Annotated bibliography (20 hours)

Centre for Biomedicine, Self and Society; Usher Institute; University of Edinburgh, Old Medical
School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom.

Email: [email protected]

Perspectives in Biology and Medicine, volume 63, number 1 (winter 2020): 111–125.
© 2020 by Johns Hopkins University Press

111

Playing it Safe?

precaution, risk, and responsibility
in human genome editing

Sarah Chan

ABSTRACT Human germline genetic modification has long been a controversial
topic. Until recently it remained largely a hypothetical debate: whether one accepted
or opposed the idea in principle, it was not only too risky but impractical to execute
in reality. With the advent of genome editing technologies, however, heritable modi-
fications to the human genome became a much more concrete possibility; nonetheless,
the consensus has to date remained that human heritable genome editing is not yet safe
enough for clinical application. The announcement of the birth of two genome-ed-
ited babies in late 2018, therefore, was condemned almost universally as premature,
irresponsible, and dangerous. But what does responsibility require, and from whom?
How should risk and precaution be balanced in assessing heritable genome editing, and
against what alternatives? This paper reexamines commonly held assumptions about
risk and responsibility with respect to human genome editing and argues that the pre-
cautionary approach that has so far been favored is not well justified, that the risks of
heritable versus somatic genome editing should be reassessed, and that a fuller account
of responsibility—scientific, social, and global—is required for the ethical governance
of genome editing.

On november 26, 2018, the world awoke to the news that genome edit-ing had for the first time been used to create genetically modified human

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112 Perspectives in Biology and Medicine

beings. He Jiankui, a scientist then employed by Southern University of Science
and Technology of China, Shenzhen, announced via social media and the pop-
ular press that he had performed genome editing on embryos with the aim of
disrupting the CCR5 gene in order to induce immunity to HIV, implanted the
embryos, and that twin girls had been born.

In the wake of this announcement, arguments, claims, and accusations flew.
Most commentators declared He’s actions “irresponsible,” pointing to various
statements by scientific organizations agreeing that human embryo genome edit-
ing was not yet at an appropriate stage for clinical use. Another common criticism
was the lack of transparency surrounding the work, and that He failed to follow
appropriate governance procedures with respect to consent and ethical review.
Many also condemned the experiment on the grounds that the babies had been
exposed to unjustified risk relative to the possible benefits.

This case, then, was almost universally regarded as an unfortunate occurrence.
Nonetheless, in exposing some potential fault lines in our thinking about human
genome editing with respect to risk, harm, and responsibility, it provides a timely
opportunity to reexamine these concepts. He’s actions may have been a failure
of responsibility—but responsibility to whom and for what? What does it mean
to “be responsible,” “act responsibly,” or “take responsibility” with respect to
human genome editing? In addressing these questions, I will argue that in dealing
with human genome editing, the following elements are required: an approach
to risk and responsibility that goes beyond precaution; a more robust conceptu-
alization of scientific responsibility and what it requires; a reconsideration of the
nature and distribution of harms and benefits of genome editing; and attention
to collective social responsibility and its global dimensions with respect to the
development and governance of science.

Precaution and Responsibility in Genome Editing

The generally accepted approach to human heritable genome editing (HGE)
so far has been cautious, if not outright precautionary. A recent review of over
60 statements on the subject found that most “were expressly against heritable
genome editing at the current time” (Brokowski 2018), with both the risk of
known possible harms and uncertainty and the possibility of unforeseen adverse
effects being prominent concerns. Even those that were willing to entertain the
possibility of HGE in principle, notable among them the US National Academies
(2017) and the UK’s Nuffield Council on Bioethics (2018), agreed that it should
not be permitted in practice until issues of risk and safety had been adequately
addressed, and that this was not yet the case. In light of these concerns, it seems
justified to label He’s actions as premature and irresponsible. But what level of
caution in relation to genome editing is appropriate, and is a precautionary ap-
proach warranted?

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Early formulations of the precautionary principle emerged in relation to envi-
ronmental policy. As originally articulated, it was intended to justify taking action
to forestall harm: “Where there are threats of serious or irreversible damage, lack
of scientific certainty shall not be used as a reason for postponing cost-effective
measures to prevent environmental degradation” (UN Conference on Environ-
ment and Development 1992). Subsequent iterations shifted the focus of the
principle to a presumption against doing, by placing the burden of proof on the
would-be doer to demonstrate safety (SEHN1998). This form of the principle, in
which precaution is the opposite of pro-action, is the most common characteriza-
tion in bioethical debate (Glannon 2002; Harris and Holm 2002). In this context,
it also tends to incorporate assumptions about the relative merits of the status quo
or natural, versus a human-engineered state of affairs, “a sense of nature’s ulti-
macy that precedes or supersedes human ingenuity” (Fuller and Lipinska 2014).

The Nuffield Council’s report on human heritable genome editing, in an in-
teresting reversal, entertains a more pro-actionary version of the principle itself.
Considering possible harms that might be averted by genome editing in a situ-
ation where looming environmental catastrophe threatens human survival, they
write that “at minimum [the precautionary principle] permits taking action in
the present even in the absence of clear evidence of the likelihood of a harm that
might occur in the future” (Nuffield Council 2018, 90). Nevertheless, the main
approach to managing risks and uncertainties of heritable human genome editing
can best be described as either that we ought not to proceed until we can be fairly
sure that nothing bad will happen; or that, because we cannot be sure of this, we
ought not to proceed at all, notwithstanding the Nuffield Council’s exception for
a threat to human survival—where, in a sense, all bets are off.

Adopting this sort of precautionary attitude to human genome editing com-
bines (at least) two intertwined claims about responsibility. One is quasi-empiri-
cal, about where the balance of risk lies and what would therefore be a responsible
course of action to take; the other is a moral claim about what our responsibility
would be for the consequences of our choices in various circumstances.

To explain further, the empirical balance-of-risk claim concerns how likely
it is that a change deliberately engineered by humans will produce unintended
deleterious side effects. Existing genetic variation at least has history on its side,
having survived thus far; what therefore are the chances that any change we
make is on-balance more likely to disrupt this and produce negative side-effects?
Advocates of a precautionary approach favor the idea that we ought to give
nature the benefit of the doubt (President’s Council 2003), a claim sometimes
expressed in terms of the “wisdom of nature” (Bostrom and Sandberg 2009).
Powell and Buchanan (2011), in critiquing this claim, call it the Master Engineer
Analogy: the idea that “from an evolutionary perspective, the human organism
is like the product of an engineering genius—a delicately balanced, completed,
well-functioning masterwork” and that therefore attempts to interfere with this,

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114 Perspectives in Biology and Medicine

even if well-intentioned and scientifically-grounded, are likely to be “disastrously
counterproductive” (Powell and Buchanan 2011, 7). This analogy, they argue,
relies on misconceived interpretations of evolutionary theory: we should resist
the presumption that intentional genetic modification is likely to be more dan-
gerous than “unintentional genetic modification”—that is, the process of muta-
tion, inheritance, and selection that occurs whether we like it or not. It may be
that random genetic changes are more likely to be deleterious than beneficial, but
this is not necessarily true of targeted modifications designed with some under-
standing of their likely effects.

Moreover, judgments about risk are not absolute but comparative: whether a
likely consequence is better than or worse than the alternative. Precaution as a
presumption against action assumes that the consequences of doing are probably
going to be worse than not-doing. In the case of genome editing for serious dis-
ease, it is far from evident that this is so.

To Do or Not to Do?

The moral responsibility claim concerns blameworthiness for consequences: spe-
cifically, whether more blame should attach to those consequences we cause via
our action, than those we allow via inaction. Here the precautionary approach
is often expressed in terms of “letting nature take its course.” By analogy with
the “wisdom of nature,” we might call this a “responsibility of nature” claim:
that if something happens as a result of nature, we are not responsible for having
allowed it.

Evaluating risk requires us to consider both how severe a harm would be and
how likely it is to occur. A persistent issue with heritable genome editing is that
we cannot necessarily foresee all possible harms in order to assess their severity
nor their likelihood. This is not, however, by any means a problem unique to
genome editing. We also cannot predict all the possible consequences of mobile
phone use or non-use; of fracking or not-fracking; or of failing to stop climate
change. There will be consequences either way, of a decision to use or not to
use technology; why then should we focus in the case of genome editing on the
possible consequences of doing, more than of not-doing?

The precautionary approach to human genome editing seems to presume that
it would be worse for a harm to occur as the result of our deliberate action,
than for a similar-magnitude harm to occur as the consequences of a deliberate
omission. This, however, seems to conflate causal and moral responsibility. Are
we failing to do what would be most responsible, in order to avoid being held
responsible—that is, held to blame—in the event that something goes wrong?

In moral philosophy, the distinction between acts and omissions has been most
addressed in relation to the ethics of killing versus letting die. Rachels’s (1975)
thought experiment of the evil uncles (one of whom kills his nephew in the

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bath, while the other “merely” but deliberately allows him to drown) attempts to
demonstrate that the same harm brought about by action and by deliberate omis-
sion is morally equivalent. Genome editing, however, is not quite analogous: this
is a case where in acting to attempt to prevent one foreseeable harm, we incur a
risk of causing a different harm. How then should we weigh our responsibility for
allowing versus causing harm in each instance?

Perhaps a more appropriate analogy is a Good Samaritan case, in which one is
presented with an opportunity to render aid to the needy. In such cases, a per-
son who is “not responsible” for the situation, such as a passer-by, is not usually
legally liable for failing to help. A person who “takes responsibility” by choosing
to attempt to help, however, might subsequently be “held responsible” if their
efforts to help somehow go wrong, providing they are sufficiently careless in the
attempt.

The law in general attaches more responsibility to actions than omissions,
a distinction that has led to some convoluted legal reasoning particularly with
respect to end-of-life decisions (Airedale NHS Trust v Bland (1993) 1 All ER
821). Imposing a precautionary, rather than a pro-actionary, approach to human
genome editing, however, would seem to broaden this rather narrow legal ap-
proach to acts versus omissions much more widely in order to draw the same
conclusion about moral responsibility—namely that we should be considered
more blameworthy for harms we cause (even unintentionally) than for those we
deliberately allow.

The acts/omissions distinction certainly has legal relevance, but should it have
moral relevance? Moral philosophy is quicker than law to recognize obligations
of beneficence, such as a “duty of rescue,” where accomplishing the rescue
would not cause undue or disproportionate burden to the rescuer. Moreover,
even within a legalistic frame, consider that in the Good Samaritan example, a
genuine attempt to assist by acting in good faith, with the reasonable belief that
one’s actions would help rather than harm, is unlikely to result in either legal or
moral blame if the attempt miscarries. Our evaluation of what responsible parents
and scientists should do with respect to genome editing, and what they ought to
be held responsible (morally blameworthy) for, ought also to take into account
similar criteria of reasonable belief and intention.

Furthermore, parents are not bystanders: they do have special moral responsi-
bility for their children’s welfare. Given this, a presumption against action seems
unwarranted. As the Nuffield Council (2018) report puts it, “we have to take
responsibility for both acts and conscious omissions: deciding not to use an avail-
able technology and whether to discover knowledge about the genome or to
intervene in it may still count as choices that engage moral responsibility” (73).

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Who Is Responsible?

To summarize so far, responsibility with respect to human genome editing en-
compasses both what it would be responsible to do, and for what consequences
we should be held responsible. These two senses are entwined, in that (1) if we
fail to behave responsibly, it is reasonable to think that (2) we ought to be held
responsible for that failure. But there is one further element needed to connect
these points: namely, (3) our having responsibility (or taking it, or being respon-
sible) for doing the right thing in the first place.

For example, imagine a teenager charged with looking after his younger sib-
lings for the evening; instead of watching them, he goes upstairs to read a book,
falls asleep, and they set the house on fire. Clearly, he has been irresponsible and
should be held to account for any harms that result. (Note also that this is respon-
sibility for an omission, failing to act.) Alternatively, now imagine that his mother
comes home earlier than expected and tells him, “Go upstairs and read; I’ll watch
the kids.” If in this situation he falls asleep reading and, his mother failing to pay
attention, the children burn the house down, it seems that he should not be held
responsible.

One might argue that, despite having been “let off the hook,” it would none-
theless “be responsible” for the teenager to take additional responsibility for en-
suring all is well with his family and to check on them. All this shows, however,
is that transferring responsibility is not necessarily simply a matter of two parties
agreeing between themselves that one will be responsible and the other not; ex-
traneous factors may still lead us to conclude that the would-be transferor retains
some responsibility. Unilateral assumptions and assignations of responsibility also
require cautious evaluation: simply declaring myself to be responsible does not
necessarily make me so, nor can I render someone else responsible just by saying
so.

In the case of human genome editing, then, who is responsible, who takes
responsibility, and who should be held accountable? It is now generally accepted
that scientists bear some degree of responsibility for their work, collectively as
well as individually: that is, being a scientist in itself imposes certain responsibility
(Ehni 2008; Jonas 1984; Verhoog 1981). We should also, though, recognize the
significance of responsibility-taking as a form of asserting authority. Calling He’s
work a “failure of self-regulation” (Cyranoski 2018) not only takes responsibility
on behalf of scientists, it also stakes an implicit claim to governance. This claim,
and the associated questions of how scientific responsibility is distributed and
how it is to be discharged, demand more critical scrutiny.

What Does Scientific Responsibility Require?

Scientific responsibility in human genome editing is not just a matter of indi-
vidual case-by-case risk management: calling something “irresponsible” is not

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identical with saying it is “too dangerous.” The statement issued after the first
International Summit on Human Gene Editing in 2015 declared that:

It would be irresponsible to proceed with any clinical use of germline editing
unless and until (i) the relevant safety and efficacy issues have been resolved,
based on appropriate understanding and balancing of risks, potential benefits,
and alternatives, and (ii) there is broad societal consensus about the appropriate-
ness of the proposed application. (NAS 2017)

The implication is that conducting heritable human genome editing at the
present time would be irresponsible because it is currently too dangerous, but
that with proper investigation it might become less so. Some have suggested that
responsibility may even require us to undertake such investigation: Lovell-Badge
(2019), for example, comments that “it would actually be irresponsible for us
not to explore this opportunity further.” This is partly because of the medical
need that genome editing might help to address, an argument that parallels bio-
ethical claims about moral obligations to pursue gene therapy and enhancement.
Additionally, however, scientific responsibility requires complying with norms
of scientific knowledge production and communication, including “high-quali-
ty experimental design,” “appropriate review,” and “transparency” (NAS 2017,
24). This includes appropriate standards and procedures at a community-wide
level, for which a thorough understanding of the relevant science is necessary.

Assigning and judging scientists’ responsibility to avoid bad behavior is rel-
atively simple. It is clear that in carrying out heritable human genome editing,
against almost all scientific opinion and without any chance for public discussion,
clandestinely, and without attention to appropriate standards of clinical research
design or review, He breached scientific responsibility on multiple counts. Less
easy, however, is determining what positive duties scientific responsibility might
impose, and on whom. Who else might bear some responsibility in this case?
Although He’s name is most prominently associated with the work, he did not
act alone: fertility specialists must have been involved in the procedures required.
Further, from reports that have since emerged, it seems other academics in the
US may have been directly involved, while an additional number knew or sus-
pected what was afoot. This appears to be more than just an individual failure on
He’s part.

The more difficult problem, however, is what these other scientists could or
should have done in response. If peer review and ethical oversight are the ex-
pected routes via which scientific work is subjected to examination, what should
scientists do about work that avoids or evades these pathways? Are scientists ex-
pected to be aware of regulatory requirements across all national contexts and
to act as whistleblowers to promote enforcement? How far does the positive
obligation to discourage or prevent the malfeasance of other scientists extend:
might there be a collective responsibility to develop community standards and

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118 Perspectives in Biology and Medicine

mechanisms that would have enabled those in the know more effectively to act?
More work is required to turn the claims about irresponsibility that have attached
to He’s case into a robust framework for scientific responsibility in human ge-
nome editing. Does knowing that a scientist is abrogating agreed upon standards
of research and behavior make those scientists in the know culpable?

Relative Risks and Sociocultural Harms

A focal criticism of He’s experiment was that the procedure was largely unnec-
essary and of marginal benefit, given that HIV infection can easily be avoided in
other ways and can be well managed with current treatments, and that therefore
exposing the babies to the risks of heritable genome editing was unjustified.

He’s argument was that with an HIV-positive parent, the children were at
greater than normal risk of infection; that within the Chinese health system, ac-
cess to top-line antiretrovirals is not necessarily assured; and that furthermore, in
China, those who are HIV-positive face high levels of stigma and social discrimi-
nation. In a context where HIV is severely stigmatized and has drastic social, not
only health, implications, might the culturally relative risk be higher and there-
fore change the risk-benefit ratio of the treatment?

