Available online at www.sciencedirect.
com
ScienceDirect
Ethical issues in genetic modification and why
application matters
Megan Munsie1 and Christopher Gyngell2
Advances in genome editing techniques have generated
renewed interest in the ethical implications of genetic
modification. In this article, we review the recent literature and
discuss in detail ethical issues pertaining to the application of
this technology to five areas; human embryo research,
organoid research, the prospect of genetically modified babies,
mitochondrial replacement therapy and the creation of
chimeric organisms. We point to a central issue which cuts
through these different areas: the need to clearly frame how
using the technology provides benefit that cannot be met by
other means. Failure to provide reasonable justification, and
address how risks — if any — will be mitigated, is likely to
erode public trust and undermine progress in medical research
and its clinical translation.
Addresses
1
Centre for Stem Cell Systems, School of Biomedical Sciences,
University of Melbourne, Parkville, Australia
2
Murdoch Children’s Research Institute and University of Melbourne,
Parkville, Australia
Corresponding author: Munsie, Megan (megan.munsie@unimelb.edu.au)
Current Opinion in Genetics & Development 2018, 52:7–12
This review comes from a themed issue on Cell reprogramming,
regeneration and repair
Edited by Knut Woltjen and Alex Bortvin
For a complete overview see the Issue and the Editorial
Available online 23rd May 2018
https://doi.org/10.1016/j.gde.2018.05.002
0959-437/ã 2018 Elsevier Ltd. All rights reserved.
Introduction
For over 40 years, scientists have been able to genetically
modify the genome of mammalian cells. The first
‘transgenic’ mouse was created by Rudolf Jaenisch in
1974 [1]. Since this time various techniques have been
used to insert, delete or modify DNA, in order to create
animals with altered physical [2], cognitive [3] and social
[4] characteristics. While invaluable to advance basic
research, the potential clinical applications have been
hampered by the challenge of reliably modifying the
desired genome sequence without any off-target effects.
However, advances over the past six years have led to
more precise and efficient methods for genetic
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engineering, raising the spectre of ‘editing’ the genomes
our own cells or even those of our descendants at will.
The most notable of these advanced ‘genome editing’
techniques is the clustered regularly interspaced short
palindromic repeats (CRISPR-Cas9) system. This
approach, developed by a team at UC Berkeley in
2012, showed that CRISPR-Cas9 could be modified so
that it could target virtually any DNA sequence [5],
giving researchers the ability to delete, add, or modify
DNA sequences with greatly increased precision. The
CRISPR-Cas9 approach has since been used to modify
the genome of mice [6], dogs [7], pigs [8] and primates [9].
These developments have brought to focus a number of
important ethical questions. In this review, we discuss the
ethical issues raised by genome modification technologies
and why application remains a paramount consideration
for the future.
Recent controversy — editing the human germline
In April 2015, a team in China became the first to use
genome editing technologies on human embryos [10].
The study, which attempted to correct the gene respon-
sible for b-thalassaemia using ‘non-viable’ IVF embryos,
sparked a worldwide debate about how research involving
germline genome editing (a practice we will call GGE3)
should be regulated. Some scientists and public interest
groups, including the United Nations Educational Scien-
tific and Cultural Organization have called for an inter-
national ban on any gene editing research in human
embryos [11]. The U.S. based National Institutes of
Health, maintained that performing such research passed
‘a line that should not be crossed’ [12]. Opinion articles in
the leading journals Nature and Science called for a mora-
torium on any GGE research [13,14].
In response to this development, some called for collec-
tive efforts to carefully analyse the ethical, legal, and
social implications for altering the germline, and called for
broad public discussion on the issue [15]. In December
2015, the Hinxton Group, an international consortium of
scientists, ethicists and policy experts, convened a meet-
ing to analyse the ethics of gene editing technologies.
The Hinxton Report resisted calls for moratorium on all
GGE research. While it makes clear that any reproductive
3
By GGE, we mean the editing of any cells, including gametes and
cells in early cleavage stage embryos, in which the changes made to the
genome could be inherited by decedents of that cell.
Current Opinion in Genetics & Development 2018, 52:7–12
8 Cell reprogramming, regeneration and repair
use of GGE is premature, it highlights the important roles
that GGE could achieve in basic research, such as helping
us understand the mechanisms that underlie early human
development [16].
In 2016, International Society for Stem Cell Research
released its ‘Guidelines for Stem Cell Science and Clini-
cal Translation’. Like the Hinxton Report, this publica-
tion highlighted the importance of basic research which
could be accomplished with GGE. However, it takes a
harder line on the use of these technologies for reproduc-
