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The American Journal of Bioethics
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CRISPR-Cas Gene Editing to Cure Serious Diseases:
Treat the Patient, Not the Germ Line
Ante S. Lundberg & Rodger Novak
To cite this article: Ante S. Lundberg & Rodger Novak (2015) CRISPR-Cas Gene Editing to Cure
Serious Diseases: Treat the Patient, Not the Germ Line, The American Journal of Bioethics,
15:12, 38-40, DOI: 10.1080/15265161.2015.1103817
To link to this article: http://dx.doi.org/10.1080/15265161.2015.1103817
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Ante S. Lundberg and Rodger Novak
Published online: 02 Dec 2015.
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Date: 08 December 2015, At: 14:43
The American Journal of Bioethics
CRISPR-Cas Gene Editing to Cure
Serious Diseases: Treat the Patient,
Not the Germ Line
Downloaded by [65.254.18.186] at 14:43 08 December 2015
Ante S. Lundberg, CRISPR Therapeutics
Rodger Novak, CRISPR Therapeutics
CRISPR-Cas9 is a powerful new technique that allows for
precise editing of DNA, the genetic code in all the cells of
our body. It is also broadly available and easy to use,
which has raised the fear of improper intervention into
human biology and led to calls for a moratorium on some
types of gene editing research (Lander 2015; Lanphier et al.
2015). As physicians experienced in the discovery and
development of new treatments for disease (currently we
are both senior executives of CRISPR Therapeutics), we do
not believe that a blanket moratorium is the right
approach. While we welcome considerations regarding the
ethical uses of gene-editing technologies, it is at least as
important—and ethically relevant—to also consider the
powerful potential of gene editing in general, and CRISPRCas9 in particular, to treat the millions of patients who are
impacted by a number of very serious diseases. For the
vast majority of diseases, a gene editing approach need not
employ the heritable germ line cells that transmit genetic
information to subsequent generations. Instead, genetic
diseases typically manifest in, and gene editing can be
applied in, somatic cells, for which the older gene therapy
methods are widely accepted and where a well-established
and tested regulatory framework already exists in both the
United States and Europe.
CRISPR-Cas9 itself and as a tool for gene editing was
elucidated just a few years ago by a cofounder of CRISPR
Therapeutics, Emmanuelle Charpentier, and her colleagues (Deltcheva et al. 2011), and in collaboration with
Jennifer Doudna and colleagues (Jinek et al. 2012). The
importance of this discovery—to be able to more easily
and selectively edit the underlying DNA code of cells—
cannot be overstated. CRISPR has already revolutionized
basic research by allowing scientists to readily modify the
genome of cells and model organisms, enabling the development of an expanding set of tools to understand fundamental biological questions. “CRISPR” derives from the
“clustered regularly interspersed short palindromic
repeats” in the bacterial genome where the gene editing
machinery was found, and Cas9 is an endonuclease protein that breaks up and thus deactivates the DNA of invading viruses. This system has been characterized in a wide
range of bacteria (reviewed in Makarova et al. 2013). The
adoption of CRISPR gene editing for use in research, and
for developing novel medicines, has been remarkably rapid,
in part because it is so easy to apply these fundamental discoveries to higher organisms including, in principle,
humans (reviewed in Doudna and Charpentier 2014). These
easy and accessible methods are making DNA programmable in a way that is already having a profound impact on
human, animal, and crop plant biology. The scientists and
developers of treatments based on this new technology are
becoming the ultimate coders (Keller 2015).
The rapid advance of CRISPR gene editing has evoked
a predictable debate regarding “reprogramming DNA,”
similar to the concerns regarding genetic manipulation
that have been raised since the earliest days of gene cloning (reviewed in Comfort 2015). In particular, modifying
DNA of germline cells, which is passed down to subsequent generations, may have lasting effects on the human
gene pool. While the effects of modifying the genome with
gene editing in a somatic, non-germline cell of a patient
are increasingly being understood, the longer term effects
of modifying the germ line, including in the patient’s
descendants, are less well known. The concern is more
than theoretical: A research group in China recently
employed CRISPR-Cas9 technology to make changes in
human germline cells, changes that could in principle both
be expressed in a human being and then later be passed on
via sperm or egg cells to subsequent generations. We
should emphasize that these particular experiments were
performed in nonviable human embryos and the results
were never going to be able to be expressed in a human
being. Nonetheless, the experimental approach of germline
gene editing employed by this research group, if applied to
viable human embryos, could potentially be expressed in a
human and passed on to descendants.
Ó Ante S. Lundberg and Rodger Novak
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/
licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited. The moral rights of the named author(s) have been asserted.
Address correspondence to Ante S. Lundberg, CRISPR Therapeutics, 675 W. Kendall St., Cambridge MA 02142, USA. E-mail:
[email protected]
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Ethical Tensions Surrounding Germline Editing
Our company is not undertaking any editing of human
germline cells and we have no plans to do so in the future.
Virtually all serious genetic defects manifest in the nonheritable somatic cells, where we find the greatest and most
immediate need, for therapeutic purposes, in editing or
correcting the DNA. It is also more appropriate to apply a
new technology like CRISPR-Cas9 in the setting in which
the consequences of the therapy are directed only to the
patient and are not passed on to or altering the gene pool
for future generations. Ethical support for providing gene
editing therapies in a somatic cell is much like any other
therapy directed at and for the patient, grounded in the
principles of autonomy (the patient’s right to decide),
beneficence (providing benefit), and nonmaleficence (not
doing harm). These issues are represented by the need for
patient informed consent and a favorable risk–benefit profile for a treatment.