Risks can be differently materially relative—that is, the same event can have
different consequences in light of different material circumstances. For example,
suffering a simple cut to one’s finger at home is fairly insignificant and unlikely to
cause much of a problem; the same wound suffered in the jungle, without access
to antibiotics and several days’ journey from medical assistance, might result in
infection, loss of a finger or limb, or even death. One would be justified in taking
proportionately greater precautions to avoid the latter than the former. Insofar as
cultural context makes up part of the material circumstances in which our deci-
sions are taken, it may well be the case that a particular characteristic represents
more of a harm in one social context than in another. In such circumstances it
seems sensible that the level of risk that can justifiably be incurred in trying to
avoid it would likewise vary.

One response might be that the appropriate solution to the social disadvantage
of being HIV-positive is to seek to reduce discrimination, rather than to geneti-
cally engineer immunity. Disability advocates and scholars have long argued for
this “social model” with respect to people with disabilities or genetic conditions
such as Down syndrome (Shakespeare 2013): that the “harm” of such conditions
is at least in part socially constructed, and that it is society that ought to change
rather than imposing a technological solution. Nonetheless, it is commonly seen
as justifiable to expose embryos in vitro or fetuses in utero to procedures such as
pre-implantation genetic testing (PGT) and prenatal screening in order to avoid
such conditions.

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Comparing responses to He’s work with the practices and attitudes surround-
ing the use of reproductive technologies we already commonly accept, if we are
to apply the “social model” to judge one, we should apply it in equal measure
to the other. In both cases, we ought to give more consideration to the ways in
which welfare is, as the Nuffield Council report recognizes, “to an extent, so-
cially and historically determined.” Importantly, both for this case and as genome
editing develops globally, we should also acknowledge the socioculturally relative
ways in which our attitudes towards different uses of technology are conditioned,
and how this might differentially affect assessments of justifiable risk in each case.

Harm and Benefit to Whom?

A wrinkle in assessing the harms and benefits of HGE is that, at least as we
presently envisage its application, it would need to be performed in advance of
any genetic testing of the embryo, at the single-cell stage or even at the point
of fertilization. If using it to increase the chances of obtaining a suitable embryo
for transfer where some embryos might already have the desired genotype, as has
been one proposed application, this would mean some embryos would have been
exposed unnecessarily to the procedure—but we would not know which.

This is in some ways comparable to the existing distribution of risk in PGT:
the embryos that are eventually transferred are subjected to blastomere biopsy
only to prove that they are healthy. Insofar as this procedure might entail some
risk of harm, had they been implanted without testing they might have been
better off. For potential children produced from both PGT and genome editing,
however, the application of the technique should be regarded as a precondi-
tion of their existence—assuming that parents would otherwise not reproduce or
(more likely) would choose to reproduce in another way, meaning the creation
of different embryos resulting in different future persons.

In the case of the genome-edited twins, their parents might still have chosen
assisted reproduction in order to enable the sperm-washing procedure to prevent
HIV-transmission, but differences in the timing and circumstances would surely
have resulted in a different combination of egg and sperm, and thus a differ-
ent child or children being born. And, although He’s decision (on his account,
in accordance with the parents’ wishes) to transfer one of the embryos despite
knowing that the genome editing had not worked as intended has been criticized
for incurring the risk of HGE with no justificatory benefit, the alternative for that
child would have been nonexistence.

The task of assigning harm or benefit to children who might result from
potential genome editing procedures thus encounters the knotty philosophical
problem of identity, or rather nonidentity (Parfit 1984): can we say a child has
been harmed by being subjected to genome editing when the alternative, had
their parents not chosen to use this process, is that a different child altogether
would have been born?

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120 Perspectives in Biology and Medicine

Identity issues raise various difficulties for reproductive law. The regulation of
PGT and its acceptable uses has been criticized for inconsistency in this regard
(Sheldon and Wilkinson 2004); indeed, the entire category of “wrongful life”
cases is problematic in comparing the harms of existence to nonexistence. Such
abstract philosophical considerations are also rather far removed from parents
making decisions about their future families. For example, in the debate over
mitochondrial replacement therapy (MRT), philosophers were quick to pounce
on and dissect the question of whether MRT affects numerical identity and how
this might influence assessments of harm (see, for example, Cavaliere and Pala-
cios-Gonzalez 2018; Liao 2017; Palacios-Gonzalez 2017; Rulli 2017; Wrigley,
Wilkinson, and Appleby 2015). Prospective parents and would-be users’ views,
however, centered much more on concern for the health of future children and
how the parent-child relationship might be negotiated via genetic and social fac-
tors (Nuffield Council 2012).

What this means for genome editing is that solving the nonidentity problem
is not our biggest concern. We should not be so caught up in metaphysical co-
nundrums regarding future persons that we fail to cash out harms and benefits
to current persons. In fact, HGE is also for the benefit of prospective parents, in
enabling them to fulfil significant procreative interests (Nuffield Council 2018).
Likewise, although clearly it is to be hoped that the genome-edited twins are
healthy and unharmed, we should consider who else might be harmed by He’s
actions, or by others who might be inclined to attempt a similar exercise. Nota-
bly, if premature, reckless or “irresponsible” (in any sense of the word) application
of genome editing leads to a delay in development of valuable therapies, those
patients and their families who miss out on beneficial treatment will be harmed.
We should therefore consider the possible dangers of an over-hasty approach, not
only for eager patients who may be willing to try experimental genome editing
procedures no matter how risky, but also for those who await benefit from ge-
nome editing developed in a responsible and acceptable way.

Intergenerational Risk and the
Somatic/Germline Distinction

It is usually taken for granted that somatic genome editing is “less risky,” and
that this justifies pursuing it in preference to germline editing. This assumption,
however, warrants further questioning. The risks and harms involved in germline
editing may be of a different nature and differently distributed, but it is not neces-
sarily straightforwardly the case that assessment of risks and possible harms should
lead us to favor somatic genome editing.

For example, somatic gene therapy for inherited anemias involves bone mar-
row harvesting (a nontrivial procedure), in vitro manipulation, and re-transplan-
tation (Dever and Porteus 2017). Each stage has its own attendant risks; there is

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uncertainty regarding whether it will succeed overall or have some unintended
adverse consequence; and during the whole procedure the patient suffers the ef-
fects of the disease. The latter can be significant: a recent case of somatic therapy,
for instance, involved a young boy with junctional epidermolysis bullosa, a severe
skin adhesion disorder (Hirsch et al. 2017). The treatment was a success for the
patient and as an example of cell and gene therapy, but had it been possible to
cure the disease at an embryonic stage instead, this would have saved the patient
from enduring several years of pain and suffering, including losing 80% of the
skin from his body before being treated.

Additionally, if the recipients of somatic genome editing wish to have genet-
ically related children and avoid passing the disease on, they must resort to IVF
and PGT, procedures which carry their own risks and burdens and are not always
successful. These procedures are also currently not available for carrier status, at
least in the UK; thus, a patient with a recessive genetic condition who has been
cured by somatic genome editing would, unless their reproductive partner also
has the condition or is a carrier, not necessarily have access to PGT to remove the
mutation from their line of descent.

In other words, to continually prefer somatic to germline intervention is to
say that each manifestation of disease in subsequent generations should be treated
with somatic therapy, which in itself entails a not-inconsequential degree of risk
and suffering. So even if a single instance of germline editing carries greater risk
in comparison to a single instance of somatic editing, a decision over which to
pursue must take into account the cumulative risks and harms of the multiple
instances of somatic editing that are being traded off.

A further consideration is that the risk of germline editing falls primarily
on one individual, while the risk of repeated somatic procedures is distributed
amongst many, including persons who do not yet exist. We might of course say
that in the case of germline editing, not only the “editee” but their potential fu-
ture descendants are exposed to risk. This depends, however, on the reproductive
choices made by the editee, choices that are likely to be strongly influenced by
whether the genome editing procedure has worked as intended, or whether some
unintended adverse consequence has occurred.

Nevertheless, it seems that there may be a relevant difference between a single
risk-taking event followed by decisions that can be made knowing what the con-
sequences in fact were, versus multiple sequential risk-taking events each involv-
ing possible negative consequences and influencing subsequent decisions. What
this demonstrates is that we need a more thorough ethical, as well as scientific,
analysis of risk in both somatic and germline genome editing, in order properly
to be able to make decisions about when to pursue each possibility.

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122 Perspectives in Biology and Medicine

Responsibilities to Global Society

Thus far we have focused mainly on the responsibilities that scientists, scientific
communities, and parents have with respect to genome editing at the individual
level. What might collective social responsibility with respect to genome editing
require?

In a wider social context, we might also have obligations regarding how we
use (or refrain from using), in the broadest sense of the word, human genome
editing. The Nuffield Council suggests that heritable genome editing should be
“permitted only in circumstances in which it cannot reasonably be expected to
produce or exacerbate social division or the unmitigated marginalization or dis-
advantage of groups within society.” We might take this a step further: if we can
envisage a way in which this technology might be used that would give us a rea-
sonable expectation of reducing social division, marginalization, or disadvantage,
these circumstances might provide a reason not only to permit HGE, but a posi-
tive reason to use it. Additionally, though, we ought not to assume that it is only
the direct application of genome editing itself that will lead to marginalization, or
that only genome-edited humans will either be its victims or agents.

What is usually envisaged when equity concerns over genetic modification are
raised is the division of society into GeneRich and GenePoor: that those who
are already sufficiently advantaged to afford genetic technologies will become
even better off as a result, widening existing inequities. Extreme versions of this
concern envision this resulting in the fragmentation of humanity into different
species, who will then inevitably turn on each other (Annas, Andrews, and Isasi
2002). This argument ignores, however, that as history unfortunately shows, hu-
mans are quite capable of creating social divisions liable to end in genocide even
without the help of genetic modification. Avoiding human genome editing only
solves part of this problem, and not the most immediate part: the “fix” here must
be social, not anti-technological. Indeed, if the spectre of genome-edited spe-
ciation prompts us to develop better moral and political frameworks in order to
avoid future posthuman genocide, this might contribute to reducing conflict and
promoting more equitable treatment of all human beings today—which would
certainly be a good thing!

In any case, however, there are at least two other, probably more immediate
ways in which genome editing might lead indirectly to social division and mar-
ginalization. The first is via the geneticization of discourse: even before genome
editing comes into widespread use, the way in which we discuss its potential and
our moral obligations with respect to it might promote “geneticized” thinking,
which in turn can lead to discrimination. Overbroad versions of the “moral im-
perative” argument, which posit genome editing as the remedy for all manner of
complex biosocial problems such as health-care resource allocation and inequali-
ties in socioeconomic status and educational outcomes (Gyngell, Bowman-Smart,
and Savulescu 2019), may pose a particular danger here: it is not a very great leap

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from urging that genes are the solution we have a moral obligation to pursue, to
concluding that genes are the cause of the problem. Given how far we are from
the promissory future in which genome editing does solve such problems (if in-
deed it ever can), this is just as likely to result in pseudo-genetic discrimination.

Second, genes aside and on a global scale, we are already ScienceRich and
SciencePoor. Vast disparities exist between countries in terms of scientific capi-
tal: those countries with more advanced scientific capacity also tend to dominate
ethical and regulatory discourse and wield greater influence in determining the
global norms of science. Looking at the recent history of human genome edit-
ing as well as other emerging technologies, there is a very real possibility that
the trajectory through which human genome editing is realized, including the
discourses surrounding and shaping its realization, will increase inequity between
countries and worsen divisions amongst global scientific communities (Chan,
Palacios-Gonzalez, and De Jesus Medina Arellano 2017). Even before He’s an-
nouncement, China’s human genome editing endeavors were already disadvan-
taged by stereotypical perceptions of a “Wild East” deficient in ethics, regulation,
and scientific norms (Ho 2016; Sipp and Pei 2016). Regardless of whether “ob-
jectively” justified or not, such perceptions are also a product of existing scientific
capital; reiterating them, whether as justification or critique, further reinforces
inequalities. We must attend to the effects of this in considering how we move
forward with, and shape discourse around, human genome editing and its gov-
ernance at a global level. Discussions of genome editing must therefore move
us to new modes of global ethical discourse and scientific governance, not only
because of the technology’s potential to cross borders, but because of its role as a
paradigmatic example of emerging, ethically contested science.

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Bostrom, N., and A. Sandberg. 2009. “The Wisdom of Nature: An Evolutionary Heu-
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Brokowski, C. 2018. “Do CRISPR Germline Ethics Statements Cut It?” CRISPR J 1
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Cavaliere, G., and C. Palacios-Gonzalez. 2018. “Lesbian Motherhood and Mitochondrial
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Dever, D. P., and M. H. Porteus. 2017. “The Changing Landscape of Gene Editing in
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Ehni, H. J. 2008. “Dual Use and the Ethical Responsibility of Scientists.” Arch Immunol
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Gyngell, C., H. Bowman-Smart, and J. Savulescu. 2019. “Moral Reasons to Edit the Hu-
man Genome: Picking Up from the Nuffield Report.” J Med Ethics. DOI: 10.1136/
medethics-2018-105084.

Harris, J., and S. Holm. 2002. “Extending Human Lifespan and the Precautionary Para-
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Ho, C. W.-L. 2016. “CRISPR Gene-Editing Controversy Shows Old Ideas About East
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Numerical Identity?” Bioethics 31 (1): 20–26. DOI: 10.1111/bioe.12308.
Lovell-Badge, R. 2019. “CRISPR Babies: A View from the Centre of the Storm.” De-

velopment 146 (3). DOI: 10.1242/dev.175778.
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ews/newsitem.aspx?RecordID=12032015a.

National Academies of Sciences, Engineering and Medicine (NAS). 2017. Human Ge-
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Nuffield Council on Bioethics. 2018. Genome Editing and Human Reproduction. London:
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Palacios-Gonzalez, C. 2017. “Does Egg Donation For Mitochondrial Replacement
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Reproduced with permission of copyright owner. Further
reproduction prohibited without permission.

514 Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

Moral reasons to edit the human genome: picking up
from the Nuffield report
Christopher Gyngell,1,2 Hilary Bowman-Smart,  2 Julian Savulescu2,3

Feature article

To cite: Gyngell C,
Bowman-Smart H,
Savulescu J. J Med Ethics
2019;45:514–523.

1Department of Paediatrics,
University of Melbourne,
Melbourne, Victoria, Australia
2Murdoch Children’s Research
Institute, Melbourne, Victoria,
Australia
3Faculty of Philosophy, Oxford
Uehiro Centre for Practical
Ethics, Oxford, UK

Correspondence to
Professor Julian Savulescu,
Faculty of Philosophy, The
Oxford Uehiro Centre for
Practical Ethics, Oxford OX1
1PT, UK;
julian. [email protected] philosophy.
ox. ac. uk

Received 7 September 2018
Revised 2 December 2018
Accepted 11 December 2018
Published Online First
24 January 2019

► http:// dx. doi. org/ 10. 1136/
medethics- 2018- 105316

► http:// dx. doi. org/ 10. 1136/
medethics- 2019- 105390

► http:// dx. doi. org/ 10. 1136/
medethics- 2019- 105395

► http:// dx. doi. org/ 10. 1136/
medethics- 2019- 105713

© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY.
Published by BMJ.

AbsTrACT
In July 2018, the Nuffield Council of Bioethics released
its long-awaited report on heritable genome editing
(HGE). The Nuffield report was notable for finding that
HGE could be morally permissible, even in cases of
human enhancement. In this paper, we summarise the
findings of the Nuffield Council report, critically examine
the guiding principles they endorse and suggest ways
in which the guiding principles could be strengthened.
While we support the approach taken by the Nuffield
Council, we argue that detailed consideration of the
moral implications of genome editing yields much
stronger conclusions than they draw. Rather than being
merely ’morally permissible’, many instances of genome
editing will be moral imperatives.

InTroduCTIon
Genome editing technologies have developed
rapidly in the last few years, and point to a future
where we can precisely edit the human germline.
The most powerful gene editing technology is the
CRISPR (Clustered Regularly Interspaced Short
Palindromic Repeats)-Cas9 system. CRISPR-Cas9 is
found naturally in bacteria, where it functions as a
defence against viruses by cutting viral DNA into
small, non-functional fragments. In 2012, a team at
UC Berkeley showed that CRISPR-Cas9 could be
modified in the lab, so that it could target virtu-
ally any DNA sequence.1 This allows researchers
to cut effectively any part of the genome. Further-
more, once a DNA strand is broken, the cell’s own
repair mechanisms could be recruited to delete,
add or modify the sequence. In April 2015, it was
announced that CRISPR had been used to make
edits in human embryos for the first time.2 In
August 2017, researchers in the USA used CRISPR
to correct a mutation in human embryos that
leads to a fatal heart condition—with virtually no
off-target mutations.3 In November 2018, Dr He
Jiankui announced that he had used the CRIS-
PR-Cas9 system to edit the genomes of twins Lulu
and Nana, in an attempt to make them resistant to
HIV.4 Although this has not been independently
confirmed, if true, it would be the first use of
genome editing for human reproduction. This
attempt has largely been met with condemnation,
including by one of the authors of this paper,5 due
to its experimental nature and lack of consideration
for the welfare of the children. Such research has
generated wide debate about the ethics of genome
modification.

