Human Germline Interventions–Think First

Abstract

Recent studies using gene editing tools such as CRISPR/Cas9 have shown an enormously broad spectrum of possible future applications. This genetic engineering technique allows researchers to easily disable, insert, or replace DNA fragments, while raising risks such as incomplete or inaccurate editing, off-target mutations, and other unintended consequences. Whereas there is consensus that possible future uses in somatic cells hold enormous promise in clinical contexts, human germline interventions, i.e., the genetic modification of human gametes or embryos, are highly controversial (Baltimore et al., 2015; Lander, 2015; Lanphier et al., 2015; Miller, 2015; Pollack, 2015; Savulescu et al., 2015).

Full text

OPINION
published: 09 May 2016
doi: 10.3389/fgene.2016.00081
Frontiers in Genetics | www.frontiersin.org 1May 2016 | Volume 7 | Article 81
Edited by:
Dov Greenbaum,
Yale University, USA
Reviewed by:
Amy L. Fletcher,
University of Canterbury, New Zealand
Nanibaa’ A. Garrison,
Seattle Children’s Research Institute,
USA
Bettina Bock Von Wülfingen,
Humboldt-Universität zu Berlin,
Germany
*Correspondence:
Elisabeth Hildt
ehildt@iit.edu
Specialty section:
This article was submitted to
ELSI in Science and Genetics,
a section of the journal
Frontiers in Genetics
Received: 24 February 2016
Accepted: 20 April 2016
Published: 09 May 2016
Citation:
Hildt E (2016) Human Germline
Interventions–Think First.
Front. Genet. 7:81.
doi: 10.3389/fgene.2016.00081
Human Germline Interventions–Think
First
Elisabeth Hildt *
Center for the Study of Ethics in the Professions, Illinois Institute of Technology, Chicago, IL, USA
Keywords: germline, gene editing, CRISPR, gene therapy, human embryo, ethics, societal implications, ELSI
Recent studies using gene editing tools such as CRISPR/Cas9 have shown an enormously broad
spectrum of possible future applications. This genetic engineering technique allows researchers to
easily disable, insert, or replace DNA fragments, while raising risks such as incomplete or inaccurate
editing, off-target mutations, and other unintended consequences. Whereas there is consensus that
possible future uses in somatic cells hold enormous promise in clinical contexts, human germline
interventions, i.e., the genetic modification of human gametes or embryos, are highly controversial
(Baltimore et al., 2015; Lander, 2015; Lanphier et al., 2015; Miller, 2015; Pollack, 2015; Savulescu
et al., 2015).
Up to now, at least in Western countries, there has been a broad consensus to
ban interventions that aim to modify the human germline. For example, the Council of
Europe’s Convention on Human Rights and Biomedicine from 1997 (http://conventions.
coe.int/Treaty/en/Treaties/Html/164.htm) reads in Article 13:
“An intervention seeking to modify the human genome may only be undertaken for preventive,
diagnostic, or therapeutic purposes and only if its aim is not to introduce any modification in the
genome of any descendants.”
In December 2015, the Council of Europe’s Committee on Bioethics adopted a Statement
on Genome Editing Technologies (https://rm.coe.int/CoERMPublicCommonSearchServices/
DisplayDCTMContent?documentId=090000168049034a) that stresses the relevance of the
Convention on Human Rights and Biomedicine with regard to gene editing techniques.
Article 1 of UNESCO’s Universal Declaration on the Human Genome and Human Rights
from 1997 states (http://portal.unesco.org/en/ev.php-URL_ID=13177&URL_DO=DO_TOPIC&
URL_SECTION=201.html):
“The human genome underlies the fundamental unity of all members of the human family, as well as the
recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity.”
This can be seen in the context of UNESCO’s Universal Declaration on Bioethics and Human
Rights (2005) (http://portal.unesco.org/en/ev.php-URL_ID=31058&URL_DO=DO_TOPIC&
URL_SECTION=201.html) which says in Article 16: “The impact of life sciences on future
generations, including on their genetic constitution, should be given due regard.”
In October 2015, a UNESCO panel of experts called for a temporary ban on
editing the human germline (http://www.unesco.org/new/en/social-and-human-sciences/
themes/bioethics/sv0/news/unesco_panel_of_experts_calls_for_ban_on_editing_of_human_dna_
to_avoid_unethical_tampering_with_hereditary_traits/#.VwgJUvkrJaQ).
Many countries ban germline genetic modification either by law or by guidelines, while other
countries are ambiguous about the legal status of germline modifications (cf. Araki and Ishii, 2014).
These regulations and agreements are to be seen against the background of a long
interdisciplinary debate on ethical and societal issues of germline interventions that began in the