Yet even if parents and their physicians agree that
avoiding heritable genetic disease in the current and future
generations is desirable, there are already several ways to
achieve this outcome. Couples can undertake genetic testing prior to pregnancy, or employ in vitro fertilization and
preimplantation genetic diagnosis to implant only those
embryos known to be not at risk for a specific disease.
Some have argued for germline genome editing “in the
extremely rare case when one parent is homozygous for a
dominant disorder [so all offspring inherit one of the dominant disease-associated genes] or both parents are homozygous for a recessive disorder” (such that all offspring
inherit two copies of the recessive disease-associated
genes, one from each parent) (Lander 2015). Even in these
rare cases, however, most diseases will occur, and in principle can be corrected, in specific somatic cells. Given the
existence of alternative non-germline approaches to treat
most Mendelian disorders and the uncertainty of the
impact of the technology on the germline, no modern regulatory system would authorize clinical use of germline
gene editing at the present time.
The challenge of developing CRISPR-Cas-based drugs
for patients, therefore, is not to enable modification of
DNA in germline cells, but rather to apply the current regulatory framework of somatic cell gene modification to
CRISPR-Cas-based medicines. The U.S. Food and Drug
Administration (FDA) guidances and European Medicines
Agency (EMA) guidelines already provide recommendations for manufacturing, preclinical assessment, clinical
evaluation, and product approval for advanced therapy
medicinal products (ATMP) and cellular and gene therapy
products (e.g., see EMA 2010; 2015; FDA 2008; 2013; 2015).
Yet the FDA and EMA procedures differ in important
ways. In the United States the FDA Center for Biologics
Evaluation and Research regulates cellular and gene therapy products on the basis of Section 351 of the Public
Health Service Act (PHS Act 42 U.S.C. 262) on Cellular,
Tissue and Gene Therapies. In the European Union (EU), a
regulation and a set of directives specify the development
of ATMP, regulated through a centralized procedure. A
directive in the EU, but not the United States, also specifies
December, Volume 15, Number 12, 2015
that “no gene therapy clinical trials may be carried out
which result in modifications to the subjects germ line
genetic identity” (European Parliament 2001). The regulatory oversight of clinical trials, and the release of genetically modified organisms (GMOs), are both governed by
directives implemented into national law in each of the EU
member states. Finally each member state can legislate
additional national or regional regulations regarding clinical trials or GMO. For example, in the case of the recently
approved mitochondrial donation therapy for parents of
children conceived by in vitro fertilization, so-called
“three-parent babies,” only the UK Human Fertility &
Embryology Authority undertook a 4-year process of
extensive ethical review, public consultation, reports on
safety and efficacy, review of draft regulations, and recommendations for further research prior to legislative
approval (UK Department of Health 2014). Considerable
work remains to harmonize the processes in developing
ATMPs across the EU member states.
Despite the complex landscape of regulations and regulatory processes across the United States and Europe,
these are well established and tested in the context of
somatic cell gene therapy, and issues requiring harmonization are being addressed. We strongly recommend their
appropriate, flexible application to the clinical evaluation
and marketing authorization of CRISPR-Cas gene editing,
and oppose calls for a blanket moratorium. The vast majority of Mendelian diseases manifest in the somatic cells of a
patient, and it is here, not in the germline, that we must
focus our therapeutic efforts. Given the ease and facility
with which CRISPR gene editing has been able to correct
many different disease causing gene defects in the laboratory, we need to now move forward with developing new
CRISPR gene editing therapies to treat, or even cure, the
many patients currently suffering from a wide range of
devastating diseases.
CONFLICTS OF INTEREST
Ante Lundberg is an employee and shareholder of CRISPR
Therapeutics. Rodger Novak is an employee, shareholder
and director of CRISPR Therapeutics. &
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Editing the Genome of the Human
Germline: May Cool Heads Prevail
Eli Y. Adashi, Brown University
I. Glenn Cohen, Harvard University
Concerns over the prospect of germline modification of the
human genome have recently been rekindled by critical
advances in genome editing paradigms and by a highly
publicized effort to edit the genome of nontransferrable
aneuploid (tripronuclear) human zygotes (Liang, Xu, and
Zhang 2015). As such, these developments have reenergized the debate on the possibility of editing the genome
of the human germline (as Charo and Greely [2015] note in
this issue, animals raise some additional issues). The
articles and commentaries that form this symposium cover
many topics (including the use of metaphor, the role of
social responsibility in science as an evaluative framework,
model regulatory frameworks, and the sense of dej
a vu to
old debates), but they do not attempt to map the rapid
development of policy in this area. In this commentary we
trace the evolving reactions to the prospect of germline
modification and examine where they are converging.
Early to recognize the profound implications of the
new genome editing technology, some parties have called
for an all-out voluntary moratorium on editing the genome
of the human germline in both the research and clinical
arenas (Lanphier et al. 2015; Wadhwa 2015). A comparable
position statement issued by the Society for Developmental Biology proposed a “voluntary moratorium by members of the scientific community on all manipulations of
pre-implantation human embryos by gene editing” (Society for Developmental Biology 2015). The American Society for Gene and Cell Therapy, for its part, advanced a
“strong ban on human germ-line gene editing or other
germ-line genetic modification” until such time that a
“societal consensus [has been] reached” (Friedmann, Jonlin, and King 2015). Finally, the National Institutes of
Health (NIH) announced that it “will not fund any use of
gene-editing technologies in human embryos” (Collins
Address correspondence to Eli Y. Adashi, Professor of Medical Science, The Warren Alpert Medical School, Brown University, 101
Dudley Street, Providence, RI 02905, USA. E-mail: [email protected]
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