatment/enhancement dichotomy and somatic/germline dichotomy. (b) Modern reality formulation, in which disease prevention
occupies a middle ground, melding at its borders into both treatment and enhancement.
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they operate at a probabilistic (stochastic) level rather than a deterministic level. As a result, it is not
possible to be certain that a given individual at increased risk will actually develop the disorder. At
the population level, however, it is virtually certain that modifying the genomes of a large number
of individuals with the variants would result in a decrease in the incidence of the illness.
Preventing disease by modifying risk-associated variants thus occupies a middle ground be-
tween treatment and enhancement and bleeds into both of those categories (Figure 1b) (68). For
example, based on both the reduced risk of cardiovascular disease in association with reduced
cholesterol levels in individuals heterozygous for inactivating variants in the gene PCSK9 (40)
and the demonstrated risk reduction afforded by drugs that antagonize the enzymatic activity of
PCSK9 (72), I suspect that most people would consider inactivating one PCSK9 gene in a pa-
tient with a history of several heart attacks and elevated cholesterol levels refractory to currently
available drugs a treatment. Performing the same genetic modification in the patient’s younger
brother, who has not yet had a heart attack but has an elevated cholesterol level, would probably be
considered an act of prevention. But what about performing the same intervention on the patient’s
21-year-old healthy son, who does not have an elevated cholesterol level, in order to decrease his
future risk of cardiovascular disease? Is that prevention, enhancement, or both?
Views on Human Enhancement

While as noted, there is a broad consensus supporting the use of nonheritable (somatic) genetic
modifications to treat patients with serious illness, there is nearly universal discomfort about using
genetic modifications for human enhancement, despite the recognition that to some extent genetic
enhancement is an essential feature underlying all of evolution (2, 10, 24, 25). Individuals who
espouse the principles of transhumanism are an exception, contending that humans are obligated
to improve themselves by any means available (73–75).
The psychological anxiety elicited by the concept of enhancement may be rooted in two mutu-
ally conflicting aspects of our evolutionary background, namely, the desire for personal success and
the need for communal cooperation. If one views human evolution exclusively from the standpoint
of the “selfish gene” (76), one will emphasize the importance of individual reproductive success,
which undoubtedly benefits from enhancements in attractiveness and performance, with the latter
translating in our modern world into material success and financial security. It is not surprising,
therefore, that most nongenetic enhancements in society are directly or indirectly connected to
appearance, which translates into attractiveness for preferred mate selection, or to physical or
mental abilities and knowledge that are likely to result in professional success. The strength of
the desire for such enhancements is attested to by the risks individuals are willing to accept (e.g.,
those of cosmetic surgery), as well as the costs (e.g., that of a college education), in exchange for
the perceived benefits. Thus, there is compelling evidence that individuals have a strong desire to
compete with others for success and to stand out from the crowd.
More recently, however, in order to explain the biologic advantages conferred by humans’
large brains and ability to communicate by language, evolutionary biologists have emphasized the
benefits of group cooperation, as for example in communal hunting. Such cooperation requires
conformity to social norms of group cohesion and mechanisms to enforce such norms (77), and
storytelling made possible by human language may play an important role (78). A reasonably fair
distribution of resources is one of the cardinal elements in such group behavior, and so it is of
especial interest that children as young as six years of age are willing to forego receiving candy in
order to prevent others from benefiting from an unfair distribution of candy (79).
The tension between these principles—individual achievement and recognition versus group
cooperative success and social cohesion—is perhaps most dramatically seen in the field of sports.