tive purposes, starting that that such uses ought to be
prohibited; and that there needs to be ‘a deeper and more
rigorous deliberation on the ethical, legal, and societal
implications of modifying the human germ line is essen-
tial if clinical application is ever to be sanctioned’ [17].
In 2017, a comprehensive joint report from the U.S.
National Academy of Sciences and U.S. National Acad-
emy of Medicine, was released which looked at the
ethical and regulatory implications for human genome
editing. This report builds on fundamental ethical prin-
ciples [18] to describe the overarching considerations for
the conduct and oversight of genome editing technologies
for basic research and clinical application [19]. Notably,
the report states that clinical trials using GGE could be
considered if 10 steps are met, importantly whether the
clinical objectives are unable to be reached through
reasonable alternatives (see Table 1).
The recent public attention on modifying human
embryos has generated much discussion on the ethics
of such research; but also the ethical issues raised by
genetically modifying human cells more generally. We
review the major issues below, distinguishing between
issues raised by genetic modification in basic research and
issues raised through areas of future clinical application of
genetic modification.
Ethical issues raised in research
Genetically modifying embryos
To date, all of the research involving the germline modi-
fication has taken place during early embryo development;
at, or immediately after, fertilisation (see Table 2). For
those who think that early embryos have the same moral
status as adult humans, this is morally problematic [20].
Initial GGE studies using human embryos tried to miti-
gate these concerns by using ‘non-viable’ IVF embryos4
that were identified as being abnormally fertilised and
therefore not suitable for infertility treatment. As Savu-
lescu et al., commented ‘as trialling the CRISPR system in
these zygotes had no chance of resulting in a live birth, it is
unclear how the study could harm or wrong anyone
4
Researchers used one-cell embryos, also referred to as zygotes, that
displayed more than two pro-nuclei following fertilisation; indicating
abnormal fertilisation.
Current Opinion in Genetics & Development 2018, 52:7–12
directly . . . ’ [21]. However, it is also unclear how infor-
mative experiments using genetically abnormal embryos
are in advancing the technology given that information
about off-target mutations, mosaicism and about human
development, cannot be easily extrapolated [16].
These limitations raise the question of how ‘normally’
fertilised human embryos could be ethically sourced. Most
human embryos used in research are ‘left-over’ from IVF
treatment. These embryos, normally fertilised and at the
early stages of pre-implantation embryonic development,
are no longer required by the couple and maybe available
to donate to research. Using CRISPR-Cas9 on these
embryos (often 4–8 cell or blastocyst stage) is likely to
give variable results with genetic modification being
achieved in some cells and not others, resulting in a
mosaic of edited and non-edited expression across the
embryo. Normally fertilised zygotes are rarely available
for research. Therefore, from a research perspective, it has
been argued that it may be better to specifically create
zygotes using donated eggs and sperm for the purpose of
research — an approach adopted in two recent gene edit-
ing studies [22,23]. While such a strategy may be accept-
able to some, and has received ethics approval, such an
approach opens these studies up to objections that they
are unethical by creating an embryo whose sole purpose is
to be used as a means for research [24]. How, where and
from whom to source appropriate material to progress
GGE using human gametes and embryos, and how to
regulate such research, is likely to be an ongoing chal-
lenge for the field.
Organoids
Research involving organoids — clusters of cells derived
from tissue or pluripotent stem cells that self-organize in
ways which mimic tissue and organ function — allows
scientists to create models which can further our under-
standing of biological processes underpinning develop-
ment and the progression of disease [25]. It has also been
proposed that in the future organoids may be a source of
functional tissues and organs for transplantation, a quest
that still has many challenges in terms of meeting neces-
sary standards of scale and maturity. However, the recent
report where gene editing techniques were used to
restore normal function in intestinal organoids derived
from cystic fibrosis patients provide an indication of
future therapeutic applications [26].
Organoid research raises a number of important ethical
issues [27]. Specifically, organoid research raises ques-
tions around moral status of these structures, about
whether their creation constitutes ‘life’ or if they hold
independent interest and rights. This is particularly rele-
vant for research involving gastruloids, structures that are
made in the lab from pluripotent stem cells and that
mimic post-implantation embryonic development [28].
While most jurisdictions limit the development of human
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 Ethics and genetic modification: why application matters Munsie and Gyngell 9