Hildt Human Germline Interventions–Think First
1980s. In this debate, a broad spectrum of topics has been
discussed, including medical issues concerning safety and
efficacy, possible health benefits, risks and unintended
consequences for future generations, and ethical issues such as
individual and collective responsibility, reproductive autonomy,
human dignity, the moral status of human embryos, human
nature, tampering with human evolution, playing God, eugenics,
discrimination, human enhancement, and transhumanist
visions.
Up to a few months ago, in the absence of a technique to
modify the human germline by disabling, inserting, or replacing
DNA fragments, the debate on human germline interventions
seemed to be rather academic and theoretical, far away from
any reality. It is the advent of this new technique of gene
editing and the observation that it can in principle be used to
modify the DNA of the resulting organism and its offspring
that revitalizes the debate on germline interventions and gives
it a new direction. In this, the mere availability of a technique
that allows us to modify the human germline seems to provide
a strong push toward human germline interventions. Whereas
the plausibility or implausibility of the various arguments
in the debate around human germline interventions has not
changed, the situation around this debate is quickly evolving:
the worldwide scientific community watches an exciting scientific
breakthrough, scientists are engaging in a new field of research,
and manuscripts are appearing that put pressure on scientific
journals to publish them (Sharma and Scott, 2015). All of this
seems to develop a strong momentum of its own, resulting
in a rush toward using this new technique for germline
intervention.
Recently, a group of Chinese researchers published the
results of human germline modification experiments involving
tripronuclear zygotes, i.e., zygotes that are not capable of
developing normally (Liang et al., 2015). In December 2015, the
members of the Organizing Committee for the International
Summit on Human Gene Editing, in which leading researchers
in the field participated, published a summit statement
(http://www8.nationalacademies.org/onpinews/newsitem.aspx?
RecordID=12032015a). In this, they do not exclude in-vitro
research involving human germline interventions as long as
the modified cells are not used to establish a pregnancy, but
for the time being argue against any clinical use of germline
editing. During the past few months, also others have spoken in
favor of running in-vitro human germline genetic interventions
(Baltimore et al., 2015; Miller, 2015). Some scientists have argued
toward a general ban of human germline modifications using
the CRISPR/Cas9 technique and similar techniques, however,
(Lanphier et al., 2015; Pollack, 2015).
There is an urgent need to step back and think about
what is going on. The recent move toward running in-vitro
human germline interventions is a remarkable development.
This is particularly true as currently, in view of the high
risks and unresolved practical, societal and ethical issues
involved, nobody would ever argue toward attempting
human germline modifications that involve initiating a
pregnancy. However, the move toward in-vitro human
germline interventions attempts to set the stage for future
uses involving human reproduction. Even if in-vitro studies
involving only early stages of human embryonic development
are far less problematic from a practical and ethical point of
view than research involving the initiation of a pregnancy or
the birth of a child, they are still highly problematic. In-vitro
research with early human embryos clearly is not done in
a vacuum but has to be seen in the broader context of the
attempt to find possible future applications involving human
reproduction.
THERE ARE NO NEW POWERFUL
ARGUMENTS IN FAVOR OF HUMAN
GERMLINE INTERVENTIONS
Are there any new powerful arguments in favor of human
germline interventions? I do not see any.
The main argument put forward in favor of clinical germline
interventions is that they may serve to prevent diseases and avoid
possible suffering in future generations. It has been proposed
that germline interventions might be an appropriate tool for
the prevention of monogenic diseases in situations in which
there is a 100% probability that the disease will be passed on to
the progeny. This is the case when one parent is homozygous
for a dominant disease or both parents are homozygous for
an autosomal recessive disease. Sickle cell anemia or recessive
deafness would be examples of the latter (Wivel and Walters,
1993; Lander, 2015; Miller, 2015). However, situations like these
are very rare. It is questionable whether there would be broader
justifiable medical uses for germline interventions, especially in
view of the availability of genetic testing and pre-implantation
genetic diagnosis.
Furthermore, speculations on possible future additional
applications seem to play a considerable role in the rush toward
human germline interventions. These include the possibility
of risk reduction in widespread multigenic and multifactorial
disorders such as cardiovascular disease or cancer. However,
interactions between the numerous genetic and environmental
factors are most often very complicated so that it is questionable
whether the risks involved would ever outweigh the potential
benefits (Wivel and Walters, 1993; Lander, 2015).
In addition, germline interventions may be considered a
future option for parents who attempt to specify more than
one trait of their future offspring. It might be easier to
genetically modify the traits in question than to attempt to
select embryos with the desired traits from a limited number of
available embryos by using pre-implantation genetic diagnosis
(cf. Savulescu et al., 2015).
Beyond that, according to further speculations, germline
gene editing may render it possible to influence a broad
spectrum of traits or enhance human capabilities. With germline
genetic interventions, the choices available for future parents
would increase considerably. This opens up the debate for
speculations on improving mankind, genetic enhancements,
eugenics and designer babies, all of these clearly underlining the
manifold ethical and societal issues involved in human germline
interventions. Interestingly, with regard to human germline
Frontiers in Genetics | www.frontiersin.org 2May 2016 | Volume 7 | Article 81