Genome editing of germ cells (embryos, sperm
and egg cells) was initially very controversial and
caused some to call for an outright ban on this
application.6 Despite this, there has been a broad

consensus among expert bodies that genome editing
in research is morally permissible (see table 1 for
summary). However, genome editing for reproduc-
tion, a practice called heritable gene editing (HGE),
has been much more contentious.

In July 2018, the Nuffield Council on Bioethics
released its report ‘Genome editing and human
reproduction: social and ethical issues’.7 The
report is significant for advocating an approach
to the assessment of HGE based on ethical princi-
ples rather than applications. Any particular use of
HGE could be morally permissible, provided it was
consistent with promoting individual welfare and
social solidarity.

In this paper, we critically analyse the approach
taken by Nuffield report and its conclusions.

In the first section, The Nuffield Council’s report
on genome editing and human reproduction, we
provide a detailed summary of the Nuffield Coun-
cil’s approach. While we applaud the Nuffield
Council report as a significant step forward in the
debate, we argue there is room to build on and
strengthen their approach. In the second section,
Social harms and collective action problems, we
suggest ways their guiding principles could be
improved by removing an implicit asymmetry
between the two principles. In the third section,
Categorical limits and moral imperatives in HGE,
we argue that the conclusions stated in the report
do not go far enough. Some uses of HGE are not
merely morally permissible but are moral impera-
tives, even beyond the treatment of disease. Finally,
in the section Governance and public attitudes,
we examine the implications of recent attitudinal
research by the Pew Centre which shows that the
general public may support HGE for treatment but
not enhancement.

The nuFFIeld CounCIl’s reporT on genome
edITIng And humAn reproduCTIon
In 2016, following its report which looked at the
ethical issues associated with genome editing more
broadly (e.g., including food), the Nuffield Council
of Bioethics formed a working group to ‘examine
ethical questions relating to the attempted influ-
ence of inherited characteristics in humans, in the
light of the likely impact of genome editing tech-
nologies’. After 2 years of work, the working party
released its report titled ‘Genome editing and
human reproduction’.

The first two sections of the report contextualise
HGE within its immediate potential role as a repro-
ductive technology used by individuals, its possible
future applications and the social context in which
those applications might evolve.

515Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

Feature article

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(H

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lic
d

eb
at

e
sh

ou
ld

b
e

fo
st

er
ed

.

20
17

Fe
de

ra
tio

n
of

E
ur

op
ea

n
A

ca
de

m
ie

s
of

M
ed

ic
in

e
(F

EA
M

)
Th

e
ap

pl
ic

at
io

n
of

g
en

om
e

ed
iti

ng
in

h
um

an
s

Th
er

e
ar

e
m

aj
or

e
th

ic
al

, s
af

et
y

an
d

ef
fic

ac
y

is
su

es
t

ha
t

m
us

t
be

r
es

ol
ve

d
be

fo
re

c
lin

ic
al

a
pp

lic
at

io
ns

o
f H

G
E

ca
n

be
c

on
si

de
re

d.
T

he
re

is
n

o
br

oa
d

so
ci

et
al

c
on

se
ns

us
in

E
ur

op
e.

G

en
er

al
ly

, F
EA

M
d

oe
s

no
t

su
pp

or
t

ge
no

m
e

ed
iti

ng
fo

r
no

n-
m

ed
ic

al
in

te
rv

en
tio

ns
(i

nc
lu

di
ng

s
om

at
ic

g
en

om
e

ed
iti

ng
),

bu
t

an
tic

ip
at

es
a

w
id

e-
ra

ng
in

g
pu

bl
ic

d
is

cu
ss

io
n

on
t

hi
s

m
at

te
r.

20
17

Eu
ro

pe
an

A
ca

de
m

ie
s

Sc
ie

nc
e

A
dv

is
or

y
C

ou
nc

il
G

en
om

e
ed

iti
ng

: s
ci

en
tifi

c
op

po
rt

un
iti

es
, p

ub
lic

in
te

re
st

s
an

d
po

lic
y

op
tio

ns
in

t
he

E
ur

op
ea

n
U

ni
on

It
w

ou
ld

b
e

irr
es

po
ns

ib
le

t
o

pr
oc

ee
d

w
ith

g
er

m
lin

e
ed

iti
ng

u
nt

il
th

e
nu

m
er

ou
s

sa
fe

ty
a

nd
e

ffi
ca

cy
c

on
ce

rn
s

ha
ve

b
ee

n
re

so
lv

ed
. T

he
re

is
a

n
ee

d
fo

r
an

o
ng

oi
ng

fo
ru

m
.

20
17

A
m

er
ic

an
C

ol
le

ge
o

f M
ed

ic
al

G
en

et
ic

s
an

d
G

en
om

ic
s

G
en

om
e

ed
iti

ng
in

c
lin

ic
al

g
en

et
ic

s:
p

oi
nt

s
to

c
on

si
de

r
Th

er
e

ar
e

te
ch

ni
ca

l c
on

ce
rn

s
(e

g,
t

he
r

is
k

of
o

ff
-t

ar
ge

t
ef

fe
ct

s
or

e
pi

ge
ne

tic
e

ff
ec

ts
t

ha
t

m
ay

a
ff

ec
t

m
an

y
fu

tu
re

g
en

er
at

io
ns

) a
s

w
el

l a
s

et
hi

ca
l c

on
ce

rn
s

(w
hi

ch
v

ar
ia

nt
s

th
at

a
re

t
o

be

ed
ite

d
ne

ed
s

to
b

e
di

sc
us

se
d

at
a

s
oc

ie
ta

l l
ev

el
).

20
15

N
at

io
na

l A
ca

de
m

y
of

S
ci

en
ce

s,
E

ng
in

ee
rin

g
an

d
M

ed
ic

in
e

In
te

rn
at

io
na

l s
um

m
it

on
h

um
an

g
en

e
ed

iti
ng

It
w

ou
ld

b
e

irr
es

po
ns

ib
le

t
o

pr
oc

ee
d

w
ith

a
ny

c
lin

ic
al

u
se

o
f g

er
m

lin
e

ed
iti

ng
u

nl
es

s
an

d
un

til
(i

) t
he

r
el

ev
an

t
sa

fe
ty

a
nd

e
ffi

ca
cy

is
su

es
h

av
e

be
en

r
es

ol
ve

d,
b

as
ed

o
n

ap
pr

op
ria

te

un
de

rs
ta

nd
in

g
an

d
ba

la
nc

in
g

of
r

is
ks

, p
ot

en
tia

l b
en

efi
ts

a
nd

a
lte

rn
at

iv
es

, a
nd

(i
i)

th
er

e
is

b
ro

ad
s

oc
ie

ta
l c

on
se

ns
us

a
bo

ut
t

he
a

pp
ro

pr
ia

te
ne

ss
o

f t
he

p
ro

po
se

d
ap

pl
ic

at
io

n.

20
15

A
ca

de
m

y
of

M
ed

ic
al

S
ci

en
ce

s
(U

K)
‡

G
en

om
e

ed
iti

ng
in

h
um

an
c

el
ls

—
in

iti
al

jo
in

t
st

at
em

en
t

Et
hi

ca
l a

nd
r

eg
ul

at
or

y
qu

es
tio

ns
m

us
t

be
d

eb
at

ed
b

ef
or

e
cl

in
ic

al
a

pp
lic

at
io

ns
o

f e
di

tin
g

ge
rm

c
el

ls
c

an
b

e
co

ns
id

er
ed

.

20
15

H
in

xt
on

G
ro

up
§

St
at

em
en

t
on

g
en

om
e

ed
iti

ng
t

ec
hn

ol
og

ie
s

an
d

hu
m

an
g

er
m

lin
e

ge
ne

tic
m

od
ifi

ca
tio

n
W

he
n

al
l s

af
et

y,
e

ffi
ca

cy
a

nd
g

ov
er

na
nc

e
ne

ed
s

ar
e

m
et

, t
he

re
m

ay
b

e
m

or
al

ly
a

cc
ep

ta
bl

e
us

es
fo

r
H

G
E

fo
r

re
pr

od
uc

tiv
e

pu
rp

os
es

. F
ur

th
er

d
eb

at
e

as
t

o
w

ha
t

sp
ec

ifi
c

us
es

a
re

m
or

al
ly

ac

ce
pt

ab
le

is
r

eq
ui

re
d.

20
15

A
m

er
ic

an
S

oc
ie

ty
fo

r
G

en
e

an
d

C
el

l T
he

ra
py

(A
SG

C
T)

a
nd

J
ap

an

So
ci

et
y

of
G

en
e

Th
er

ap
y

(J
SG

T)
A

SG
C

T
an

d
JS

G
T

jo
in

t
po

si
tio

n
st

at
em

en
t

on
h

um
an

g
en

om
ic

e
di

tin
g

A
s

av
ai

la
bl

e
ge

no
m

e
ed

iti
ng

t
ec

hn
ol

og
ie

s
ar

e
in

ad
eq

ua
te

ly
u

nd
er

st
oo

d,
a

nd
b

ec
au

se
t

he
r

es
ul

ts
o

f s
uc

h
m

an
ip

ul
at

io
n

co
ul

d
no

t
be

u
nd

er
st

oo
d

fo
r

de
ca

de
s

or
g

en
er

at
io

ns
, t

he
se

s
af

et
y

an
d

ef
fic

ac
y

co
nc

er
ns

a
re

s
uf

fic
ie

nt
ly

s
er

io
us

t
o

su
pp

or
t

a
st

ro
ng

s
ta

nc
e

ag
ai

ns
t

H
G

E.

20
15

A
lli

an
ce

fo
r

Re
ge

ne
ra

tiv
e

M
ed

ic
in

e¶
D

o
no

t
ed

it
th

e
hu

m
an

g
er

m
lin

e
Th

e
sc

ie
nt

ifi
c

co
m

m
un

ity
is

u
rg

ed
t

o
en

ga
ge

in
d

ia
lo

gu
e

an
d

pu
t

in
p

la
ce

a
v

ol
un

ta
ry

m
or

at
or

iu
m

t
o

di
sc

ou
ra

ge
h

um
an

g
er

m
lin

e
m

od
ifi

ca
tio

n.
T

hi
s

is
d

ue
t

o
sc

ie
nt

ifi
c

an
d

et
hi

ca
l r

is
ks

su

ch
a

s
th

at
p

er
m

itt
in

g
ev

en
u

na
m

bi
gu

ou
sl

y
th

er
ap

eu
tic

in
te

rv
en

tio
ns

c
ou

ld
s

ta
rt

d
ow

n
a

pa
th

t
ow

ar
ds

n
on

-t
he

ra
pe

ut
ic

g
en

et
ic

e
nh

an
ce

m
en

t.

20
15

IG
I F

or
um

o
n

Bi
oe

th
ic

s,
N

ap
a,

C
al

ifo
rn

ia
**

A
p

ru
de

nt
p

at
h

fo
rw

ar
d

fo
r

ge
no

m
ic

e
ng

in
ee

rin
g

an
d

ge
rm

lin
e

ge
ne

m

od
ifi

ca
tio

n
1.

A

ny
a

tt
em

pt
s

at
c

lin
ic

al
a

pp
lic

at
io

ns
o

f g
er

m
lin

e
ge

ne
e

di
tin

g
ar

e
st

ro
ng

ly
d

is
co

ur
ag

ed
.

2.

Ex
pe

rt
fo

ru
m

s
of

s
ci

en
tis

ts
a

nd
b

io
et

hi
ci

st
s

m
us

t
be

h
el

d
to

fu
rt

he
r

di
sc

us
s

th
es

e
is

su
es

.
3.

Tr

an
sp

ar
en

t
re

se
ar

ch
s

ho
ul

d
be

e
nc

ou
ra

ge
d

an
d

su
pp

or
te

d.
4.

A

g
lo

ba
lly

r
ep

re
se

nt
at

iv
e

gr
ou

p
of

a
w

id
e

ra
ng

e
of

s
ta

ke
ho

ld
er

s
(in

cl
ud

in
g

th
e

ge
ne

ra
l p

ub
lic

a
nd

g
ov

er
nm

en
t

bo
di

es
) s

ho
ul

d
be

a
ss

em
bl

ed
t

o
fu

rt
he

r
di

sc
us

s
th

es
e

is
su

es
a

nd

m
ak

e
po

lic
y

re
co

m
m

en
da

tio
ns

.

20
15

In
te

rn
at

io
na

l S
oc

ie
ty

fo
r

St
em

C
el

l R
es

ea
rc

h
(IS

SC
R)

††
Th

e
IS

SC
R

st
at

em
en

t
on

h
um

an
g

er
m

lin
e

ge
no

m
e

m
od

ifi
ca

tio
n

A
ny

c
on

si
de

ra
tio

n
of

a
pp

ly
in

g
nu

cl
ea

r
ge

no
m

e
ed

iti
ng

t
o

th
e

hu
m

an
g

er
m

lin
e

in
c

lin
ic

al
p

ra
ct

ic
e

ra
is

es
s

ig
ni

fic
an

t
et

hi
ca

l,
so

ci
et

al
a

nd
s

af
et

y
co

ns
id

er
at

io
ns

. T
he

re
fo

re
, t

he
IS

SC
R

ca
lls

fo

r
a

m
or

at
or

iu
m

o
n

ge
rm

lin
e

ge
no

m
e

ed
iti

ng
in

c
lin

ic
al

p
ra

ct
ic

e
(e

xc
ep

tin
g

m
ito

ch
on

dr
ia

l r
ep

la
ce

m
en

t
th

er
ap

y)
, a

lth
ou

gh
in

v
itr

o
re

se
ar

ch
is

s
up

po
rt

ed
.

20
15

N
at

io
na

l I
ns

tit
ut

es
o

f H
ea

lth
(N

IH
)

St
at

em
en

t
on

N
IH

fu
nd

in
g

of
r

es
ea

rc
h

us
in

g
ge

ne
-e

di
tin

g
te

ch
no

lo
gi

es
in

h
um

an
e

m
br

yo
s

Sa
fe

ty
, e

th
ic

al
a

nd
r

eg
ul

at
or

y
is

su
es

m
ea

ns
t

ha
t

al
te

rin
g

th
e

hu
m

an
g

er
m

lin
e

in
e

m
br

yo
s

is
‘a

li
ne

t
ha

t
sh

ou
ld

n
ot

b
e

cr
os

se
d’

. N
IH

w
ill

n
ot

fu
nd

a
ny

u
se

o
f g

en
e

ed
iti

ng
in

e
m

br
yo

s.
(N

.B
.:

as
o

f 2
01

8,
N

IH
is

fu
nd

in
g

re
se

ar
ch

in
to

s
om

at
ic

c
el

l g
en

om
e

ed
iti

ng
).

*O
rg

an
is

at
io

na
l r

ec
om

m
en

da
tio

ns
a

re
in

cl
ud

ed
h

er
e.

A
s

ea
rc

h
w

as
c

on
du

ct
ed

u
si

ng
a

b
ra

nc
he

d
st

ra
te

gy
, b

eg
in

ni
ng

w
ith

t
he

u
se

o
f s

ea
rc

h
te

rm
s

in
d

at
ab

as
es

s
uc

h
as

P
ub

M
ed

a
nd

G
oo

gl
e

Sc
ho

la
r

us
in

g
se

ar
ch

t
er

m
s

su
ch

a
s

‘h
um

an
h

er
ita

bl
e

ge
no

m
e

ed
iti

ng
’,

‘g
er

m
lin

e
ge

ne
e

di
tin

g’
, ‘

ge
no

m
e

ed
iti

ng
e

m
br

yo
s’

, ‘
ge

rm
lin

e
en

gi
ne

er
in

g’
, ‘

hu
m

an
g

er
m

lin
e

ed
iti

ng
’+

‘e
th

ic
s’

, ‘
po

lic
y’

a
nd

/o
r

‘r
ec

om
m

en
da

tio
ns

’.
Fu

rt
he

rm
or

e,
c

ita
tio

ns
a

nd
r

ef
er

en
ce

s
w

er
e

ex
am

in
ed

t
o

ge
ne

ra
te

fu
rt

he
r

re
su

lts
. A

la
rg

e
nu

m
be

r
of

p
ap

er
s

w
er

e
id

en
tifi

ed
d

is
cu

ss
in

g
th

es
e

is
su

es
, i

nc
lu

di
ng

a
n

um
be

r
of

r
ec

om
m

en
da

tio
ns

. R
es

ul
ts

w
er

e
lim

ite
d

to
t

ho
se

fr
om

2
00

8
on

w
ar

ds
(i

e,
t

he
p

as
t

de
ca

de
a

t
tim

e
of

w
rit

in
g)

; a
ll

pa
pe

rs
b

y
in

di
vi

du
al

s
or

g
ro

up
s

of
in

di
vi

du
al

s
no

t
re

pr
es

en
tin

g
an

o
rg

an
is

at
io

n,
b

od
y

or

co
nf

er
en

ce
w

er
e

di
sc

ar
de

d,
a

s
w

el
l a

s
em

pi
ric

al
r

es
ea

rc
h

in
to

o
pi

ni
on

s
on

g
er

m
lin

e
ed

iti
ng

b
y

sp
ec

ifi
c

se
ct

or
s

of
s

oc
ie

ty
(e

g,
g

en
er

al
p

ub
lic

, h
ea

lth
ca

re
p

ro
fe

ss
io

na
ls

).
Th

e
fin

al
g

ro
up

o
f r

es
ul

ts
w

as
li

m
ite

d
to

o
rg

an
is

at
io

ns
w

ho
se

r
em

it
in

cl
ud

es
h

um
an

g
en

et
ic

s,
g

en
et

ic
s

po
lic

y,
b

io
et

hi
cs

, r
ep

ro
du

ct
iv

e
te

ch
no

lo
gi

es
a

nd
/o

r
em

er
gi

ng
t

ec
hn

ol
og

ie
s.