Table 1

Key considerations that NAS recommends must be met before undertaking clinical research using heritable human germline genome
editing [19]

Consideration
The absence of reasonable alternatives
Restriction to preventing a serious disease or condition
Restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to that disease or condition
Restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or
no evidence of adverse effects
The availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures
During the trial, ongoing, rigorous oversight of the effects of the procedure on the health and safety of the research participants
Comprehensive plans for long-term, multigenerational follow-up that still respect personal autonomy
Maximum transparency consistent with patient privacy
Continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public
Reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition

Table 2

Summary of stated rationale for GGM in recent human embryos experiments

Publication Developmental stage used Rationale for GGM Alternative approach

Liang et al., 2015 [10] Abnormally fertilised (3PN) zygotes —
donated by IVF patients
Kang et al., 2016 [52] Abnormally fertilised (3PN) zygotes —
donated by IVF patients
Tang et al., 2017 [23] Abnormally fertilised (3PN) zygotes and
normally fertilised embryos created from
immature eggs — donated by IVF patients
Ma et al., 2017 [22] Zygotes (normally fertilised) and co-
injection with sperm at fertilisation —
embryos created for research
Fogarty et al., 2017 [53] Normally fertilised zygotes — donated by
IVF patients
Correct common b-thalassemia mutation PGD on IVF embryos
Introduce mutation to disrupt receptor for Strategies to address
HIV-1 thereby reducing risk of infection HIV infection
Correct common b-thalassemia mutation PGD on IVF embryos
and X-linked mutation causing glucose-6-
phosphate dehydrogenase deficiency
Correction of mutation of which causes a PGD on IVF embryos
type of heart disease (hypertrophic
cardiomyopathy) to prevent germline
transmission and ‘rescue mutant embryos,
increase the number of embryos available
for transfer and ultimately improve
pregnancy rates.’
Explore the molecular mechanism of early None
development by inducing mutation in OCT4
gene

embryos in a lab to 14 days post fertilisation, gastruloids
make it possible study development beyond this point
and thereby provide insight into early human develop-
ment during first trimester pregnancy and miscarriage
[28]. But is such research ethical? Do gastruloids have
the same moral standing as early human embryos derived
from fertilisation, and should the same ethical principles
apply to them? [28].
Growing cerebral organoids in a dish — where they mimic
certain structural and functional aspects of the brain — is
also an area that has attracted significant concern. While
structural complexity is currently limited due to technical
challenges of maintaining these structures for sufficient
time to allow them to mature, in time these models are
likely to become more sophisticated and better able to
imitate functions of a mature brain. Questions must be
asked about the moral standing of these structures [29].
When do they begin to have experiences, or even gain the
capacity to feel pain? How can we ascertain if they do?
Such questions are vital to how we assess the moral
implications of this research. It is crucial that such ques-
tions are considerations as research continues [27].
An additional and fundamental consideration in organoid
research relates to informed consent [30]. What type of
consent procedures are appropriate? Does this need to be
modified where the research involves creation of gastru-
loids or cerebral organoids? What processes are in place to
ensure that the donor’s intentions are honoured? Further-
more, as organoids can be stored in biobanks for future
research, much like a 3D cell line, questions about the
ownership, distribution and commercialisation may need
to be considered after consent has been given [31].
Ethical issues raised by future clinical applications
While there remain considerable technical and ethical
challenges in delivering gene therapy through genetic
modification of somatic cells [32], we have elected in this
review to focus on three future applications that have