There is enormous admiration for superior individual athletic performance, coupled with adulation
for the athlete, but this is balanced by admiration for teamwork and team effort. There is near
universal disdain if athletes are self-aggrandizing at the expense of their teammates, or worse yet if it
turns out that the superior performance was aided by performance-enhancing drugs. Individuals
have literally gone from being heroes to heels overnight (80). Thus, while it is impossible to
predict how public opinion will evolve with regard to the application of human genome editing for
enhancement, concerns that some individuals will have an unfair advantage in social and economic
competition is likely to be a central element in public perception. For example, if individuals learn
which children underwent genome editing for enhancement, the children are likely to be viewed
as having an unfair advantage, perhaps eliciting the kind of response generated by athletes who
have surreptitiously used performance-enhancing drugs.
Commodification of Children
Thoughtful critics of heritable human genome editing have noted that if one has the ability to
modify the genes of one’s children, that is, to produce “designer” babies, there is a risk that the
relationship between parents and children will undergo radical changes, with parents expressing
their values, priorities, and aspirations in the genetic makeup of their children. Thus, children
will not be embraced as precious gifts regardless of their genetic makeup, but rather will become
extensions of their parents’ clever ability to design them (12, 81, 82) and “a commodity that is to be
ordered at will” (83). This commodification may have profound implications, including parental
guilt if the design does not turn out well, especially when the children reach an age when they can
question their parents’ choices.
Creation of Social Pressure to Modify Children to Maintain a Level Playing

Field with Children Modified by Other Parents
It seems self-evident that if even a small percentage of parents decide to modify their child’s DNA
to reduce the child’s risk of developing diseases or enhance the child’s functional capabilities, then
other parents will feel pressure to modify their children’s DNA in order to level the playing field
on which they will compete. This can set off a parental genetic “arms race” in which riskier and
riskier edits are attempted.
Exacerbation of Social Inequality

If genome editing is successful in advantaging those who undergo the procedure, by definition it
is likely to result in inequality. Since the wealthy are most likely to gain access to the technology,
the new biologic inequality would be grafted onto the current wealth inequality, which has been
increasing at an alarming rate over the past several decades and threatens social cohesion (84).
Unknown and Unpredictable Risks of Creating Novel Genome Variants

Converting a variant known to be associated with a disease or disability to a reference sequence
common in the individual’s genetic group that is known not to be associated with a disease or
disorder is highly unlikely to have unanticipated effects. However, DNA edits that create novel
DNA sequences that have not previously been identified in humans will necessarily confer a risk of
unforeseen and unintended consequences. Such sequences are likely to be introduced when editing
by CRISPR/Cas9 or similar technology is used to inactivate a gene, as is currently commonly
performed in animals, since the procedure relies on the double-strand break being repaired by
298 Coller
nonhomologous end joining, which introduces unpredictable sequences that may disrupt the
normal transcription and/or translation of the gene (85). This concern would also extend to any
off-target effects of genome editing, which involve making double-strand breaks in the DNA at sites
other than the intended site of editing. It also extends to the undesirable production of long DNA
deletions and complex DNA rearrangements from on-site breaks that may alter gene function or
expression (86). While remarkable advances have been made in improving the specificity of the
editing techniques and in identifying off-target effects since the technology was first developed
(87), it may not be possible to achieve certainty. An off-target edit in an unexpected gene thus
may have important consequences. The history of the unpredicted and unexpected insertional
mutagenesis leading to hematopoietic malignancies associated with the vectors used in early gene
therapy trials provides a compelling case for scientific and medical humility (88).
Potential for Harm That Will Extend to Multiple Generations

If a heritable gene edit does harm, there is the potential for that harm to extend beyond the initial
individual to their progeny. This would complicate family planning and might lead to a decision
not to have children or undergo assisted reproduction in combination with preimplantation genetic
diagnosis, with their associated risks and costs, to prevent transmission of the harmful DNA edit.
In cases where preimplantation genetic diagnosis would not be able to prevent transmission of
the harmful edit, the individual would have to consider undergoing another editing procedure to
correct the harmful edit.
Potential for State-Imposed Eugenic Applications

Totalitarian and democratic regimes have demonstrated their willingness to impose control over
human reproduction for political purposes (89–91). There is real concern, therefore, that if heri-
table human genome editing is able to produce war fighters with enhanced functional capabilities,
whether physical or mental (as for cyber warfare or disinformation campaigns), it will unleash a
genome editing arms race with serious national security consequences. Nonmilitary state-imposed
eugenics is also a potential concern; for example, a state may decide to enhance worker productiv-
ity and reduce healthcare costs by requiring heritable genome editing to reduce blood pressure,
cholesterol levels, and the risk of HIV infection, all of which can be achieved by inactivating
currently known genes.
Potential for Criminal Applications