O
rg

an
is

at
io

na
l r

es
po

ns
es

t
o

st
at

em
en

ts
a

nd

jo
ur

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516 Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

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The report states that genome editing in the context of repro-
duction must be situated against a background of increased
genetic knowledge informing reproductive options. Increased
knowledge about genetic differences has created an ‘epistemic
shift’ revealing previous dichotomies between states of health
and disease, and thus therapeutic and non-therapeutic applica-
tions, to be inadequate (p. 26). Even if one views HGE as only
permissible within the context of ‘therapeutic’ applications, its
position as a reproductive technology means that it cannot be
viewed as straightforwardly therapeutic in the same way as other
medical technologies. HGE is not therapeutic in the sense that
nobody who is in a current state of disease is being treated, but
nor is it straightforwardly preventative (because the risk could be
addressed by not having children) (pp. 22–23). Genomic inter-
vention in reproduction is distinct from other human applica-
tions because it deals with possible persons rather than existing
persons; it must be viewed as a means of fulfilling reproductive
desires rather than a means of preventing disease (p. 47, foot-
note 143).

The report goes on to say that genetic information (that can
be acquired by a number of technologies) places new responsi-
bilities on whether to act or not act on this information when
considering reproduction. Prospective parents who wish to
use this knowledge to avoid or ensure certain genetic variants
in their offspring are seeking specific outcomes. They desire a
specific kind of child, that is, one that is genetically related to
them and does/does not have a specific trait, condition or char-
acteristic (p. 23). Existing assisted reproductive technologies,
such as pre-implantation genetic diagnosis, provide one way for
parents to pursue such goals, but rely on a sufficient abundance
of embryos. If this is not possible, HGE may be more accept-
able than other means to achieve parenthood such as donated
gametes, due to the strong preference many people have for
genetically related offspring (p. 25).

The report next situates the development of genome editing
within its technical possibilities and a social and political
context. Here, the report highlights that genome editing should
not be viewed in isolation as an ‘innovation’, but instead encour-
ages us to consider what a society in which it is widely available
might look like. It outlines various strategies by which HGE
might be deployed, including at the zygote stage on embryos
created through in vitro fertilisation (IVF), and the possibility of
creating modified gametes from induced pluripotent stem (iPS)
cells instead of editing embryos directly (pp. 37–39).

There are a number of situations identified in the report where
HGE may be the only option to create a genetically related child.
These include the cases of Y-chromosome defects, or dominant
conditions where one parent is homozygous (p. 45). More
likely scenarios where HGE may be necessary are those where
the chance of an unaffected embryo would be low to very low.
For example, one or both parents may be heterozygous for a
dominant condition, or cases where there are multiple undesired
independently sorting variants (p. 45). Although not mentioned
in the report, another circumstance where HGE might be the
only option to create healthy genetically related children is when
dominant de novo mutations occur in the germ cell line, such as
within spermatogonial stem cells.

The report even raises the possibility of using HGE to avoid
complex conditions that are common in populations and are
difficult to avoid through selective approaches, because of the
large numbers of genes involved (p. 46). Looking forward to a
future in which HGE is widely available, the report envisages
a wide range of possible applications. These include increased
immunity and resistance to disease, tolerance for adverse

environmental conditions (such as that of space), superabilities
or other various factors such as the ability to make vitamins
rather than having to consume them (p. 47).

The report notes that the social and political drivers for
the development of this technology may initially be the use of
embryos for ‘basic’ research. However, researchers cannot be
morally insulated from the ethical implications of further uses
that might develop from applied research (pp. 48–49). The
report supports responsible research and innovation, encour-
aging reflection that may counteract technological momentum
(p. 49). The use of genome editing in human reproduction has
the potential to be socially transformative, and policy and regu-
lation will play a key role in how this transformation may play
out. The report identifies three kinds of concerns about the inte-
gration of new technologies into the landscape: first, that we
may simply ‘sleepwalk’ into a new world, due to uncontrolled
technological momentum; second, that the technology may
be subject to function creep, where its use expands in possibly
morally troubling ways; and third, that we may be headed down
a slippery slope with no reliable ethical or legal means to distin-
guish morally unacceptable applications from morally acceptable
ones (p. 55). Identifying these concerns can help to recognise
key points in the process where better governance and ethical
reflection may play an even more important role.

The report’s approach to the ethical issues surrounding HGE
is largely framed around the concept of human rights and inter-
ests, with a view to the production of general principles. It exam-
ines the ethical issues through the lens of three different kinds
of interests: (i) individuals directly affected by the technology
(the parents and the future person), (ii) society, particularly those
who may collaterally affected in less immediate and direct ways
(such as people with genetic conditions) and (iii) the interests of
humanity in general and future generations (p. 59). This exam-
ination concludes that ‘none of the considerations raised yields
an ethical principle that would constitute a categorical reason to
prohibit heritable genome editing interventions’ (p. xviii).

The report observes that, in terms of the interests of individ-
uals, the use of HGE must be balanced between the prospective
parents’ interests and the welfare of the future person that may
result. Prospective parents often desire a child that is geneti-
cally related to them, for a variety of reasons, most of which
are ‘felt as well as reasoned’ (p. 59). Nonetheless, it does not
necessarily follow that these desires constitute any sort of moral
claim to a genetically related child. However, the report looks at
two reasons why individuals should be supported in their repro-
ductive projects. The first is from the view that procreation is a
good, with a naturalist perspective seeing it as an essential part
of human function and flourishing or the satisfaction of a natural
human desire. More moderately, a view of procreation as a good
can come from a recognition that social arrangements favour
procreation. However, as the report concludes, it is distinctly
difficult to position procreation as a good in itself (pp. 62–63).
The second reason people should be supported in their repro-
ductive projects stems from a respect for procreative interests.
These interests lead to both a negative right and a positive right,
although the extent to which the latter is applicable is likely to
be dependent on social context (pp. 63–64).

The reproductive interests of the parents must, however, be
constrained by another set of interests: that of the future person.
This, of course, raises issues such as the non-identity problem,
which the report addresses in the following fashion. There are
a number of possible children that exist in the form of mental
images that the parents may have; as more and more decisions
are made during the reproduction process, the diversity of these

517Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

Feature article

possible children narrows to become closer to the nature of the
actual future child. These decisions can be about various proper-
ties of the child, and such properties can include those relating
to the child’s levels of welfare. The parents bear responsibility
for the state of affairs that result from their decisions, which
carry moral weight (pp. 66–67). The report examines the extent
and limits of this responsibility. It discusses arguments that have
been put forward that (i) no genome editing is permissible (such
as those autonomy-based arguments from Habermas), (ii) some
genome editing is permissible (generally drawing a distinction
between ‘therapeutic’ and ‘enhancement’ applications) and (iii)
some genome editing is morally required (similar to the principle
of procreative beneficence).

The report addresses a number of issues with all of these
approaches. The first set of arguments raise the issue of genetic
determinism, and the question of how genome editing can be
sufficiently demarcated from other parenting strategies in a
way that is morally coherent (p. 68). The second falls prey to
the difficulty of distinguishing therapeutic applications from
enhancement, including but not limited to disability rights and
feminist critiques of the normativity implicit in any such argu-
ment (pp. 69–72). About the third, the report raises concerns
about the application of this principle in practice, such as the
ability to sufficiently and reliably identify genomic variants asso-
ciated with welfare, and the risk of the burden of expectation
(p. 72). However, all these approaches inform the first principle
that the report formulates: the use of genome editing technolo-
gies must secure and be consistent with the welfare of any future
person that may be born as a result of those technologies (p. 75).
This principle is necessary but not sufficient for any application
of HGE to be morally permissible.

principle 1: the welfare of the future person
Gametes or embryos that have been subject to genome editing
procedures (or that are derived from cells that have been subject
to such procedures) should be used only where the procedure is
carried out in a manner and for a purpose that is intended to secure
the welfare of and is consistent with the welfare of a person who
may be born as a consequence of treatment using those cells.

It is notable that in the formulation of this principle, the Nuffield
Council has specifically referenced a general approach focused
on the welfare of the future person rather than any particular
distinction between different applications of HGE, such as ‘ther-
apeutic’ versus ‘enhancement’. As the report itself notes, it is
very difficult to draw a clear distinction between therapeutic
and non-therapeutic applications and this approach sidesteps
this difficulty. The report explicitly states that there is no a priori
reason that applications beyond the prevention of disease would
not also be consistent with the welfare of the future person (p.
76). This is a significant step in opening the door for a variety of
traits and characteristics to be considered for HGE. For example,
this raises the possibility of actively including certain welfare-im-
proving characteristics, rather than limiting HGE to the removal
of welfare-diminishing characteristics.

The report goes on to address the interests of society, noting
that reproduction takes place in a social context. Reproductive
behaviours already can change the composition of a society
without deliberate coordination, but reproductive technologies
allow for this with greater certainty (p. 78). Other people in
society may be collaterally and indirectly affected by the use of
HGE. The report highlights questions surrounding diversity,
shifting norms, disability critiques, social virtues and equity and
justice.

The report notes that it is possible that genome editing could
lead to changes in the level of diversity within the population—
whether more or less would depend strongly on prevailing social
factors (pp. 79–80). If the use of HGE becomes standard, this
could lead to a shift in norms and the expectation of its use,
which could decrease freedom. This can be reflected in current
concerns around prenatal screening—what people typically do
becomes what people should do, and thus what people feel pres-
sured to do (pp. 80–82). This follows on to disability critiques,
such as the expressivist objection, which states that attempts to
deselect or prevent disability expresses or presupposes a negative
view of people with a disability. However, the Nuffield Council
explicitly rejects this objection when it comes to genetic condi-
tions that significantly affect both quality and length of life (p.
82). Another set of critiques is that HGE represents attempts to
overcome fragility and weakness, which are in themselves a valu-
able part of the human condition and should not be removed.
However, the difficulty with these approaches is that a person
would have to value such fragility enough that they would be
willing to impart it on their own children (pp. 82–85). Finally,
the report considers the importance of equity and justice and
concludes that HGE should be restricted so as not to result in
unfair advantages for certain groups of people (pp. 85–86). This
leads on to the second principle formulated in the report (p. 87).

principle 2: social justice and solidarity
The use of gametes or embryos that have been subject to genome
editing procedures (or that are derived from cells that have
been subject to such procedures) should be permitted only in
circumstances in which it cannot reasonably be expected to produce
or exacerbate social division or the unmitigated marginalisation or
disadvantage of groups within society.

The third set of interests that the report addresses is that of
humanity and future generations. Potential adverse effects of
HGE may only manifest themselves after several generations,
and here the notion that we have responsibilities or moral
obligations to future generations is key (p. 89). One perspec-
tive is that HGE could offer a means to remedy harms that
have already been set in motion for future generations, such as
runaway climate change (pp. 89–90). However, invoking the
‘precautionary principle’ would suggest that the uncertainty
and possible negative consequences of HGE mean that it should
not be applied. However, as the report notes, this constitutes
no reason not to continue research and the development of the
technology as a means of hedging bets against future events (pp.
90–91).

The report also addresses the relationship between HGE
and transhumanism. Transhumanism is a concept that is closely
linked to the emergence of technologies such as HGE. HGE
could lead to the ‘self-overcoming’ of the human species to a
grander, more capable species, and the report questions whether
this constitutes a moral reason not to apply it. This may stem
from a notion of a fundamental human dignity. HGE might be
troubling because it threatens the integrity of human genetic
inheritance (interference with the line of transmission that links
the human family together) and the integrity of human genomic
identity (distinguishing the human family from non-human
beings) (p. 91). These concerns could be mitigated by replacing
variants only with wild-type or typical variants, but of course
the question of what is a wild-type or mutant variant is often
value-laden in itself. The human genome is enormously varied,
and many new variants are possible and likely to emerge. The
report responds to this by stating that concerns about moving

518 Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

Feature article

the human genome away from wild-type variants are pruden-
tial, rather than a categorical moral reason not to do so (p. 92).
However, questions remain surrounding justice and equity, and
the possibility of schisms between the ‘gene-rich’ and the ‘gene-
poor’ (pp. 92–95).

The report concludes by stating that there are no categorical
limits on the use of genome editing technologies, as long as (p.
97):

► They are not biologically reckless;
► They are consistent with the welfare of future people;
► They are not socially divisive;
► They are not initiated without prior societal debate.
We applaud the Nuffield Council’s approach to HGE and

think it is an important step forward in the debate. A strength
of the approach is that it outlines quite specific moral principles
rather than merely appealing to broad concepts—such as earlier
reports.

For example, the National Academiy of Sciences (NAS) report
on genome editing endorses the principle of:

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.

It is left unspecified whose well-being we should be promoting
through genome editing, what the components of well-being/harm
are and exactly how that principle should apply to genome editing.
Nearly all people would freely endorse this principle (and many of
the other principles relied on in the National Academy of sciences
report), but might draw radically different conclusions regarding
genome editing. In contrast, the Nuffield Council’s first principle
is much more specific and the scope and force is clear.

Nonetheless, there is room to improve and build from the
Nuffield Council’s approach. In the next section, we show how
an asymmetry in the structure between the two guiding princi-
ples leads to counterintuitive implications for an important set
of possible uses for HGE, and suggest ways their second prin-
ciple could be improved.

soCIAl hArms And ColleCTIve ACTIon problems
The first guiding principle adopted by the Nuffield Council
concerns its effect on individuals. The report draws on the
term ‘welfare’, which is explained as ‘a broader concept than
well-being (“being well”, ie, “healthy”). In this sense, psychoso-
cial welfare, and not just good health, is an important consid-
eration’ (p. 76). Genome editing is only morally permissible if
it is ‘carried out in a manner and for a purpose that is intended
to secure the welfare of and is consistent with the welfare of a
person who may be born’ (p. 75).

A relatively broad range of ways in which individuals could be
harmed or wronged is discussed in the report. This includes the
effects of genome editing on one’s physical health, and people’s
psychological well-being, including any state ‘that might give the
future person reasonable grounds to reprove their parents’ (p. 96).

In contrast, principle 2—which looks at the social effects of
genome editing—is quite specific. Genome editing would be
impermissible if it were ‘to produce or exacerbate social division
or the unmitigated marginalisation or disadvantage of groups’
(p. 87). But this principle seems to overlook the fact that there
are many ways in which society could be made worse that do
not involve the creation of social division or marginalisation.
If everyone in society were to be made significantly worse off,

but in a way that did not increase inequality (or even possibly
decreased it), we would still most likely view this as an undesir-
able state of affairs.

One strand of arguments in the literature on genetic enhance-
ment centre on so-called ‘collective action problems’.8–10 In
a collective action problem, one option is optimific from the
perspective of an individual but results in collective harms if
everyone pursues it. Imagine if it becomes possible to use HGE
select for or against the predisposition to particular personality
traits, such as extroversion. Extroversion is highly heritable11
and associated with increased levels of subjective well-being.12
Furthermore, recent studies have shown that mothers value
extroversion in their children above other traits such as intelli-
gence and conscientiousness.13 It is therefore plausible that were
parents able to access HGE to increase their chances of having
an extroverted child, they would use it. This would be consis-
tent with both of the Nuffield Council’s guiding principles. As
extroversion is associated with higher levels of subjective well-
being, such a change would be consistent with the welfare of the
child. While decreasing the frequency of introverts in society
might lead to increased division and marginalisation as they
become ‘the odd one out’, this is not necessarily so (they might
become more highly prized as they become rarer). At any rate,
the wrongness of such selection should not depend entirely on
the contingent response of individuals to the decreasing features
of a trait such as introversion.

