The American Journal of Bioethics

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CRISPR/Cas9 and Germline Modification: New

Difficulties in Obtaining Informed Consent

Joanna Smolenski

To cite this article: Joanna Smolenski (2015) CRISPR/Cas9 and Germline Modification: New
Difficulties in Obtaining Informed Consent, The American Journal of Bioethics, 15:12, 35-37, DOI:
10.1080/15265161.2015.1103816

To link to this article: https://doi.org/10.1080/15265161.2015.1103816

Published online: 02 Dec 2015.

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The American Journal of Bioethics, 15(12): 35–68, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1526-5161 print / 1536-0075 online
DOI: 10.1080/15265161.2015.1103816
Open Peer Commentaries
CRISPR/Cas9 and Germline
Modification: New Difficulties in
Obtaining Informed Consent
Joanna Smolenski, CUNY Graduate Center
Human beings have been using techniques like selective
breeding to effect changes in plant and animal genes for
thousands of years. However, in the past few decades, sci-
entists have developed technologies that enable genes to
be modified directly, without having to rely on traditional
reproductive methods to achieve desired genetic out-
comes. To describe this broad research area, “the term
”genetic engineering“ was coined (in 1965) for what has
come to be a wide range of techniques by which scientists
can add genetically determined characteristics to cells that
would not otherwise have possessed them” (President’s
Commission 1982, 8). While a large number of techniques
fall under the umbrella of genetic engineering, I focus here
on the newest and most currently controversial gene edit-
ing technology available—CRISPR/Cas9. As CRISPR/
Cas9 develops, it is likely that it will be possible to use in
modifying not only somatic cells, but also those in the
germline (i.e., reproductive cells). Ultimately, I argue that
the ethical issues with respect to informed consent
involved with pursuing such research presently outweigh
its beneficial potential.
Currently, there are a number of technologies available
or in development to modify genes, including mitochon-
drial transfer, somatic-cell nuclear transfer (SCNT), zinc-
finger nucleases (ZFNs), and transcription activator-like
effector nucleases (TALENs). However, the most recent
genome editing tool to be developed is also presently the
most efficient. Known as the clustered regularly inter-
spaced short palindromic repeat-associated system or
CRISPR/Cas9, it is “a bacteria-derived system that uses
RNA molecules that recognize specific human DNA
sequences. The RNAs act as guides, matching the nuclease
to corresponding locations in the human genome.
CRISPR/Cas9 is the simplest genome-editing tool to work
with because it relies on RNA-DNA base pairing, rather
than the engineering of proteins that bind particular DNA
Address correspondence to Joanna Smolenski, CUNY Graduate Center, Philosophy Program, 365 Fifth Avenue, Room 7113, New York,
NY, 10016, USA. E-mail: jsmolenski@gradcenter.cuny.edu
sequences” (Lanphier et al. 2015, 411). In other words,
CRISPR/Cas9 functions “as a pair of molecular scissors”
that can be guided by RNA to cut DNA at a specific point
in a cell. When the cell attempts to repair itself at the point
of cut, it often fails, which results in the knock out or
“turning off” of the targeted gene (Corbyn 2015).
Besides its speed and ease of use, CRISPR/Cas9 is also
a substantial improvement upon previous technologies
due to its comparably low cost. For example, the far more
cumbersome technique utilizing ZFNs can cost upwards
of $5,000 per use, while the price of CRISPR can be as low
as $30 (Ledford 2015, 21). It is because of this that
CRISPR/Cas9 is seen as an inexpensive and efficient alter-
native to existing gene editing technologies, and it has
already been used to successfully alter at least 36 different
organisms (Gaj, Gersbach, and Barbas 2013, 402; Ledford
2015, 21). Most controversially, however, scientists in
China recently used CRISPR/Cas9 to modify the genomes
of human embryos using non-viable embryos from fertility
clinics, despite widespread concern about the ethics of
such research (Cyranosky and Reardon 2015).
CRISPR/Cas9 is seen as one of the most promising
technologies to be developed in gene therapy in large part
based on the relative ease with which it can be deployed.
However, this ease also brings with it substantial ethical
difficulties. As Stanley Qi notes, “[Its] power is so easily
accessible by labs—you don’t need a very expensive piece
of equipment and people don’t need to get many years of
training to do this” (Ledford 2015, 21). As a result, its
experimental use is increasing rapidly, even as scientists
lack an understanding of “some of the very basic parame-
ters of the system.” As Bo Huang observes, “There is a
mentality that as long as it works, we don’t have to under-
stand how or why it works” (Ledford 2015, 21).
This is problematic, particularly with respect to
informed consent. Informed consent is required from
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The American Journal of Bioethics
subjects participating in experimental research to ensure
that they understand its potential risks and benefits.1
Because participation in medical research is taken to be
superogatory, it is impermissible to use coercion or rely on
ignorance to obtain research participants, even for the
most socially beneficial work. As germline gene modifica-
tion in its current state has no therapeutic benefits, any
research done in this domain is primarily experimental in
nature, and must involve the obtaining of requisite
consent.
However, who is the proper subject to be consented?