Hildt Human Germline Interventions–Think First
interventions, several authors consider a development toward
genetic enhancements to be inevitable (Wivel and Walters, 1993;
Baylis and Robert, 2004).
AVOID PREMATURE EXPERIMENTS
In his article “Human gene therapy: scientific and ethical
considerations” published in 1985, W. French Anderson named
three conditions that should be met prior to any attempt to
undergo germline gene therapy in humans: Substantial previous
experience with somatic cell gene therapy in humans proving
safety and efficacy of the approach; adequate animal research
that shows the reproducibility, reliability, and safety of germline
therapeutic interventions; and the informed public approval of
the procedure (Anderson, 1985).
In spite of the fact that neither comprehensive knowledge with
gene editing of somatic cells nor with germline applications in
animal studies is available at the moment, in-vitro experiments
involving human germline modifications have already been
initiated (Liang et al., 2015)1. Whereas in-vitro studies are far
less problematic than studies using gene editing in reproductive
contexts, it should not be forgotten that in-vitro studies involving
human embryos bear considerable practical and ethical issues
when it comes to the creation and destruction of human embryos
for research purposes or to the use of surplus in-vitro fertilization
(IVF) embryos. For the time being, considering the moral status
of human embryos and the lack of adequate experience with gene
editing tools, in-vitro human germline interventions involving
human embryos can hardly be justified.
Furthermore, before overriding general standards that have
been agreed upon widely in Western societies, it will be absolutely
1Albeit in this particular study, the tripronuclear zygotes involved were not capable
to develop normally.
necessary to thoroughly reflect on the issues involved. For this, a
broad societal debate on the practical, societal, and ethical issues
in human germline interventions involving the various groups
within society is urgently needed. Beyond an interdisciplinary
academic debate involving disciplines such as medicine, natural
sciences, humanities, social sciences and the law, it will be
particularly important for scientists to inform the public of the
ongoing development and to engage in a serious dialog with
critical stakeholders.
Only widely held and well informed public approval can
legitimize researchers to go on in a sensitive field like this which
has the power to affect society as a whole. For the time being,
however, not much is known on the opinion of the public. Up
to now, the controversy on gene editing and human germline
interventions is dominated by scientists involved in the field. The
general public, it seems, has difficulties keeping abreast with the
quick development and understanding the issues at stake.
For sure, a balanced debate that involves a broad spectrum of
the various societal groups will have an open outcome. It may be
the case that societal values change over time, that the balancing
of pros and cons is done differently now than it was done in the
past, or that new and important arguments in favor of or against
germline interventions will come up. But all of this needs careful
and thorough reflection.
In view of the unresolved practical, ethical and societal issues,
for the time being, it is more than advisable to refrain from any
experiments involving human germline interventions. Instead:
Think first. Don’t hastily override existing standards broadly
agreed upon.
AUTHOR CONTRIBUTIONS
The author confirms being the sole contributor of this work and
approved it for publication.
REFERENCES
Anderson, W. F. (1985). Human gene therapy: scientific and ethical considerations.
J. Med. Philos. 10, 275–291. doi: 10.1093/jmp/10.3.275
Araki, M., and Ishii, T. (2014). International regulatory landscape and integration
of corrective genome editing into in vitro fertilization. Reprod. Biol. Endocrinol.
12:108. doi: 10.1186/1477-7827-12-108
Baltimore, D., Berg, P., Botchan, M., Carroll, D., Charo, R. A., Church, G., et al.
(2015). A prudent path forward for genomic engineering and germline gene
modification. Science 348, 36–38. doi: 10.1126/science.aab1028
Baylis, F., and Robert, J. S. (2004). The inevitability of genetic enhancement
technologies. Bioethics 18, 1–26. doi: 10.1111/j.1467-8519.2004.00376.x
Lander, E. S. (2015). Brave new genome. N. Engl. J. Med. 373, 5–8. doi:
10.1056/NEJMp1506446
Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., and Smolenski, J. (2015). Don’t
edit the human germ line. Nature 519, 410–411. doi: 10.1038/519410a
Liang, P., Xu, Y., Zhang, X., Ding, C., Huang, R., Zhang, Z., et al. (2015).
CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein
Cell 6, 363–372. doi: 10.1007/s13238-015-0153-5
Miller, H. I. (2015). Germline gene therapy: we’re ready. Science 348:1325. doi:
10.1126/science.348.6241.1325-a
Pollack, R. (2015). Eugenics lurk in the shadow of CRISPR. Science 348:871. doi:
10.1126/science.348.6237.871-a
Savulescu, J., Pugh, J., Douglas, T., and Gyngell, C. (2015). The moral imperative
to continue gene editing research on human embryos. Protein Cell 6, 476–479.
doi: 10.1007/s13238-015-0184-y
Sharma, A., and Scott, C. T. (2015). The ethics of publishing human germline
research. Nat. Biotechnol. 33, 590–592. doi: 10.1038/nbt.3252
Wivel, N. A., and Walters, L. (1993). Germ-line gene modification and disease
prevention: some medical and ethical perspectives. Science 262, 533–538. doi:
10.1126/science.8211180
Conflict of Interest Statement: The author declares that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2016 Hildt. This is an open-access article distributed under the terms
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