If HGE were to dramatically increase the rate of extroverts in
society, there is a sense that this would make society imperson-
ally worse. Introverts contribute important forms of cognitive
diversity which can benefit group problem solving.14 15 Having
introverts in society can thus benefit many areas of life including
achievement in the science and the arts.16

The ability of parents to target other characteristics through
HGE, including height and innate immunity, could also lead to
collective action problems.8 Such edits would be consistent with
welfare of the child, yet if many people made those changes to
their children, it could make society worse off in ways that do
not necessarily involve increasing social division or marginalisa-
tion. If the average height of the population increased, this could
increase the amount of resources that we use, and thus damage
the environment. If many people selected similar immune genes
for their children, this could leave us more susceptible to novel
pathogens in the future.

This is not a criticism of the Nuffield Council’s report, as
the type of HGE applications which could lead to collective
problems are a long way off—and their consideration is not
a pressing concern for the regulation of HGE now. However,
reflection on them suggests ways in which the Nuffield report’s
guiding principles could be improved. Namely, the second prin-
ciple should evoke a broader concept of social harm, analogous
to the concept of welfare in the first principle.

modified principle 2: social harms
The use of gametes or embryos that have been subject to genome
editing procedures (or that are derived from cells that have
been subject to such procedures) should be permitted only in
circumstances in which it cannot reasonably be expected to produce
or exacerbate social harms, including increased social division or
the unmitigated marginalisation or disadvantage of groups within
society.

While this principle loses some of the advantageous of spec-
ificity, it has the resources to respond to concerns relating to
collective action problems.

519Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

Feature article

CATegorICAl lImITs And morAl ImperATIves In hge
As stated above, the central conclusion of the Nuffield report on
HGE was that there are no categorical limits on its use, provided
applications are consistent with its guiding principles and
preceded with broad public debate. We believe much stronger
conclusions regarding the ethics of HGE can be drawn.

Technologies like HGE cannot be good or bad absolutely. We
can speak of whether a particular application of a technology
is good or bad, or whether their availability has good or bad
effects on society—but technologies themselves are not the type
of object to which the property of ‘good’ or ‘bad’ attaches.

The most basic ethical questions regarding HGE is therefore
whether particular applications of it are good, bad, permissible,
desirable, etc. In this section, we will examine some possible
applications of HGE and show that rather than being merely
morally permissible, some applications will be moral imperatives.

single gene disorders
A mark of success of medical genetics has been the diagnosis
of the disease phenylketonuria (PKU) at birth. This is an inher-
ited metabolic disorder in which levels of the enzyme phenylal-
anine hydroxylase are lowered. This means individuals cannot
metabolise the amino acid phenylalanine. In 1962, a test was
devised that allowed PKU to be diagnosed through a blood
test.17 The ‘heel prick test’ is now routinely given to infants as
part of newborn screening. Those children who are identified
as suffering from PKU are put on a low phenylalanine diet or
else they will develop severe intellectual disability. This diet
means no bread, pasta, soybeans, egg whites, meat, legumes,
nuts, watercress and fish. Such an environmental intervention is
demanding. There is always a risk that foods containing phenyl-
alanine will be consumed by mistake. The ubiquitous sweetener,
aspartame, can cause a crisis.

Imagine an artificial enzyme was developed to replace phenyl-
alanine. If this was administered regularly it would allow
sufferers of PKU to consume a normal diet. Such a cure would be
hailed as a breakthrough. There would be a moral imperative to
provide this cure, just as there is an imperative to provide blood
transfusion for severe bleeding, and antibiotics for infection.

Now imagine that instead of getting a pharmaceutical
company to manufacture the enzyme, we could get the body to
manufacture it. By altering the DNA of someone with PKU, we
could get a patient’s own cells to produce the missing enzyme,
phenylalanine hydroxylase. There are many advantages to not
relying on pharmaceutical companies. Production inside the
body allows for a more targeted response and more accurate
dosages. Furthermore, it removes all chance that a patient would
be unable to access the treatment, such as when the company has
supply chain problems.i

Just as there would be a moral imperative to provide a replace-
ment enzyme therapy for PKU, there would be an imperative
to make safe genome edits which prevent PKU. If it becomes
possible for carriers of the PKU mutation to prevent PKU in their

i It should be noted that the parents of the affected child will need
to access HGE again if they want to ensure any future children
they have are also unaffected. Given the cost associated with
HGE, this may be seen as creating a division between parents
who can and cannot afford it. However, such issues of access
already exist for parents of children with PKU, which can cost
around US$10 000 per year for the medical food and formula.
HGE will certainly be much cheaper than the cost of treating
PKU over a lifetime—it could thus help reduce such inequities.
For a more complete discussions, see Gyngell et al.43 We thank
an anonymous reviewer for making us confront this issue.

future children through HGE, they will have an obligation to use
this technology, in the same way they would have an obligation
to use an enzyme replacement therapy.

Preimplantation genetic testing and HGE
The Nuffield report notes that in all but ‘extremely rare’ (p.44)
cases, monogenic diseases like PKU can already be prevented
through IVF in combination with preimplantation genetic testing
(PGT), with the proviso that ‘it might not be reasonable to
expect sufficient viable embryos with the characteristics sought
to be available’ (p. 46). Let us try to put some numbers around
the cases in which HGE would provide benefits over PGT in
preventing single gene disorders due to a lack of viable embryos.
In 2013 (the last year for which data are available), 18% of IVF
cycles conducted in the UK produced only one viable embryo.18
So, for every 100 couples who go through IVF with the intention
of using PGT to avoid disease, approximately 18 will produce a
single viable embryo. In 2016 (the last year for which there is
data), there were roughly 700 cycles of PGT for genetic disease
in the UK.19 So, every year in the UK, around 126 IVF cycles
are conducted for PGT and only produce one viable embryo.
In these cases, it will not be possible to use genetic selection to
avoid diseases. As people choose to attempt to conceive children
later and later in life, in part for educational and career reasons,
there will be a greater and greater scarcity of embryos.

The most common scenario in which couples use PGT is when
they are both are carriers for recessive conditions. In these cases,
there is a 25% chance that an embryo will carry both copies
of the disease-predisposing mutation. This would imply that
there are 31 cases in the UK per year in which HGE could avoid
genetic disease in an embryo which PGT cannot. However, this is
likely a conservative estimate. When parents are homozygous for
dominant conditions like Huntington’s disease, or cases where
there are multiple undesirable independently sorting variants,
the number of affected embryos will be closer to 50%. One IVF
company is on record as estimate that 48% of embryos which
undergo PGT are affected by a genetic condition,20 although this
will vary clinic to clinic.

Extrapolating from the above numbers would imply that,
worldwide, there are several hundred cases a year where HGE
would be the only option to produce unaffected offspring.

While several hundred cases a year can be considered rare,
it is not negligible. If a public health measure could reduce the
incidence of serious disease by several hundred a year, then we
would have strong reasons to implement it. It would not merely
be ‘morally permissible’ to take such a measure, but something
that we actively ought to do. Of course, in situations of limited
resources we have reasons to prefer interventions that maximise
benefit, but this does not negate the moral reasons we have to
benefit the few.

In sum, the application of HGE to prevent of single gene
disorders is a good application of technology, and something we
have moral reasons to pursue. If it were possible to use HGE to
prevent single gene disorders, there would be a moral imperative
to use it for this purpose. Of course, given this application alone
may not benefit a large number of people, it may not justify
using limited health resources developing HGE which could
be spent on more effective health measures. But HGE also has
potential to prevent far more common causes of disease, as we
will explain in the next section.

polygenic diseases
Most diseases are not the result of just a few genetic changes. They
are the result of many, sometimes hundreds, of genes combining

520 Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

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together with environmental effects. Such polygenic diseases
are among the world’s biggest killers. Cardiovascular disease is
emerging as the biggest cause of death in the low-income and
middle-income world. Together deaths from chronic diseases in
those under 70 years are responsible for approximately 30% of
all deaths worldwide.21 In addition to causing pain and death
to individuals, chronic diseases place a huge burden on national
health systems, consuming resources that could be used else-
where. One study found that the healthcare cost associated with
treating cardiovascular disease totalled €104 billion annually, for
countries within the European Union.22

We know that there are genetic contributions to chronic
diseases. Genome-wide association studies have identified at
least 44 genes involved in diabetes23; 35 genes involved in coro-
nary artery disease24 and over 300 genes involved in common
cancers.25

It is possible to differentiate between individuals based on
their genetic risk of developing chronic diseases. Using next-gen-
eration sequencing technologies (like whole genome or whole
exome sequencing), polymorphisms occurring across many
genes can be tallied and weighted giving an individual a ‘poly-
genic risk score’ that reflects their genetic predispositions to
develop particular diseases and traits. Individuals can then be
stratified into different risk categories (such as high risk, medium
risk and low risk) based on their polygenic risk score.26

As genome editing technologies can target many genes at one
time, it may become possible to use them to alter an individual’s
polygenic risk score at the embryonic stage,ii and shift individ-
uals from a high-risk category to a low-risk category.iiiiv

Alternatively, it will be possible for individuals who know they
have a high polygenic risk to particular diseases to use HGE to
alter their gametes to ensure they do not pass this high risk on
to their children.

For example, by editing around 27 mutations associated with
coronary heart disease, it would be possible to reduce an individ-
ual’s lifetime risk by 42%27; by editing 12 genetic variants one’s
lifetime risk of bladder cancer could be reduced by almost 75%.28

This application cannot be achieved through current methods
of genetic selection. Say a couple want to use PGT to select for
15 different genes in an embryo, to reduce their likelihood of
cardiovascular disease. Then they would need to create thou-
sands of embryos to make it sufficiently likely that one will have
the right combination at all 15 loci. The chance of the couple
having such an embryo would be <1% with traditional IVF and
PGD.29

Given the massive disease burden caused by chronic diseases,
we have strong moral reasons to develop technologies that
reduce their incidence—whether these operate through genetic
or environmental mechanisms. Imagine scientists develop a new
technology which potentially could be incorporated into exhaust
filters, and would drastically reduce the amount of air pollution
cars emit. In cities where cars are fitted with the exhaust filter,
the incidence of respiratory disease would be decreased by 40%.

ii This first require an embryo to be biopsied at very early stage
(eg, two-cell or four-cell stage), to reduce risks of mosaicism.
iii This possibility was first brought to our attention by Roman
Teo Oliynyk’s unpublished manuscript ‘Could future gene
therapy prevent aging diseases?’44
iv In each of these case, there is a possibility that people in the
low-risk group are overall worse off than those in the high-risk
group, as the genes associated with high risk are beneficial in
some other way. There will be a need for greater research into
the overall effects of particular mutation before this application
of HGE was undertaken.

There are clearly strong moral reasons to develop this tech-
nology and pursue its applications. Developing the exhaust filter
is not merely something it would be permissible to do, but some-
thing that there is an imperative to do. The very same reasons
apply to the development of HGE.

One might respond that the clear difference between this case
and HGE, is that HGE makes heritable changes and will thus
affect future generations. However, air pollution is a known
epigenetic modifier,30 that is, it makes changes to gene expres-
sion which can be inherited by future generations.31 Hence,
reducing air pollution could also affect future generations. Of
course, we need to consider what the long-term effects of any
changes will be. But if the likely effect of a genetic change in one
generation is to reduce risk of disease in future generations, this
seems only to strengthen the case in favour of those changes.

If HGE could make genetic changes which reduce risks of
polygenic disease in current and future generations, there would
be an imperative to use it. Obviously, this application is a long
way away from being plausible, possibly decades. One major
difficulty is that we do not understand polygenic scores well
enough to accurately predict the effects of large-scale changes.
Still, we have moral reasons to develop HGE with the inten-
tion of using them for this purpose. First, it will reduce rates of
premature death and disability due to chronic disease. Second,
the use of HGE to make the highest risk individuals the same
as the lowest risk individuals will be equality-promoting. Third,
using HGE to lower the incidence of chronic disease will also
promote justice. As stated above, health systems spend billions
in resources to treat and prevent chronic disease. Using HGE
in germline cells will probably be a relatively cheap way (in the
proximity of US$20 000) of reducing someone’s susceptibility to
chronic diseases. In a world of limited resources, taking a more
expensive therapy has the opportunity cost of preventing the
treatment of someone else’s disease. Justice requires we choose
the most cost-effective option, other things being equal. If we do
not invest in the most cost-effective option, we harm others who
could use these resources.

enhancement
Just as polygenic scores could in theory be used to reduce rates of
complex disease, they can target complex traits like intelligence.

General intelligence—the ability to learn, reason and solve
problems—is the best known predictor of education and occu-
pational outcomes.32

For decades, it has been known that around 50% of the observed
variation in intelligence is due to genetic factors. A number of recent
large studies have identified many polymorphisms, which help
explain 20% of the heritable variation in intelligence.32

As with complex disease, using the polygenic scores it is
possible to stratify the population into three board groups ‘high
predisposition to high intelligence’; ‘medium predisposition to
high intelligence’ and ‘low predisposition to high intelligence’.
It will become theoretically possible to use HGE to shift indi-
viduals from the low or medium predisposition groups, into the
high predisposition group.

Enhancing based on intelligence using polygenic scores would,
in the words of the Nuffield report, be a form of enhancement
that uses only ‘wild-type’ variants (variants that already exist in
the species) rather than a form of enhancing that goes beyond
what currently exists in the species. In other words, it is a form
of ‘normal range human enhancement’.33 While it may be
possible in the future to enhance intelligence beyond levels that
are currently observed in the species—such forms of enhance-
ment are much less feasible at present.

521Gyngell C, et al. J Med Ethics 2019;45:514–523. doi:10.1136/medethics-2018-105084

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Imagine a prenatal nutritional programme was developed,
which was predicted to increase intelligence in children born
with low innate predisposition to high intelligence. This would
be seen as a breakthrough. We may soon be able to achieve the
same with HGE.

One of the most intuitive concerns about technologies like
germline engineering is the effect on equality. It is feared that
germline engineering would only be available to the rich, and
that it could widen the gap between rich and poor, adding
biological advantages to already existing social ones. This is an
important and complex issue, faced not just by genome editing
but other goods like education. Ethically, we must take steps to
ensure that the benefits and costs of HGE are evenly or fairly
shared. As recognised by the Nuffield Council, this is not a
reason to ban the technology, or fail to develop it, but a reason
to ensure it is developed responsibly.

However, it is also possible to use HGE to directly improve
equality, as the intelligence example shows. Nature is a biolog-
ical lottery which has no mind to fairness. Some are born gifted
and talented, others with short painful lives or severe disabili-
ties. Currently, diet, education, special services and other social
interventions are used to correct natural inequality. It may be
that targeting combinations of genes is an effective means of
promoting equality in education. For example, there are natural
variations in people’s innate ability to learn how to read. This
often matters little for people in higher socioeconomic groups,
who can afford to spend extra time with their children teaching
them how to read, or employ tutors, etc. However, for those
in lower socioeconomic groups, this predisposition can leave
them illiterate for life. While other measures could in theory no
doubt remedy this inequity of outcomes, evening out the genetic
starting point could prove the most effective way. This method
would have the additional benefit of being passed to future
generations. Genome editing could be used as a part of public
healthcare for egalitarian reasons.

Boosting intelligence and other cognitive traits through HGE
will be an ‘enhancement’, rather than disease prevention. As
noted by the Nuffield report, this does not by itself reduce the
moral reasons we have to pursue it. We have a moral imperative
to use all reasonable means to produce equality in education.

Future generations and intergenerational justice
One of the key interests considered by the Nuffield Council
report is that of future generations. It is crucial that the very long-
term consequences of developing or failing to develop HGE be
considered. Humans often exhibit a cognitive bias towards the
near future and neglect then how our actions may affect the very
far future. This can distort our appraisal of technologies.

The obligations we have to future generations are often
described in terms of intergenerational justice. We owe future
generations the same considerations that we owe our contempo-
raries. We should not unnecessarily deplete the ozone layer, for
example, if this will greatly harm future persons at an only small
benefit to ourselves.

Some worry that by engaging in HGE we risk harming future
generations by negatively altering our genome. There is no doubt
that some application of HGE could harm future generations
(e.g., see discussion of collective action problems in Section 3);
however, such applications are not the inevitable consequences
of the development of HGE, and can be mitigated or avoided.