Human embryos are not experimental subjects in an analo-
gous way to human persons, as they are not afforded the
moral status of personhood. Nevertheless, the full conse-
quences of any germline modification will only be evident
upon the transferring and implantation of a modified
embryo, as well as further, long-term study of how this
modification impacts the life of the resulting person. Thus,
undertaking such research at the embryonic level seems to
commit the future person in question to ongoing monitor-
ing throughout their lives, and plausibly the lives of their
children as well (surely, one area of research interest will
be how these germline modifications manifest themselves
in future generations that inherit the modified genetic
material).
It may be objected that this is why current consent pro-
tocols involve an “escape clause”—when a subject no lon-
ger desires to participate in a research project, that
subject’s consent can be revoked at any time and he or she
can be removed from further study. However, at the point
that a genetically modified person is in a position to revoke
consent to continued study participation—either via
parental proxy if underage or directly—the intervention
will already irreversibly have been made, and will affect
both the subject and any genetically related progeny the
subject has in perpetuity, no matter the actions taken on
the part of the subject. Thus, while revoking consent may
result in the cessation of continued monitoring as part of
the study, it can do nothing to mitigate any unwanted
effects of the intervention itself.
Also, an unborn child has no say in whether it wishes
to take part in such experimental procedures and manage
any accompanying complications that might arise. Because
of the extreme nature of this kind of intervention, we can-
not presume to know whether such research participation
would be in line with the future child’s desires or interests,
nor can we presume that a legal proxy can reasonably
anticipate such desires or interests. Though young chil-
dren are typically considered incapable of consent and so
participate in research upon the consent of a legal guard-
ian or proxy, in such cases, parents have at least some inti-
mate knowledge of their children, and can either make an
1. While the use of CRISPR/Cas9 in human subjects is not pres-
ently viable, some scientists speculate that “the first clinical trials
of [CRISPR-based gene therapy] could happen in the next one or
two years” (Ledford 2015, 21).
36 ajob
educated guess as to what their child may want or even
ask directly if the child assents to participation. Parents
have no such access to their unborn children, so proxy con-
sent would be based entirely on unjustifiable parental
speculation.
Nevertheless, some may suggest that an unborn child
has no say in anything, whatsoever. As we have already
noted, unborn children are not persons, and requiring
informed consent from those entities that are literally inca-
pable of providing it imposes an impossible burden on
researchers. Furthermore, parents make decisions on
behalf of their children all the time, both prior to birth (e.
g., through the use of techniques like preimplantation
genetic diagnosis) and after (selecting certain extracurricu-
lar activities, schools, childhood playmates, and so on). As
guardians of their children, we consider it permissible for
parents to make such decisions, and one might argue that
germline modifications are just another kind of parenting
intervention in line with others that parents routinely
make.
However, such argumentation is premature. Firstly,
standard forms of parental intervention—selecting
schools, extracurricular activities, and so on—while in
some sense constraining for a child, are not irreversible. If
a child ultimately decides that she dislikes organized
sports or painting classes or her childhood playmates,
there is no sense in which she is bound to continue to pur-
sue such activities or companions merely because her
parents had previously selected them. Children mature
and become able to make their own decisions, at which
point they can freely reject the choices their parents have
made on their behalf. However, germline modifications do
not operate in a comparable way. Here, parental interven-
tion would result in permanent changes to the child and
her future lineage; there would be no going back. As a con-
sequence, such modifications cannot be seen as a natural
extension of those parental interventions that we currently
accept.
Additionally, we permit parents to intervene on their
children’s behalf based on the presumption that they are
doing so to confer some sort of benefit, and many countries
have laws prohibiting nonbeneficial interventions, even
when parents strongly desire them. For example, some
couples with disabilities—like the United Kingdom’s
Tomato Lichy and Paula Garfield, who are deaf—seek to
use in vitro fertilization (IVF) to select for offspring who
share their disability, arguing that they can better relate to
and care for a child with similar needs to their own. Never-
theless, legal precedents exist in many jurisdictions to for-
bid such a practice, as in the United Kingdom, where the
law “specifically prohibits the selection of an embryo with
a genetic disability or disease in preference to a ‘healthy’
one,” even in contexts where both of the parents are dis-
abled and do not consider their disability a barrier to a
high quality of life (Wilkinson and Garrard, 2013, 18). As
such, parental liberty with respect to decision making is
not limitless, and cannot be seen to trump all other
considerations.
December, Volume 15, Number 12, 2015