A 2016 announcement of a new television series in development, starring Jennifer Lopez and titled
C.R.I.S.P.R., stated that each episode will explore a bio-attack and crime related to genome editing.
Story lines include a genetic assassination attempt on the president and the framing of an unborn
child for murder. The villain is a diabolical genius scientist with a “twisted God complex” (92). If
Hollywood can dream up criminal applications, it is not farfetched to think that real criminals can
as well.
NAS/NAM COMMITTEE RECOMMENDATIONS ON HERITABLE

HUMAN GENOME EDITING
The NAS/NAM committee report details the statements by international groups expressing
reservations about considering heritable human genome editing, including the clear legal barrier
created by the European Oviedo Convention (5, 6, 8, 20). Despite these concerns, the report rec-
ommends that clinical trials be permitted to proceed for limited purposes under strict controls. The

NAS/NAM report (31) recommends that clinical trials using heritable genome editing be permit-
ted only within a robust and effective regulatory framework that includes the following conditions:
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 ben-
efits 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 follow-up 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.
In making this recommendation, the committee emphasized the complexity of balancing
individual-level benefits and societal-level risks. On one side, the report acknowledges the de-
sire of a couple to use the technology to have an unaffected biologically related child who would
have a level playing field on which to compete against other children; on the other side, it ac-
knowledges potential societal harms, which may include those detailed above, as well as concern
that the desire for a biologically related child involves an outdated notion of kinship in an era
when adoption, same-sex marriage, donor gametes, surrogacy, and step-parenting are increasing
(93). We currently have limited ethical frameworks and mechanisms for balancing benefits that
accrue primarily to individuals against what some perceive as societal harms, as attested to by
the ongoing intense debate about abortion. In the realm of human experimentation, it is unclear
how much latitude Institutional Review Boards have in adjudicating group cultural risks of re-
search beyond the direct risks to individuals, and there are few precedents and little experience in
weighing such complex factors (94). From a US legal standpoint, if the state decides to restrict a
person’s freedom to choose an activity, it needs to present at least a rational basis for its action if
ordinary liberties are restricted, but it needs a much more compelling justification if it denies or
closely regulates fundamental liberties, especially those enumerated in the Bill of Rights (31). The
procreative rights of parents fall within a disputed area between these categories, often receiving
a form of intermediate scrutiny, and so it is uncertain how courts may rule if parents challenge
state restrictions on their perceived right to utilize heritable genome editing (95). As noted above,
there is a theoretical possibility that parents may be considered legally negligent if they have an
affected child with a genetic disorder that might have been avoided by genome editing.
Perhaps most important, from a policy standpoint, is the serious concern that genome editing
will diminish support for laws protecting individuals with disabilities. In this regard, it is comforting
that the same era that has seen improved genetic screening and preimplantation genetic diagnosis
has also seen strong support for laws protecting individuals with disabilities. It is notable, therefore,
that even within the disability community, people hold widely varying views of the benefits and
risks of genome editing technology (96–98).
Finally, some individuals oppose performing any heritable human genome editing, even when
they do not oppose its use to prevent transmission of a serious disease or condition, because they
300 Coller
fear a “slippery slope” in which its permitted use for a desirable purpose will one day expand to
include its use for undesirable purposes, most notably enhancement (52). Similar arguments were
advanced to challenge the introduction of in vitro fertilization and preimplantation genetic diag-
nosis, but in fact, neither technique expanded into the disconcerting realms predicted. Whether
heritable human genome editing will follow these precedents or slide down a slippery slope is
currently unknowable.
CONCLUSION
The NAS/NAM report supports crossing what has been a bright red line by recommending that
clinical trials of heritable human genome editing be allowed. However, by restricting its use to
preventing a serious disease or condition, limiting the editing procedure to prevent the creation
of novel DNA sequences, and requiring a robust bioethical and regulatory framework, the report
focuses the technology on the goal of having healthy babies, not designer babies. Public reaction
to the report has been generally favorable, and its publication has triggered multiple proposals to
widen the opportunities for broad, ongoing societal input (99, 100). An excerpt from an editorial
in the Washington Post soon after the publication (101) provides one eloquent example.
A line would have to be drawn between heritable changes that are clearly valuable and those that risk
unnecessarily humiliating people, destabilizing society and changing the nature of humanity. The panel
attempted to draw a preliminary line—and put it in the right place . . . . The debate will not—and should
not—end there. But before society has a full chance to process these questions, the panel’s approach is
the right one. The goal should be to stop crippling diseases, not to build designer babies.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
I thank Harriet Rabb, Dr. Eli Adashi, and Zachary Shapiro for valuable comments. This work was
supported in part by grant UL1 TR001866 from the National Center for Advancing Translational
Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award
(CTSA) program.
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Annual Review of
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Contents Volume 70, 2019
Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward