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10 Cell reprogramming, regeneration and repair
attracted substantial community interest, generate novel
ethical challenges, and merit careful consideration around
justification and public engagement.
Genome edited babies
By far, the prospect of genetically modified children is the
ethical issue that has generated the most discussion in
relation genome editing technologies. Proponents of this
application state that such technologies can help fight
disease and reduce suffering more broadly — and that
there is therefore a moral imperative to develop them
[33]. In contrast, many critics of gene editing claim it will
be wrong at one or more levels [34]. They will harm the
child as they will lead to the commodification of children
[35]; they will harm parents by hurting their relationships
with their children [36]; harm society by exacerbating
social inequalities [37], or harm the species by altering our
evolutionary trajectory [38]. Proponents argue that either
these concerns are either unfounded, or that they also
apply to existing reproductive technologies, like Pre-
implantation Genetic Diagnosis (PGD) — where
embryos are selected based on their pattern of gene
expression — and the risks could be captured under
existing regulatory frameworks [39].therapy
While the use of GGE for reproduction remains in the
future, another type of genetic modification has been
legalised in the United Kingdom [40]. Mitochondrial
replacement therapy (MRT) is a broad term referring
to techniques which involve the creation of human
embryos using mitochondria from third party [41].
Employed to prevent transmission of mitochondrial dis-
ease and allow a woman to conceive a child that is
biologically hers, a child created using this technology
will inherit their genomic (nuclear) DNA from their
‘biological’ parents but their mitochondria (and the
DNA contained within these organelles) from an egg
donor.
The key ethical issues that MRT raises include questions
about the long-term safety of the technology [42];
whether mitochondrial changes can alter the identity of
a child [43,44]; and whether it should be considered as a
type of germline therapy [41]. In response to some of
these concerns, the National Academy of Sciences has
recommended limiting MRT, to male children [45]; who
do not pass their mitochondria on to future generations.
Chimeric organisms
Chimeras are organisms composed of cells from two or
more ‘individuals’. While chimeric mice — usually cre-
ated by aggregating cells from different embryos or by
introducing an embryonic stem cell into a developing
blastocyst — have been an essential aspect of biological
research for decades, more recently researchers have been
using these techniques to create animals where the chi-
meric contribution from human cells is predominantly
restricted one organ. For example, in an effort to address
Current Opinion in Genetics & Development 2018, 52:7–12
the organ transplant shortage, one U.S. group is seeking to
create genetically modified pigs, where the pancreas is
composed of human cells [46]. The resulting genetically
modified pigs could help save lives with some arguing we
have strong moral imperative to develop these chimeras
for use in organ transplantation [47]. Others point to
worries that growing human cells in an animal could
inadvertently affect the developing animal in ways that
go well beyond the localized formation of human organs.
For example, it is possible that human cells could migrate
to the nervous system and effect brain development,
resulting in animals with ambiguous moral status [48].
The need to justify application
A theme cutting through all of the above ethical issues is
the need for a feasible justification to underpin the
application. While deepening understanding and advanc-
ing progress towards a therapeutic outcome may be
sufficient to justify GGE in basic research, applications
aiming at reproductive uses of GGE should only be
considered in a limited set of circumstances (see Table 1).
Despite this, four out the five initial studies performing
GGE have justified their work through speculative ther-
apeutic goals that could arguably be met using existing
reproductive technologies (see Table 2). Only one study
has used CRISPR to investigate early development.
Given the controversial nature of genetically modifying
children; and the fact that more advanced methods of
gene editing is likely to be developed in the near future,
the justification for such research is precarious. What is
the long-term value of knowing how effectively CRISPR-
Cas9 can alter HIV resistance genes, when we do not even
know how significant of a health problem HIV will be in
50 years? Why correct for a mutation that causes thalas-
semia or heart disease when PGD has already been shown
to be able to select embryos that do not carry these, and
similar genetic conditions, without the risk of off-site
genetic modifications to the child?
The risks are not just to scientific progress. While surveys
of public opinions are generally supportive of gene edit-
ing technologies [49,50], this could quickly erode. We
echo concerns expressed elsewhere that pursuit of gene
editing research aimed at reproductive applications needs
to consider assumptions related to reproductive options
and disease ‘seriousness’ [51]. Researchers have a duty of
care to be involved in the ongoing debate.
Conflict of interest
Neither MM or CG work for, consult, own shares in or
receive funding from any company or organisation that
would benefit from this article.
Acknowledgements
Christopher Gyngell, through his involvement with the Murdoch Children’s
Research Institute, received funding from the Victorian State Government
through the Operational Infrastructure Support (OIS) Program.
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 Ethics and genetic modification: why application matters Munsie and Gyngell 11
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Frames a discussion about human/nonhuman chimera research by not-
ing that the National Institutes of Health (NIH) is poised to lift its funding
moratorium on research. Notes how the creation of chimeric organisms
has been possible for decades, however recent technologies — such as
blastocyst complementation — allow for acute levels of human/nonhu-
man mixing in stem-cell–based chimeras, which may create novel ethical
issues. Hyun, next notes the benefits of such research, including that it
could allow human organs to be grown in others animals for transplanta-
tion. Hyun then discusses a risk of such research, namely that embryo
complementation could inadvertently affect the developing animal in
ways that cause it to have an ambiguous moral status, for example,
through effecting the development of the organisations brain. This worry
Hyun refers to as ‘moral humanising’ of the research animal. It concludes
that ‘chimera research should prioritize animal welfare principles while at
the same time enabling scientific progress in areas of humanitarian
importance, albeit in a manner consistent with these principles.’.
49. Scheufele DA, Xenos MA, Howell EL, Rose KM, Brossard D,
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51. Hyun I, Osbourne C: Query the merits of embryo editing for
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Letter to the editor in relation to ‘questionable value assumptions’ raised
in first report to correct gene mutation in viable human embryos. Places
this in context of recent NAS guidelines highlighting gaps/ambiguity in
interpretation of three of these suggested requirements: Firstly, determin-
ing if there are reasonable alternatives; secondly, how to determine
seriousness of disease or condition and finally, how to establish health
and societal benefits AND risks via broad and ongoing public engage-
ment. Noting ‘waiting until after the preclinical stages of research are well
under way bypasses discussion about the philosophical and ethical
wisdom of even pursuing clinical embryo editing in the first place’.
52. Kang X, He W, Huang Y, Yu Q, Chen Y, Gao X, Sun X, Fan Y:
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