It is presently unclear whether germline interventions
ultimately do result in any benefit at all, and in fact, they
may result in substantial harm. Research has shown that
CRISPR/Cas9 can make off-target cuts in cells upward of
60% of the time, and “even low-frequency events could
potentially be dangerous if they accelerate a cell’s growth
and lead to cancer” (Ledford 2015, 22). This likelihood of
mutations in off-target sites was also demonstrated by the
recent CRISPR/Cas9 research performed in China, where
“the rates of such mutations were much higher than those
observed in gene-editing studies of mouse embryos or
human adult cells.” Furthermore, of the 86 embryos that
were injected, only 71 survived, and of these just 22
cleaved successfully (Liang et al. 2015, 367). Among these
embryos, only a small number contained the intended
replacement genetic material (Cyranoski and Reardon
2015). As a result, the authors concluded “that clinical
applications of the CRISPR/Cas9 system may be prema-
ture at this stage” (Liang et al. 2015, 364). So, not only is it
unclear what consenting procedures should legitimately
be utilized for CRISPR/Cas9 clinical trials, but the technol-
ogy itself has thus far failed to demonstrate benefit or gen-
erated unexpected results in many of its applications.
Knowing that we do not permit parents to choose interven-
tions for their children that are taken to be harmful, at the
present stage, it seems as though parents ought not to be
permitted to intervene in this way on their children’s
behalf.
Germline alternations are concerning because of the
possibility of unknowable, serious and/or debilitating
health issues continuing or worsening through future gen-
erations, and such apprehensions have been validated by
the unpredictability of the results of the Chinese CRISPR/
Cas9 research. It is not clear at present how research on
germline modification in humans could be pursued in
light of the substantial difficulties in ensuring adequate
consent not only on the part of the experimental subject,
but also on the part of the future generations that will be
impacted by the intervention. As the technology is likely
to develop far more rapidly than legal precedent can
emerge to legislate it, it is imperative for the scientific and
bioethical communities to critically examine the work they
December, Volume 15, Number 12, 2015
Ethical Tensions Surrounding Germline Editing
are doing to ensure the scientific outcomes are in line with
our ethical priorities.
CONFLICTS OF INTEREST
The author was paid as a consultant by the Alliance for
Regenerative Medicine in 2015 that resulted in a coau-
thored paper in Nature and was a paid bioethics intern for
Genepeeks in 2013. &
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