Personalized Management
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Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of
Atrial Fibrillation
Alexander C. Fanaroff and E. Magnus Ohman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p61
Molecular Diagnostics for Mycobacterium tuberculosis Infection
Kristen V. Dicks and Jason E. Stout p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
Structure-Based Vaccine Antigen Design
Barney S. Graham, Morgan S.A. Gilman, and Jason S. McLellan p p p p p p p p p p p p p p p p p p p p p p p91
The Global Landscape of Tuberculosis Therapeutics
Jeffrey A. Tornheim and Kelly E. Dooley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Zika Virus Vaccine Development: Progress in the Face of New
Challenges
Michael S. Diamond, Julie E. Ledgerwood, and Theodore C. Pierson p p p p p p p p p p p p p p p p p p p p 121
Long-Acting HIV Drugs for Treatment and Prevention
Roy M. Gulick and Charles Flexner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 137
DNA Methylation and Susceptibility to Autism Spectrum Disorder
Martine W. Tremblay and Yong-hui Jiang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 151
Metformin for Treatment of Fragile X Syndrome and Other
Neurological Disorders
Ilse Gantois, Jelena Popic, Arkady Khoutorsky, and Nahum Sonenberg p p p p p p p p p p p p p p p p p 167
v
Postpartum Depression: Pathophysiology, Treatment,

and Emerging Therapeutics
Donna E. Stewart and Simone N. Vigod p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 183
Cystic Fibrosis: Emerging Understanding and Therapies
Michael M. Rey, Michael P. Bonk, and Denis Hadjiliadis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 197
Progress in Understanding and Treating Idiopathic Pulmonary
Fibrosis
Jonathan A. Kropski and Timothy S. Blackwell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 211
Current Status of Living Donor Liver Transplantation
in the United States
Samir Abu-Gazala and Kim M. Olthoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225

CRISPR Correction of Duchenne Muscular Dystrophy

Yi-Li Min, Rhonda Bassel-Duby, and Eric N. Olson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 239
Emerging Genetic Therapy for Sickle Cell Disease
Stuart H. Orkin and Daniel E. Bauer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 257
Entering the Modern Era of Gene Therapy
Xavier M. Anguela and Katherine A. High p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 273
Ethics of Human Genome Editing
Barry S. Coller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 289
Therapeutic Antisense Oligonucleotides Are Coming of Age
C. Frank Bennett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Sodium–Glucose Cotransporter–2 (SGLT-2) Inhibitors and the
Treatment of Type 2 Diabetes
Caroline K. Kramer and Bernard Zinman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323
Clinical Application and Potential of Fecal Microbiota Transplantation
R.E. Ooijevaar, E.M. Terveer, H.W. Verspaget, E.J. Kuijper, and J.J. Keller p p p p p p p p p 335
Gastric Cancer Etiology and Management in Asia and the West
Ashley E. Russo and Vivian E. Strong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
Active Surveillance as First-Line Management of Papillary
Microcarcinoma
Yasuhiro Ito and Akira Miyauchi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Expanding Therapeutic Opportunities for Hematopoietic Stem Cell
Transplantation: T Cell Depletion as a Model for the Targeted
Allograft
Christina Cho and Miguel-Angel Perales p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 381
Harnessing Tumor Mutations for Truly Individualized Cancer
Vaccines
vi Contents
Mathias Vormehr, Özlem Türeci, and Ugur Sahin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 395