Moreover, a deep engagement with the interests of future
generations will show why there is strong moral imperative to
develop HGE as a matter of intergenerational justice.34

Modern medicine is removing selection pressures that humans
have historically been subjected to. This is increasing the rate of
random mutations accumulating in the genome and poses a risk
to future generations, as made clear by Michael Lynch in a 2016
article in the journal Genetics:

What is exceptional about humans is the recent detachment
from the challenges of the natural environment and the ability to
modify phenotypic traits in ways that mitigate the fitness effects
of mutations, for example, precision and personalized medicine.
This results in a relaxation of selection against mildly deleterious
mutations, including those magnifying the mutation rate itself.
The long-term consequence of such effects is an expected genetic
deterioration in the baseline human condition, potentially
measurable on the timescale of a few generations in westernized
societies.35

As we develop effective and accessible treatments for disease,
we all but guarantee that the incidence of those diseases will
increase in future generations. This is because mutations which
arise that contribute to those diseases are no longer selected
against.

For example, short sightedness (myopia) has been historically
very rare because it was selected against in hunter-gatherer soci-
eties.36 Modern technologies such as glasses, contact lenses and
Lasik eye surgery help correct such vision problems. In modern
societies, those with naturally poor eyesight have the same
fitness as those who have naturally good eyesight. This allows
deleterious mutations to occur in the genes which influence
vision and not be selected against. Rates of myopia are now over
50% in many countries, making populations increasingly reliant
on technology for this basic biological function. It is likely that
reduced selection against poor vision has caused some of this
increase. While it is easy to correct for myopia, the same process
will allow mutations to accumulate in genes which influence
other biological functions.

The percentage of people who require blood pressure medi-
cation,37 assisted reproductive technologies38 and have genetic
predispositions to deafness, are all increasing. While social
changes play a major role in these changes (eg, poor diet and
sedentary lifestyle, delayed childbearing), biological factors also
play an important part.39 40 In future generations, nearly all
people may be reliant on technologies for these basic functions,
as well as many others.

This will be bad for individuals, who become increasingly
dependent on technologies for basic functions, and need to spend
much of their time and money acquiring a range of therapeutic
goods. Similarly, society will become burdened with spiralling
healthcare costs. Furthermore, the consequence of natural disas-
ters will become much more severe if people are reliant on a
variety of complex technologies whose supply can be disrupted.

Fortunately, there is a way for our descendants to avoid such
a medicalised future. Using HGE, we could edit out disease-
causing mutations as they arise in our genome. This will allow
our descendants to enjoy the same level of genetic health as we
enjoy today.

Of course, many diseases have a lifestyle element—we have
mentioned cardiovascular disease and infertility. Many resist
using biological interventions to treat lifestyle problems. For
example, it seems absurd to genetically modify human beings
to be able to tolerate a diet consisting solely of foods with low
nutritional value.

However, as we have argued, there are biological components
to many contemporary diseases that are worthy of modification.

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Moreover, even if such diseases were entirely lifestyle or social
in origin, which intervention we ought to choose—modifying
the biological, psychological, social or natural environment—
depends on the costs and benefits of the particular interven-
tion, and relevant moral values. For example, it may be possible
to prevent skin cancer by avoiding exposure to the sun, or
by increasing the production of melanin, or by increasing the
capacity of our immune cells to attack skin cancers. Which we
should choose depends on the context.

A common assumption in environmental ethics is that we have
obligations to members of future generations. According to one
principle of intergenerational justice, ‘existing generations ought
not act so as to worsen the position of future generations by
depleting non-renewable resources with no compensatory action
or recompense’.41

It is clear that the use of modern medicine is worsening the
position of members of future generation, by allowing random
mutations to occur to our genome. Fortunately, there is a straight-
forward compensatory action—developing HGE. This is not
something that is merely permissible—but a moral imperative.

governAnCe And publIC ATTITudes
Ultimately, it is up to the public to make decisions about the
ways genome editing can be applied. This is a guiding principle
of liberal democracies. As noted by the Nuffield Council (p.
162), before any changes are made to the laws governing HGE,
broad and inclusive public debate is necessary.

We endorse this view, but wish to add that public debates
surrounding HGE need to be supplemented by public educa-
tion initiatives. Making truly informed decisions about complex
scientific matters requires people to understand science. A recent
study by the Pew Study showed that 86% of Americans with high
scientific knowledge approved of the use of HGE to prevent
diseases that would be apparent at birth. This drops to 56% of
people with low knowledge of science.42 Such research shows
how familiarity with a subject matter shapes one’s view of it.

The Pew Research also shows a great divide between people
who think HGE is permissible to prevent disease (72% for
disease present at birth; 60% for later onset diseases) and those
that think it is permissible for enhancement (18%). This is inter-
esting because as noted by the Nuffield Council, there seems
not to be essential reasons as to why the use of HGE to prevent
disease is different than its use for human enhancement. What
is important is that any use be consistent with promoting indi-
vidual welfare, and does not negatively impact society.

Just as is the case with science, for people to make truly
informed decision on ethical matters, ethical education is
required. People should learn about concepts such as justice,
freedom and well-being from an earlier age, and learn how to
think critically about such topics. Only then can we truly make
informed decisions about technologies like HGE.

ConClusIon
Genome editing technologies are developing rapidly, and so too
is our understanding of their moral implications. The consensus
of various expert bodies on the ethical implications of genome
editing has shifted in response to greater engagement with the
underlying philosophical issues. This has been exemplified by
the recent Nuffield Council report, ‘genome editing and human
reproduction’. Rather than drawing arbitrary lines between
different possible uses of HGE, the Nuffield Council report
engages with the fundamental ethical principles that should

guide our appraisal of genome editing—concerns for individ-
uals, for society as a whole and for future generations.

Nonetheless, we think deep engagement with underlying
ethical issues of HGE yields much stronger conclusions than
those drawn by the Nuffield Council. It will be ‘morally permis-
sible’ to engage in HGE and will be morally ‘required’ in some
instances.

The human genome was created by a blind process of muta-
tion and selection occurring over thousands of generations. This
process had no foresight for the creatures it would produce.
This has resulted in vast natural inequality. The most extreme
examples are single gene disorders, where some people become
destined to a short life with much pain due to random quirks in
their DNA. Others are born with high risks of chronic disease
like heart disease and cancer. We ought to use powerful technol-
ogies like HGE to correct these inequalities and promote human
flourishing. Such actions are moral imperatives.

Contributors Dr CG conducted the initial research, helped drafted the initial
manuscript, made revisions and prepared the manuscript for submission. HBS
researched and summarised the Nuffield Council report and other institutional
statements, and edited the manuscript. Professor JS conceptualised the project,
helped draft the initial manuscript, provided feedback on drafts and made revisions
to the manuscript. All authors approved the final manuscript as submitted and agree
to be accountable for all aspects of the work.

Funding CG, HBS and JS, through their involvement with the Murdoch, received
funding from the Victorian State Government through the Operational Infrastructure
Support (OIS) Programme.

Competing interests None declared.

patient consent Not required.

provenance and peer review Commissioned; externally peer reviewed.

data sharing statement Not applicable.

open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
others to copy, redistribute, remix, transform and build upon this work for any
purpose, provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made. See: https:// creativecommons. org/
licenses/ by/ 4. 0/.

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Computational and Structural Biotechnology Journal 18 (2020) 887–896

journal homepage: www.elsevier.com/locate/csbj

Review

Ethical issues related to research on genome editing in human embryos

https://doi.org/10.1016/j.csbj.2020.03.014
2001-0370/� 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

⇑ Corresponding author.
E-mail addresses: [email protected] (E. Niemiec), Heidi.ho[email protected]

(H.C. Howard).

Emilia Niemiec ⇑, Heidi Carmen Howard
Centre for Research Ethics and Bioethics, Uppsala University, Box 564, 751 22 Uppsala, Sweden

a r t i c l e i n f o a b s t r a c t

Article history:
Received 15 November 2019
Received in revised form 13 March 2020
Accepted 14 March 2020
Available online 21 March 2020

Keywords:
Genome editing
CRISPR-Cas9
Oocyte donation
Egg donation
Whole genome sequencing
Research ethics

Although the potential advantages of clinical germline genome editing (GGE) over currently available
methods are limited, the implementation of GGE in the clinic has been proposed and discussed. Ethical
issues related to such an application have been extensively debated, meanwhile, seemingly less attention
has been paid to ethical implications of studies which would have to be conducted in order to evaluate
potential clinical uses of GGE.
In this article, we first provide an overview of the debate on potential clinical uses of GGE. Then, we

discuss questions and ethical issues related to the studies relevant to evaluation of potential clinical uses
of GGE. In particular, we describe the problems related to the acceptable safety threshold, current tech-
nical hurdles in human GGE, the destruction of human embryos used in the experiments, involvement of
egg donors, and genomic sequencing performed on the samples of the research participants.
The technical and ethical problems related to studies on GGE should be acknowledged and carefully

considered in the process of deciding to apply technology in such a way that will provide benefits and
minimize harms.

� 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and
Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.

org/licenses/by/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887
2. Germline genome editing in the clinic: potential benefits, risks and ethical issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
3. Current guidelines on the potential use of GGE in the clinic: how do these impact research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
4. Research context of GGE and ethical implications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889

4.1. Challenges related to the evaluation of safety and efficacy of GGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
4.2. Safety issues in germline genome editing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
4.3. Use of embryos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
4.4. Oocyte procurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
4.5. Genomic sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
4.6. Other issues related to research on GGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894

5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894
CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895

1. Introduction

The CRISPR-Cas9 genome editing (GE) system allows for precise,
efficient, relatively cheap, and fast modification of DNA in various
organisms and types of cells. GE has been found to have applica-
tions in many research areas, including, among others, gene func-

888 E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896

tion studies, gene therapy studies, drug development, and produc-
tion of modified crops in agriculture [1]. In 2015, the first experi-
ment with CRISPR-Cas9 on human embryos was reported; the
authors demonstrated that the GE system performed targeted
cleavage in the b-globin gene, which when mutated causes b-
thalassemia [2]. Following this publication, discussion on prospec-
tive clinical applications of germline genome editing (GGE) in
humans and related ethical issues was ignited. While the term
GGE refers to applications of GE on progenitor cells of gametes,
gametes, or embryos, in this article, we focus our reflection on
GGE conducted on human embryos.

In spite of legal prohibitions on germline genome modification
to establish a pregnancy (i.e. what we consider a clinical use)
enacted in many countries [3], clinical uses of GGE have been dis-
cussed by prominent scientists [5,64]. Many meetings and groups
have been convened to address the ethical questions surrounding
the technique and a voluminous academic literature on this topic
has quickly grown. The majority of the scientific community cur-
rently considers the clinical applications of GGE premature and
many groups have called for a moratorium for such uses [5,6]. Nev-
ertheless, future implementation of GGE in the clinic has not been
excluded as a possibility. Many policy documents, professional rec-
ommendations, and groups of authors either state or seem to imply
that GGE in the clinic could be acceptable if certain conditions are
met. Requirements specified most often include adequate safety
and efficacy of the method, societal debate and/or societal consen-
sus, and appropriate governance [7–11].

Benefits, risks, and ethical issues of potential clinical uses of GGE
have been discussed at length, meanwhile, seemingly less attention
has been given to the questions raised by research on human GGE
which would have to be conducted in order to address safety and
efficacy of the technique. In this article we offer an analysis of eth-
ical issues related to the research context of GGE, including interre-
lated conceptual and technical aspects. To place this analysis in a
broader context, we first present the discussion on potential clinical
uses of GGE in humans focusing on claimed benefits, risks and
selected ethical issues. We then tackle the questions related specif-
ically to research on human GGE concerning: challenges in the eval-
uation of safety and efficacy; technical shortcomings and the safety
risks they pose; problems related to use of embryos in research;
oocyte procurement; and genomic sequencing.

2. Germline genome editing in the clinic: potential benefits,
risks and ethical issues

Although claims of the potential benefits of GGE often relate to
the possibilities of curing or preventing disease (see for example
Gyngell, 2017 [12]), the actual advantage of GGE over available
methods is uncertain and currently appears limited. Firstly, GGE
does not have curative aims per se since there is no patient involved
in the procedure who could be cured1 [13]. Instead, GGE in the
clinic would be coupled with the in vitro fertilization (IVF) technique
in order to create a genetically-related child (for a given couple) who
would then possess a desired trait (e.g. would not be affected by a
given disease).

This approach would be offered in the first instance to couples
who have a combination of genotypes that will result (at least in
theory) in some of their children being affected by a genetic
disease and who are aware of this and would like to avoid passing

1 In one of the approaches of GGE, the embryo can be considered as the subject
which could be cured, that is, when GGE is applied on an existing embryo. This
approach, however, is known to cause mosaicism in embryos, and as such, is unlikely
to be seriously considered for clinical uses. The method of adding the components of a
GE system at the moment of fertilization seems more advantageous in terms of safety
of potential clinical uses.

the disease to their offspring. Importantly, such couples currently
have a number of options available to achieve the desired goal:
1) undergo IVF coupled with preimplantation genetic diagnosis
(PGD) to select ‘‘unaffected” embryos and use them to establish
pregnancy; PGD can detect post-IVF embryos which carry
disease-causing alleles and allows for the selection of embryos
without these (combinations of) alleles; 2) use donor gametes in
IVF; 3) adopt a child; 4) decide to not have a child together.

In the majority of cases, IVF coupled with PGD can be applied2

and GGE does not seem to have a clear advantage over it, as we
explain in the paragraph below. Yet, at least in theory, there are rare
cases where all children of a couple would be affected by a disease
(for example, when one parent is homozygous for a dominant dis-
ease, or both parents are homozygous for a recessive mutation) and
there is no option for PGD and embryo selection. In such situations,
GGE might potentially be the only alternative to have a genetically
related child not affected by a disease, and, as such, it could bring
an advantage over currently available methods [14]. Importantly, it
is not clear whether such couples exist and if they do exist, whether
they would be willing to undergo GGE. Indeed, the theoretical esti-
mation based on available data on prevalence of genetic disorders
in the USA suggests that the clinical demand for GGE would be very
small [15]. For example, the analysis indicates that in the USA in a
given time there is only one couple at reproductive age in which both
persons are homozygous for variants causing cystic fibrosis [15].

Some authors have suggested another benefit of GGE, namely
the possibility to rescue embryos already created in IVF, where
disease-causing variants are detected by PGD and which would
normally be discarded [16,17]. As argued by these authors, such
embryos could undergo GGE and subsequently be transferred in
utero to establish a pregnancy; this, as the authors claim, would
rescue embryos and increase efficiency of the procedure of IVF.
This view of ‘‘rescuing” embryos is, however, challenged by techni-
cal hurdles, for example, the fact that GGE seems to be best applied
at the moment of fertilization to prevent mosaicism, which pre-
cludes the possibility of testing and identifying embryos with a
disease-causing gene variant [14,15].

Another suggested group of applications of GGE has, as a goal,
the general enhancement of (often complex) traits and an
increased resistance to diseases (the latter often regarded as a sub-
set of enhancement, namely disease-prevention enhancement).
The proposals to enhance traits such as intelligence and other com-
plex traits are currently premature due to scientific and technical
limitations. These are primarily related to an incomplete knowl-
edge about the (often limited) genetic contributions to complex
traits, as well as difficulties related to the more complicated
approach that would have to be employed to edit multiple gene
variants. Regarding the suggestion to increase resistance to a dis-
ease, controversially, the first reported case of clinical GGE repre-
sents such an attempt. In November 2018, He Jiankui, a scientist
at the Southern University of Science and Technology in Shenzhen
(China) showed results of his clinical study in which he edited gen-
omes of human embryos that were subsequently used to establish
a pregnancy [18]. He claims that two baby girls with edited gen-
omes were born as a result of this experiment. The goal of this
GGE clinical study was to modify the gene CCR5 with an aim to
increase resistance to HIV in children whose biological father
was affected by AIDS. The study of He Jiankui has been widely crit-
icized not only due to a lack of medical need justifying the research
and the presence of alternative measures to avoid contraction of

2 The risks and impact of PGD on the human organism are more understood than
those of GGE, since PGD has been used in the clinic for nearly 30 years. Yet, PGD raises
ethical issues as well, many of which are common with GGE, for example, the
questions related to the potential impacts on family relationships and more broadly
on the whole society (see the discussion below).

E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896 889

HIV in that situation, but also due to violation of a number of eth-
ical requirements including not seeking and gaining ethical
approval of the study and not ensuring that adequate informed
consent was obtained [18].

Potential benefits of GGE may be discussed, as argued by some
authors, from a broader perspective which includes long-term ben-
efits on a population level such as a decrease in prevalence of
genetic diseases [19]. Importantly, such a prognosis assumes not
only that the technique will be efficient and safe, but also that its
uptake will be high, neither of which can be taken for granted. Even
if the prospect of reducing the frequency of diseases in a popula-
tion was realistic, such an advantage and related economic gains
should be weighed against harm which may be caused to individ-
uals, on which we elaborate below.