New Hope for Therapeutic Cancer Vaccines in the Era of Immune
Checkpoint Modulation
Michael A. Curran and Bonnie S. Glisson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409
PD-1 Blockade in Early-Stage Lung Cancer
Samuel Rosner, Joshua E. Reuss, and Patrick M. Forde p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 425
Redirected T Cell Cytotoxicity in Cancer Therapy
John R. Desjarlais and Raphael A. Clynes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 437
Prostate Magnetic Resonance Imaging: Lesion Detection and Local
Staging
Baris Turkbey and Peter L. Choyke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451
Imaging of Prostate-Specific Membrane Antigen with Small-Molecule

PET Radiotracers: From the Bench to Advanced Clinical
Applications
Steven P. Rowe, Michael A. Gorin, and Martin G. Pomper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 461
Treatment of Advanced Prostate Cancer
Min Yuen Teo, Dana E. Rathkopf, and Philip Kantoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479
Abbreviated Magnetic Resonance Imaging (MRI) for Breast Cancer
Screening: Rationale, Concept, and Transfer to Clinical Practice
Christiane K. Kuhl p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 501
New Drugs in Multiple Myeloma
Chutima Kunacheewa and Robert Z. Orlowski p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 521
Indexes
Cumulative Index of Contributing Authors, Volumes 66–70 p p p p p p p p p p p p p p p p p p p p p p p p p p p 549

Cumulative Index of Article Titles, Volumes 66–70 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 553
Errata
An online log of corrections to Annual Review of Medicine articles may be found at

http://www.annualreviews.org/errata/med
Contents vii

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ME70CH20_Coller ARI 22 December 2018 8:47

Annual Review of Medicine

Ethics of Human Genome

University, New York, NY 10065, USA; email: [email protected]

Annu. Rev. Med. 2019. 70:289–305 Keywords

NONHERITABLE (SOMATIC) HUMAN GENOME EDITING

www.annualreviews.org • Ethics of Human Genome Editing 291

HERITABLE (GERMLINE) HUMAN GENOME EDITING

Table 1 Concerns about heritable (germline) human genome editing

Potential to create harm that will extend to multiple

Potential for criminal applications

OBJECTIONS COMMON TO ALL FORMS OF HUMAN GERMLINE

Disrespect of Human DNA as a Human Heritage

www.annualreviews.org • Ethics of Human Genome Editing 293

Challenging God’s Role in Creation

Lack of Informed Consent by the Child and Future Generations

Negative Impact on Individuals with Disabilities Related to Genetic Variants

www.annualreviews.org • Ethics of Human Genome Editing 295

Perceptions of Parental Negligence for Deciding Against Performing

and may even have legal implications.

OBJECTIONS SPECIFIC FOR APPLICATIONS OTHER THAN

a Traditional ethical formulation b Modern reality

Treatment Somatic therapy Germline therapy Treatment Prevention Enhancement

Enhancement Somatic Germline

Views on Human Enhancement

www.annualreviews.org • Ethics of Human Genome Editing 297

Creation of Social Pressure to Modify Children to Maintain a Level Playing

Exacerbation of Social Inequality

Unknown and Unpredictable Risks of Creating Novel Genome Variants

Potential for Harm That Will Extend to Multiple Generations

Potential for State-Imposed Eugenic Applications

Potential for Criminal Applications

NAS/NAM COMMITTEE RECOMMENDATIONS ON HERITABLE

www.annualreviews.org • Ethics of Human Genome Editing 299

maximum transparency consistent with patient privacy;

www.annualreviews.org • Ethics of Human Genome Editing 301

www.annualreviews.org • Ethics of Human Genome Editing 303

www.annualreviews.org • Ethics of Human Genome Editing 305

Contents Volume 70, 2019

Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward

Cynthia A. James and Hugh Calkins p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1

Capitalizing on Insights from Human Genetics to Identify Novel

Postpartum Depression: Pathophysiology, Treatment,

Samir Abu-Gazala and Kim M. Olthoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225

CRISPR Correction of Duchenne Muscular Dystrophy

Mathias Vormehr, Özlem Türeci, and Ugur Sahin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 395

Imaging of Prostate-Specific Membrane Antigen with Small-Molecule

Cumulative Index of Contributing Authors, Volumes 66–70 p p p p p p p p p p p p p p p p p p p p p p p p p p p 549

An online log of corrections to Annual Review of Medicine articles may be found at

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