Importantly, in both types of GGE applications (to obtain a child
without a disease-causing gene and for enhancement), the
approach would be used to satisfy a desire to have a genetically-
related child with a chosen feature. It is important to acknowledge
that as such, GGE does not fulfill a therapeutic purpose per se, since
the technique is being used to create the child (with a specific trait)
and not to treat an already existing child. As such, the rationale of
fulfilling the desire for a biologically related child with trait ‘‘X”
funded by (public) healthcare services can be challenged, as has
been done with other reproductive technologies [20].

Furthermore, GGE in the clinic poses many additional ethical
problems and risks. First, proceeding with first-in-human uses of
GGE, unlike in the case of other ‘‘standard” clinical trials, will
involve creating a research participant, who would be involuntarily
involved in a research project. Importantly, the main expected ben-
efit of such a trial would be, as already mentioned, satisfying the
parents’ desire to have a genetically-related child not affected by
a given disease. To achieve this goal, a child would be involved in
an experiment with relatively high uncertainties, risks, and poten-
tially irreversible consequences. Furthermore, the experimentation
and consequent need for monitoring may result in such a person (as
well as their children and grandchildren etc.) taking part in a life-
long experiment or clinical trial essentially without having given
consent. Such a situation raises fundamental questions about the
autonomy and best interest of a child. Smolenski (2015) suggests
that a decision to place a child in such a situation is not similar to
other decisions parents routinely make for their children (e.g.
because it is irreversible) and may extend the limits of parental lib-
erty and decision making over a child to unacceptable levels [21].

Additionally, there are questions about the impact of such an
intervention on child-parent relationships. In particular, the risk
of reducing these relationships ‘‘to an overt commercial transaction”
has been discussed [22], as well as the risk of making ‘‘parents less
tolerant of perceived imperfections or differences within their fami-
lies”, and of eroding ‘‘parental instincts for unconditional acceptance.”
[9] Moreover, the efforts to obtain a child with desired traits, raise
concerns about the rise of consumer eugenics ‘‘in which affluent
parents seek to choose socially preferred qualities for their children”
[23]. An increased focus on avoiding certain traits and increasing
others may also lead to a decrease of compassion and general
acceptance of disabled persons in society.

While not specific to GGE, ethical concerns about the creation
and destruction of supernumerary embryos created during IVF but
not used to establish a pregnancy may be also debated. We discuss
ethical positions on the moral status of embryos in the section
below.

3. Current guidelines on the potential use of GGE in the clinic:
how do these impact research?

The theoretical or potential benefits of GGE in the clinic
currently appear limited and uncertain (especially given the

availability of alternative approaches), while the potential risks
including the ethical problems it raises are numerous. There are
authors who have been explicit about their view that GGE should
not be pursued [24,25]. There seems to be, however, many recom-
mendations issued by professional organizations, policy-making
groups, and other groups of authors (not representing any one
group) that state that GGE is not currently permissible, but that
such applications might be permissible provided certain conditions
are met [7–11].

What conditions should be met to pursue the (currently theo-
retical) limited benefits of GGE in the clinic according to the docu-
ments mentioned above? Most common recommendations refer to
the need to address the current uncertainties surrounding the
science, especially safety and efficacy concerns, and consequently
to continue research on GGE [8–11]. The other, often expressed
conditions are of societal debate and/or societal consensus on the
issues of clinical GGE and appropriate oversight [7–11].

In the remainder of this article we focus on the research context
of GGE, as it is being supported, especially as stated above to
address further uncertainties surrounding the science of GGE and
especially its safety and efficacy (which we consider herein as
including the basic science of how well genome editing tools are
working on target edits).

4. Research context of GGE and ethical implications

4.1. Challenges related to the evaluation of safety and efficacy of GGE

As mentioned above, many policy documents and recommen-
dations issued by professional groups as well as by individual
authors state that safety and efficacy of GGE must be further stud-
ied and evaluated in order to consider its potential implementation
in the clinic. However, less attention has been given to trying to
answer the question: what is an acceptable threshold of safety
and efficacy to proceed with clinical trials? And, exactly what kind
of studies should be conducted in order to provide satisfactory evi-
dence? While we do not offer the answers to these questions, we
show in this subsection how these aspects are particularly prob-
lematic for GGE research and how this is recognised by different
professional and policy groups.

Importantly, the above-mentioned questions arise in a broader
context of a benefit-risk evaluation, which should precede any
decision on initiation of a clinical trial. The classic and widely
accepted medical ethics document, the Declaration of Helsinki
states:

‘‘Medical research involving human subjects may only be con-
ducted if the importance of the objective outweighs the risks and
burdens to the research subjects. (. . .) All medical research involv-
ing human subjects must be preceded by careful assessment of pre-
dictable risks and burdens to the individuals and groups involved in
the research in comparison with foreseeable benefits to them and
to other individuals or groups affected by the condition under
investigation.’’ [26]

In this specific context of GGE, a question may be posed: could
the importance of the objective of the trial, that is to create a
genetically related child not affected by a given condition ever out-
weigh and justify exposing a child to the risks and uncertainties
involved in GGE? Or, in other words, should the desire to have a
genetically-related child be satisfied in spite of the harm the pro-
cess can cause?

Of note, a positive answer to this question has already been
given in the context of other reproductive technologies such as
IVF, PGD, and more recently, nuclear genome transfer (also known
as a mitochondrial replacement), which are now used in the clinic.

890 E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896

The acceptance and clinical uses of nuclear genome transfer, which
is considered by some as the first germline genome modification in
the clinic,3 may, to some extent, pave the way to the potential
implementation of GGE in the clinic. In this context, it is important
to recognize that these approaches raised safety concerns and ethical
issues, which were deemed tolerable as clinical uses were allowed.
Flaws in the process of policy-making on these technologies have
been discussed by commentators. For example, with regard to
nuclear genome transfer, Drabiak explains:

“The HFEA Review acknowledged the potential for complications
pertaining to safety and efficacy, but unilaterally disregarded what
the scientific community has described as numerous substantial
barriers.” [27]

These concerns should prompt us to increase vigilance over the
processes leading to decisions on the uses of GGE.

The challenges around safety assessments pertain not only to
the fact that GGE in the clinic would not be, strictly speaking, ther-
apeutic and involve the creation of a child, but also to the problem
of long-term impacts from the irreversible changes introduced,
both on the developing organism of a ‘‘genome-modified” person
as well as on her descendants. The American Society for Gene
and Cell Therapy and the Japan Society of Gene Therapy address
this issue with the following:

‘‘The requirement that the results of an experiment be susceptible
to analysis and characterization before further applications are
undertaken cannot be met with human germ-line modification
with current methods, because the results of any such manipula-
tion could not be analyzed or understood for decades or genera-
tions—a situation incompatible with ethical imperatives and with
the scientific method.’’ [28]

In spite of the open question of whether a thorough assessment
of the technique is possible at all, efforts have been taken to pro-
vide some guidance regarding what evidence is needed. The Amer-
ican Society of Human Genetics (2017) specified that the

‘‘(. . .) minimum necessary developments should include the
following:
-Definitions of broadly acceptable methodologies and minimum
standards for measuring off-target mutagenesis.
-Consensus regarding the likely impact of, and maximum accept-
able thresholds for, off-target mutations.
-Consensus regarding the types of acceptable genome edits with
regard to their potential for unintended consequences.”[9]

In the summer of 2019, the International Commission on the
Clinical Use of Human Germline Genome Editing (convened by
the UK’s Royal Society and the US National Academies of Sciences
and Medicine) issued a call for evidence, that is, a request directed
to experts in the field of genome editing to answer questions such
as

‘‘If there were to be an appropriate use case for human germline
genome editing, what evidence would be needed to proceed to
first in human use?”

‘‘What is the status of the technology for validating that a correct edit
(on target characterization) has been made and that unintended
edits (e.g., off target effects, mosaicism, etc.) have not occurred in a

3 While technically, nuclear genome transfer does imply a change in the
genome since there is no longer the same combination of nuclear DNA and
mitochondrial DNA – lumping both genome editing of specific nucleotides with the
much coarser exchange of mitochondria (and cytoplasm) is somewhat misleading.
Indeed, these two proceedures do not work at all on the same scale or entail the same
type of changes at the DNA level and consequently the same types of risks and
benefits. It has been suggested that by grouping them in the same category, the
acceptance of one will open the door to the acceptance of the other.

range of cell and tissue types? If possible, please provide evidence
drawn from work on early stage human embryos.” [29]

The Commission has, as its main goal, the development of ‘‘a
framework for considering technical, scientific, medical, regulatory,
and ethical requirements for germline genome editing, should society
conclude such applications are acceptable.” [58]. In addition, they list
specific requirements (or tasks) to identify appropriate pre-clinical
approaches to assess on- and off- target effects, mosaicism, and
long-term side effects, among other thing [58].

In the next section, we aim to provide a general overview of the
selected technical aspects of the studies which raise important eth-
ical implications. Importantly, studies addressing safety and effi-
cacy of human GGE may be performed on animals or human
embryos. Although we do not dismiss the importance of address-
ing ethics of the former, due to the limited space herein we focus
on the problems raised by research on human embryos.

4.2. Safety issues in germline genome editing

In Table 1 we list studies published in English that have used
GGE in human embryos. Although the goals of the experiments
vary, all these studies may, to varying degrees, provide information
on the functioning of genome editing in embryos. We may distin-
guish research which alludes to GGE in the clinic more directly,
that is, studies in which disease-causing variants have been cor-
rected with GE [30–32] or a study in which an allele of the gene
CCR5 associated with a resistance or slower progression of HIV
infections has been introduced [33]. There are also studies which
aimed to show feasibility of a given approach, but unlike the pre-
vious group of experiments, they did not focus on correcting
disease-causing genes or variants relevant to disease resistance
[34,35]. Furthermore, research examining the role of a gene in
embryogenesis using GE has been published [36].

The studies presented in Table 1 reveal, among other aspects,
various technical hurdles, which render potential clinical applica-
tions of GGE unsafe. The main technical problems with safety
implications for potential clinical GGE in human embryos revealed
therein include:

1) mosaicism, a situation where not all cells of an embryo/or-
ganism have the same DNA – in this case the desired DNA
modification;

2) off-target effects, where unintended changes in the genome
outside of the targeted sequence occur;

3) on-target undesired modifications introduced within or next
to the targeted locus [16].

All of these phenomena may have negative and difficult to pre-
dict effects on an organism. Some strategies exist to address these
problems, albeit to varying degrees. For example, a study by Ma
et al. (2017) has shown that injection of CRISPR-Cas9 system at
the moment of fertilization reduces mosaicism [30]. Ma and col-
leagues also explicitly admitted technical shortcomings of their
approach, in particular occurrence of on-target effects:

‘‘Despite remarkable targeting efficiency and high HDR [homology-
directed repair] frequency, some CRISPR–Cas9-treated human
embryos demonstrated NHEJ [non-homologous end joining]
induced indels and thus would not be suitable for transfer. There-
fore, genome editing approaches must be further optimized before
clinical application of germline correction can be considered.” [30]

An alternative GE approach has been developed and tested in
human embryos, whereby, unlike in CRISPR-Cas9 system, sequence
is not cut, but a base pair is directly modified [32,34,36]. As such,
this base editing approach does not involve a repair mechanism

Table 1
Studies conducted using germline genome editing on human embryos. This table is based on Table 1 included in the article by Niemiec and Howard (2020) published under
Creative Common Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/4.0/).

Year Authors Title Type of modification introduced Type of embryos used

Clinic 2018 He Jiankui (unpublished,
presented at the
International Summit on
Human Gene Editing, Hong
Kong, 2018)

Developing a CCR5-targeted
gene editing strategy for
embryos using CRISPR/Cas9

Modification of CCR5 gene to
increase resistance to HIV
infections

Embryos created with sperm of a man who
contracted AIDS. Two embryos were
implanted to establish a pregnancy which
resulted in the live birth of twin girls

Research 2019 Li et al. Efficient generation of
pathogenic A-to-G mutations in
human tripronuclear embryos
via ABE-mediated base editing

Single nucleotide substitutions
in a few genes (base editing)

Tripronuclear embryos created in clinical IVF
procedures

2019 Zhang et al. Human cleaving embryos
enable robust homozygotic
nucleotide substitutions by base
editors

Single nucleotide substitutions
in a few genes (base editing)

Embryos created using immature oocytes
from patients undergoing clinical IVF
procedures and sperm from donors
Tripronuclear embryos obtained in clinical
IVF procedures

2018 Zeng et al. Correction of the Marfan
syndrome pathogenic FBN1
mutation by base editing in
human cells and heterozygous
embryos

Correction of a mutation in FBN1
gene causing Marfan syndrome
by base editing

Embryos created for the purpose of research
using immature oocytes from women
undergoing IVF procedures

2017 Zhou et al. Highly efficient base editing in
human tripronuclear zygotes

Single nucleotide substitutions
in a few genes (base editing)

Tripronuclear embryos

2017 Li et al. Highly efficient and precise base
editing in discarded human
tripronuclear embryos

Single nucleotide substitutions
in a few genes (base editing)

Tripronuclear embryos created in clinical IVF
procedures

2017 Ma et al. Correction of a pathogenic gene
mutation in human embryos

Correction of a mutation that
causes hypertrophic
cardiomyopathy

Embryos created for the purpose of research
(over 100 embryos were created) using
oocytes and sperm procured specifically for
research

2017 Tang et al. CRISPR/Cas9-mediated gene
editing in human zygotes using
Cas9 protein

Correction of a mutation in HBB
gene causing b-thalassemia and
a mutation in G6PD gene related
to an enzyme deficiency

Embryos created for the purpose of research
using immature oocytes and sperm from
patients undergoing clinical IVF procedures
Tripronuclear embryos created in clinical IVF
procedures

2017 Liang et al. Correction of b-thalassemia
mutant by base editor in human
embryos

Correction of a mutation in the
HBB gene which causes b-
thalassemia (base editing)

Embryos obtained by somatic cell nuclear
transfer; immature oocytes were donated by
women undergoing IVF procedures

2017 Fogarty et al. Genome editing reveals a role
for OCT4 in human
embryogenesis

Study of the function of the
pluripotency transcription factor
OCT4 during embryogenesis

Surplus embryos created in clinical IVF
procedures

2016 Kang et al. Introducing Precise Genetic
Modifications into Human 3PN
Embryos by CRISPR/Cas-
Mediated Genome Editing.

Introduction of an allele of the
gene CCR5 associated with a
resistance or slower progression
of HIV infections

Tripronuclear embryos created in clinical IVF
procedures

2015 Liang et al. CRISPR/Cas9-Mediated Gene
Editing in Human Tripronuclear
Zygotes

Modification of HBB gene, which
when mutated causes b-
thalassemia

Tripronuclear embryos created in clinical IVF
procedures

E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896 891

which could introduce undesired on-target modifications. Yet, this
technique is not only relatively new and not thoroughly tested, but
also was shown to introduce off-target modifications [59,60].

Not only does the elimination of these undesired events in the
genome pose challenges, but so do the very techniques used to
attempt to detect these changes. In order to control the effects of
genome editing, an embryo has to be biopsied, DNA isolated and
sequenced. Since the amount of isolated DNA in such context is rel-
atively low, DNA has to be pre-amplified which introduces risks of
errors [16]. Furthermore, there are problems with an adequate ref-
erence genome sequence to which the sequence of an edited
embryo could be compared. The DNA sequence of an edited

embryo can be compared to the parents’ sequences and reference
genome (assembled, representative for humans whole genome
sequence); in this case, however, potential off-target modifications
have to be distinguished from other variations among genomes
[16].

Besides the technical shortcomings revealed by the studies,
there are also broader problems related to cell physiology and
genomic interactions, which may be relevant to safety of potential
clinical uses of GGE. For example, epigenetic effects may occur,
which, as the American College of Medical Genetics and Genomics
explains, ‘‘may alter normal patterns of gene expression in some tis-
sues” [37]. Additionally, we may inquire about what would be

4 For an overview of arguments related to moral status/value of human embryos,
see for example, the report of the Nuffiled Council on Bioethics on the related topic
[41].

5 It may be argued that 14-days rule protects more developed embryos from use
and destruction in research, however, it does so by requesting destruction of less
developed embryos.

892 E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896

the impact of a given DNA modification more broadly on the func-
tioning of a given organism which may vary depending on, for
instance, environmental factors. There are also questions about
multiple (sometimes not yet discovered) functions of edited genes.
Given the complexity of the human genome and the variability
among individuals as well as epigenetic mechanisms (which are
not yet completely understood), it is difficult or even impossible
to predict all the consequences of GGE on an organism (and on
future generations). Furthermore, the effects of each modification
may be different, depending on what gene is edited, its function
and location on the chromosome, as well as the type of editing
used. Additionally, the impact of factors such as medium used to
culture the embryos and the way of administrating the GE system
may be considered.

Above we presented a general and non-exhaustive description
of technical hurdles in GGE. Indeed, there are many nuances of
methodological aspects, which may have impact on the technical
outcome of GGE and its potential safety in humans, which we do
not address here. To thoroughly evaluate the current state-of-art
of GGE with regard to technical issues, safety, and efficacy, a sys-
tematic literature review should be conducted (of research con-
ducted both in human cells and animals). Importantly, such a
review can only be meaningful if so called ‘‘unsuccessful” experi-
ments are also published and accessible [38]. In addition to techni-
cal shortcomings, there are questions about methodology and
reproducibility of the studies.

Furthermore, the process of answering whether some technical
deficiencies and uncertainties are acceptable in the pursuit of the
potential limited (added) benefits of clinical GGE will involve dif-
ferent value judgments by stakeholders with a priori different val-
ues, priorities, and opinions. This brings us back to the more
fundamental questions of whether safety issues can be fully
addressed and what level of uncertainty we are able or willing to
accept.

Notwithstanding the limitations of this overview, it is clear that
there remain a number of important technical problems (and
hence with safety) with GGE and currently there are no straightfor-
ward solutions to surmount them. We may expect that many stud-
ies would have to be conducted to address these issues, both on
human embryos and animals. Below we attend to the ethical prob-
lems raised by the former group of experiments.

4.3. Use of embryos

The use of embryos in research, including the studies listed in
Table 1, raises a number of ethical aspects. One commonly dis-
cussed ethical issue is that related to the destruction of human
embryos. We can distinguish the following types of embryos used
in GGE research based on their source:

1) so called supernumerary or surplus embryos, which are left
over after clinical IVF procedures,

2) embryos created specifically for the purpose of research
using gametes left over (surplus) from IVF,

3) embryos created specifically for the purpose of research
using gametes procured specifically for research.

Furthermore, we may distinguish viable and non-viable
embryos. The former term means that embryos are considered to
be able to develop “normally” and result in a live birth when
implanted into a woman’s uterus; non-viable embryos (e.g.
tripronuclear embryos) are considered unable to develop “nor-
mally” and to result in a live birth if implanted into a woman’s
uterus. Of note, from the scientific point of view, viable embryos
are, in general, more advantageous than non-viable embryos, as
the latter type possess abnormalities impacting their functioning.

Since human embryos are humans in the earliest developmen-
tal stage, their destruction raises ethical questions. While the full
discussion behind different considerations of the human embryo
is beyond the remit of this article, we can distinguish broadly,
three main positions in discussions on the moral status/value4 of
the human embryo:

a) human embryos have the same moral status as any other
born human;

b) human embryos have some moral status/value, but not the
same as a born human; there are variations within this view,
for example, some say that moral status or value of embryos
increases during their development;

c) human embryos have no moral status or their moral status/-
value is the same as of any other type of human cells.

If we assume the position that human embryos have the same
moral status as persons, GGE experiments are considered unac-
ceptable. Research on embryos is prohibited in some countries
(e.g. Austria, Germany, Italy, Poland), however, the formulations
of these legislations differ (https://hpscreg.eu/map). Furthermore,
two important public agencies that fund research, the European
Commission and National Institutes of Health in the USA, do not
fund research projects involving the destruction of embryos
[39,40].

The second view on the moral status of embryos has been
entrenched in the legislation of more countries whereby research
on embryos is allowed with some restrictions (that is, some protec-
tion is granted to embryos) (see https://hpscreg.eu/map). An
example, although debatable,5 of such protection is the so called
14-day rule stating that research can be conducted only until 14 days
after fertilization; after this time, embryos have to be destroyed [41].
Furthermore, if assumed that human embryos have some moral sta-
tus/value, the type of research they are used in and their number
may be discussed, and conditioned, for example, upon the expected
benefit of research. Moreover, some laws make a distinction
between using embryos left over from IVF procedures and those cre-
ated specifically for research. The Oviedo Convention, for instance,
states that the creation of embryos specifically for research is not
permissible [42].

In the studies on GGE, both viable and non-viable embryos have
been used; in one study, by Ma et al. (2017) embryos were created
specifically for the purpose of research. Notably, the usual number
of embryos used in such procedures can be high. For instance, in
the study conducted by Ma et al. (2017), over 100 human embryos
were created and destroyed. The continuation of such experiments
would certainly multiply these numbers. We believe that this eth-
ical issue related to the implementation of GGE in the clinic, should
be acknowledged and discussed, and society informed about it
when public discussions are conducted.

4.4. Oocyte procurement

The study of Ma et al. (2017) showed that the strategy of
administering CRISPR-Cas9 system at the point of fertilization is
advantageous as it reduces the mosaicism in embryos [30]. To fol-
low such a strategy, embryos have to be created specifically for
research. Furthermore, since the authors aimed to ‘‘correct” a
specific gene mutation, it was essential to obtain, and, in this case,
create embryos with exactly this genotype. Creating embryos for

E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896 893

GGE research raises questions about the source of gametes used,
particularly human eggs. While supernumerary oocytes and sperm
from IVF procedures can be used, there may be limited availability
of gametes with desired genotypes. If a scientist would be inter-
ested to study embryos heterozygous for a given (disease-
causing) gene, an alternative approach could consist of deriving
sperm from an affected man and using wild types oocytes donated
as surplus after IVF, as was done in the study of Zhang et al. (2019)
[35]. Oocytes can also be procured from women specifically for
research, which raises more profound ethical issues.

Within the studies on human GGE listed in Table 1, five exper-
iments involved egg donation: in one study, oocytes were procured
specifically for research [30], in the remaining studies, immature
oocytes obtained in clinical IVF procedures were used
[31,32,35,61]. Although immature oocytes retrieved in IVF proce-
dures are usually discarded, it has been shown that some of such
oocytes can undergo in vitro maturation, be fertilized and develop
into embryos and live births [62]. Consequently, it may be ques-
tioned whether all immature oocytes can be considered useless
in the context of clinical IVF and whether women should be invited
to donate such eggs. When donation of mature and “healthy”
oocytes obtained during IVF process is considered, such questions
seem even more pertinent. Ballantyne and de Lacey explain that:

‘‘Women having IVF have the option of fertilizing all the eggs
retrieved and freezing spare embryos for future use. When women
do not wish, for personal reasons, to freeze embryos, freezing spare
eggs for fertilization and transfer in future attempts is a viable
option. If the woman donates some of her eggs for research and
her initial embryos fail to implant, she must undergo additional
cycles of egg retrieval that may otherwise have been unnecessary.
Although the personal costs of egg donation will differ for each indi-
vidual woman, depending on her specific fertility problem, there
are currently no cost-free eggs. Due to the uncertainties surround-
ing egg fertilization, embryo implantation, successful pregnancy,
and the desire for future children; infertile women always are being
asked to donate a potentially valuable resource. Therefore, it is not
the case that women are being asked to donate ‘‘spare” or ‘‘surplus”
eggs. Rather, they are being asked to donate eggs that are a poten-
tially valuable personal resource that has typically required signif-
icant investment of time, money, discomfort, and anxiety to
produce.” [43]

Egg donation specifically for the purpose of research raises
additional concerns. Oocyte procurement is a physically invasive
procedure, which involves ovarian suppression, followed by ovar-
ian stimulation and a surgical procedure of oocyte retrieval. The
whole process involves not only many inconveniences, but also
risks to the physical health or even the life of the woman involved.
Discomforts include frequent visits to doctor’s office, injections of
medicines, and undergoing a surgical procedure under sedation.
Most frequent side effects include nausea, irritability and head-
aches, among others [63]. Ovarian hyperstimulation syndrome is
a rarer, yet more serious complication, which may, in the worst-
case scenario, result in death [44]. Notably, in the consent forms
used in the study by Ma et al. (2017) death was mentioned three
times in the context of different procedures6. Additionally, Schnei-
der et al. have drawn attention to long-term potential risks for
oocyte donors, such as breast cancer, which has not yet been ade-
quately studied [45].

The question of whether experiments involving the procedure
of oocyte retrieval are ethically acceptable is not new and has been
discussed in the context of stem cell research. Magnus and Cho

6 The forms were provided at our request by one of the co-authors of the study of
Ma et al. (2017). To our knowledge they are not available online.

highlight the disproportion between the risks involved and poten-
tial benefits in this context:

‘‘These women are not pursuing the procedure for any reproductive
or medical benefit to themselves; rather, they are exposing them-
selves to risk entirely for the benefit of others. If we were to think
of them as simply clinical patients, their physician’s fiduciary obli-
gations would seem to require counsel against undergoing such a
procedure for no benefit.” [46]

Importantly, in the case of GGE, which is strictly speaking not a
therapeutic procedure, as explained above, the ratio of benefits to
risks is even more difficult to accept.

Despite serious arguments against studies involving oocyte
retrieval, such research on stem cells has been conducted and
accepted by professional societies as permissible [47,48] raising
other sets of questions on how women should be engaged in such
studies. In particular, a key issue is on ensuring that consent to
research is informed and women are adequately compensated for
the risks and inconveniences to which they are exposed. Sums of
a few thousand dollars in compensation (in the study of Ma et al.
(2017) of 5000 US dollars) do not seem inflated when we consider
the serious risks involved in egg procurement. On the other hand,
such amounts of money may constitute undue inducement to
some women who are suffering various degrees of financial hard-
ship or socio-economic disadvantage. Indeed, it may be difficult to
avoid undue inducement and at the same time offer fair
compensation.

As explained above, studies involving the creation of human
embryos seem to be currently advantageous over other approaches
from scientific point of view. Until now (to our knowledge) only
one study involving embryo creation and egg donation for purpose
of research has been performed to study GE, yet, if the goal of
addressing safety and efficacy of GGE is to be pursued, we may
expect more of such studies. This will entail exposing many
women to risks. We believe that these aspects should be recog-
nized and acknowledged in the discussions on GGE.

4.5. Genomic sequencing

As mentioned above, in order to verify whether an embryo has
been edited in the desired way and to assess for off-target events,
genome sequencing of embryonic cells is conducted. The entire
genome of gamete donors is also sequenced (e.g. from blood) in
order to act as a reference sequence. In these ways, researchers also
obtain a lot of genomic sequencing information from gamete
donors. One may ask if gamete donors are aware that all (or a large
part of) their DNA will be sequenced and know the implications of
this fact. Indeed, our recent study of informed consent forms used
in the study of Ma et al. (2017) shows that genomic sequencing has
not been explicitly mentioned in the forms, which raises questions
about whether research participants were adequately informed
about this important aspect of the research [49].

Importantly, the use of whole genome sequencing (WGS) and
whole exome sequencing (WES) of research subjects in the “regu-
lar” (i.e. non GGE) genomic research context already raises impor-
tant ethical, legal and social issues (ELSI). These ELSI commonly
revolve around issues of privacy and confidentiality of the genomic
data; how to obtain fully informed consent from research subjects;
the possibility of subjects to withdraw from research; as well as
issues regarding the return of research results, including the right
not to know. While going into depth into each of these issues is
beyond the scope of this article (see Pinxten and Howard 2014
for a review) [50], we provide an example of the complexity of
some ELSI by explaining the challenges of obtaining informed con-
sent below. We also highlight that in general, the ELSI surrounding

894 E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896

the use of WGS and WES in research is still being debated and the
logistics and policies needed to be implemented to offer responsi-
ble genomic sequencing are still being developed. Hence the use of
an already ethically challenging approach such as genomic
sequencing within the highly ethically contentious context of
GGE only serves to exacerbate the ELSI, especially where gamete
donors are concerned.

The difficulties related to obtaining truly informed consent for
genomic sequencing (even outside of the context of GGE) have
been discussed [51]. A requirement for informed consent is com-
municating relevant possible risks and benefits to research sub-
jects. With genome sequencing, the amount of data generated,
and the different results that could be obtained above and beyond
the results for the initial reason to sequence, as well as the uncer-
tainties still surrounding sequencing [52] are so great that it is not
obvious that all this information can be transmitted explicitly and
meaningfully during the informed consent process. For example,
data about family relations, or about DNA variants that may cause
susceptibility to other diseases (other than the one that triggered
the initial need for sequencing) may be revealed by the sequence
information. Questions then arise about which types of informa-
tion should be returned to research participants, how it would be
done and by whom? Ideally, the consent process should include
all these possibilities, but ironically this is likely to result in very
long consent forms, the length and volume of information alone
sometimes contributing to confusion and lack of understanding.
Consent procedures should also address the security of data stor-
age and for how long data will be kept and if it will be used for sec-
ondary purposes or shared with any third parties nationally or
internationally. Clearly this is a lot of information and providing
it in a way that truly supports decision making (instead of simply
being an exchange and signature of forms) is a challenge.

4.6. Other issues related to research on GGE

In addition to the issues described above, there are other con-
cerns related to the research which would have to be conducted
to introduce GGE to the clinic. As mentioned earlier, in addition
to the studies on human embryos, research on animals would be
necessary to assess the impact of embryonic DNA modifications
on the development and functioning of an adult organism and
future generations. Such research, similarly to the studies con-
ducted in humans would likely involve oocyte retrieval, in vitro
fertilization, and implantation of the fertilized eggs to establish
pregnancy; these procedures may cause pain and distress to ani-
mals. Although the problem of harm caused to animals in research
is neither new nor unique for the studies on GGE, the question of
whether the objective of the study can justify the harm caused to
animals seems to be particular in the context of GGE given the
problems its potential clinical use entails.

Research on animals is widely (yet not universally) accepted if
the experiments are scientifically justified and follow the frame-
work of three ‘‘Rs” relating to the reduction of the number of ani-
mals in the experiments, refinement of the protocols (so that
animals’ suffering is minimized) and replacement with other
approaches not involving animals where possible (see, for exam-
ple, the Directive of the European Union [53]). Each study involving
GGE in animals will have to follow the local legislation and guide-
lines for this kind of research.

Another ethical aspect related to GGE research is the opportu-
nity costs of funding this type of research instead of other types,
as Baylis puts it in her recent book:

‘‘What other valuable research is not being done as a result of this
investment? (. . .) what other medical needs are being
underfunded?” [54]

We could also ask, more concretely, whether research efforts,
talents, and funds should not be directed to the studies investigat-
ing somatic GE, which does not involve so many contentious ethi-
cal aspects as GGE, yet, is a promising approach to treat or even
cure a number of genetic diseases [55].

5. Conclusions

Despite the limited and uncertain medical need for clinical GGE,
numerous ethical issues and risks related to such an application,
and current prohibitions of germline genome modification in many
countries, uses of GGE have been proposed and discussed. Further-
more, in some circles, it seems that the focus of the debate has
recently shifted from the question of if GGE should be introduced
to the clinic to how it should be done [56,57]. Indeed, influential
actors such as the US National Academy of Sciences have under-
taken efforts to establish a framework for a potential translational
pathway for clinical GGE [58].

Not only does the potential clinical use of GGE raise ethical
issues, but so does the research context of this approach, including
all the studies that would be required to evaluate GGE before its
potential introduction into the clinic. Firstly, it can be questioned
whether safety of the procedure could ever be sufficiently evalu-
ated in the non-clinical studies since the effects of GGE on a devel-
oping human organism cannot be fully predicted. Related to this,
there are questions about the degree to which numerous technical
and scientific hurdles would have to be addressed and the type of
evidence needed from the studies both on human embryos and
animals. GGE research using embryos raises questions about the
moral status of the human embryo, the involvement of egg dona-
tion, which entails serious risks to women, as well as the ethical
issues related to whole genome sequencing. To evaluate the effects
of germline DNA modification on a developing and adult organism
as well as on future generations, research on animals would have
to be involved, which raises ethical concerns as well. Last but not
least, we may question whether continuation of such research is
the best allocation of the resources, both in terms of funds and
personnel.

We argue that these additional ‘‘costs” of bringing GGE to the
clinic, related to the research context, should be acknowledged
and carefully considered along with the potential benefits when
evaluating further research and the potential clinical applications
of GGE.

CRediT authorship contribution statement

Emilia Niemiec: Conceptualization, Investigation, Writing –
original draft. Heidi Carmen Howard: Conceptualization, Investi-
gation, Writing – original draft, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.

Acknowledgments

We thank Dr. Oliver Feeney for his help with language editing
and insightful comments on this manuscript.

This work is supported by a grant from the Swedish Research
Council ‘‘Ethical, legal, and social issues of gene editing” (2017–
01710). Some sections of this article are also partly based on
reports 2.1 and 2.4 from the SIENNA project (Stakeholder-
informed ethics for new technologies with high socio-economic

E. Niemiec, H.C. Howard / Computational and Structural Biotechnology Journal 18 (2020) 887–896 895

and human rights impact) – which has received funding under the
European Union’s H2020 research and innovation programme
under grant agreement No 741716.

This article and its contents reflect only the views of the authors
and does not intend to reflect those of the European Commission.
The European Commission is not responsible for any use that
may be made of the information it contains.

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