Mammalian Genome

https://doi.org/10.1007/s00335-018-9791-2

Fearful old world? A commentary on the Second International Summit

on human genome editing
Andy Greenfield1 

Received: 17 December 2018 / Accepted: 19 December 2018

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Genome editing is revolutionising our ability to modify genomes with exquisite precision for medical and agricultural
applications, and in basic research. The first International Summit on Human Genome Editing, organised jointly by the US
National Academies of Sciences and Medicine, the Chinese Academy of Sciences and the UK Royal Society, was held in
Washington DC at the end of 2015. Its aim was to explore scientific, legal and ethical perspectives on the prospective use of
human genome editing as a therapeutic intervention in disease (so-called somatic genome editing) and as a possible inter-
vention in human reproduction (so-called germ-line genome editing). Following that Summit, the Organising Committee
had, in a press release, come to the conclusion that: “It would be irresponsible to proceed with any clinical use of germ line
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 appropriateness of
the proposed application” (http://www8.natio​nalac​ademi​es.org/onpin​ews/newsi​tem.aspx?Recor​dID=12032​015a). A report
from the US National Academies subsequently reiterated and developed the approach.

Introduction societal consensus about the appropriateness of the proposed

Genome editing is revolutionising our ability to modify
genomes with exquisite precision for medical and agricul-
tural applications, and in basic research. The first Interna-
tional Summit on Human Genome Editing, organised jointly
by the US National Academies of Sciences and Medicine,
the Chinese Academy of Sciences and the UK Royal Society,
was held in Washington DC at the end of 2015. Its aim was
to explore scientific, legal and ethical perspectives on the
prospective use of human genome editing as a therapeutic
intervention in disease (so-called somatic genome editing)
and as a possible intervention in human reproduction (so-
called germ-line genome editing). Following that Summit,
the Organising Committee had, in a press release, come to
the conclusion that: “It would be irresponsible to proceed
with any clinical use of germ line 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
* Andy Greenfield
a.greenfield@har.mrc.ac.uk
1
MRC Mammalian Genetics Unit, Harwell Institute, Harwell,
Oxfordshire OX11 0RD, UK
application” (http://www8.nation​ alaca​ demie​ s.org/onpine​ ws/
newsi​tem.aspx?Recor​dID=12032​015a). A report from the
US National Academies subsequently reiterated and devel-
oped the approach summarised in the 2015 press release
(National Academies of Sciences 2017).
It was against this backdrop, and that of ongoing and
rapid technological developments in the field of human
genome editing, that delegates assembled in Hong Kong in
November 2018 for the Second International Summit, again
organised by a group of national academies. However, as a
tabloid newspaper editor might exclaim, the summit was
‘rocked’ before it had even begun by the news of the birth of
twins following genome editing of human embryos in China.
This commentary is a selective, and sometimes unavoid-
ably personal discussion of prominent scientific and ethical
themes that emerged during the second Summit.
To cut or not to cut? Homology‑directed
repair and base editing
Assessments of accuracy, fidelity and efficiency, defined
in a number of ways and performed in a number of bio-
logical systems, have been central to the development of

13
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 A. Greenfield
CRISPR-based genome editing since 2015. Whilst off-target
events are widely thought to be minimal in the most studied
experimental model, the mouse zygote (Ayabe et al. 2018),
attention has turned recently to undesirable on-target events.
The mouse model has been especially helpful here, with a
number of labs describing the generation of large on-target
deletions or other complex rearrangements (Codner et al.
2018; Kosicki et al. 2018; Shin et al. 2017), which may be
difficult to detect if primer-binding sites used for routine
PCR assays are deleted as a consequence. But these observa-
tions are not mouse-specific. In her talk describing editing of
the POU5F1 gene in human embryos, Kathy Niakan (Crick
Institute, UK) also described large deletion events and seg-
mental losses or gains of chromosome 6 (where the gene
resides) in cells derived from edited embryos. Interestingly,
such large-scale events have been suggested as an alternative
explanation (Adikusuma et al. 2018; Egli et al. 2018) for the
apparent inter-homologue repair observed in human zygotes
following an attempt at CRISPR/Cas9-mediated homology-
directed repair (HDR) of a pathogenic mutation (Ma et al.
2017), though this alternative explanation is contested (Ma
et al. 2018).
Given the difficulty of precisely controlling the manner
in which a double-stranded break in DNA is repaired, and
the apparent commonality of non-homologous end-joining
(NHEJ) or micro-homology-mediated end-joining (MMEJ)
in comparison to HDR, researchers have sought alternative
methodologies to edit genome sequences. In his talk, David
Liu (Broad Institute, USA) gave a review of the rapid pro-
gress of one such methodology, base editing, including data
from his own lab that have contributed to that progress. The
potential importance of base editing in a clinical context is
enhanced by the fact that most human diseases that have at
least some explanation at the genetic level are caused by
single nucleotide variants.
Liu’s lab first reported the use of base editing in 2016,
with the use of endonuclease-deficient Cas9 fused with cyti-
dine deaminase, which can be delivered to a specific locus
by a guide RNA in order to directly convert cytidine to uri-
dine, thereby resulting in a C to T substitution (Komor et al.
2016). Since that time, second- and third-generation base
editors have been developed, employing lab-based evolution
of novel Cas9 variants, that expand the scope of this method-
ology by maximising the breadth of the targetable genome
(Hu et al. 2018; Kim et al. 2017), reducing bystander and
off-target edits (Kim et al. 2017; Rees et al. 2017) and estab-
lishing base editing in post-mitotic somatic cells (Yeh et al.
2018). Liu described encouraging preliminary work aimed
at using base editing to correct a pathogenic mutation in
a mouse model of Hutchinson–Gilford progeria syndrome,
mediated by adeno-associated virus (AAV) delivery. High
ratios of editing to indel production are routinely reported,
as are minimal off-target events, although such undesirable
13
events have been reported by others using base editing (Yang
et al. 2018). This methodology highlights two features of
genome editing: (i) the rapid expansion of the CRISPR/
Cas toolkit and its amazing flexibility; and (ii) the difficulty
in establishing a ‘gold standard’ for assessing fidelity and
efficiency that can be used to compare data from different
labs and systems. Other speakers at the summit described
genome-editing innovations, including epigenome editing,
the possibility of RNA base editing and methodologies for
controlling the activity of Cas9 through the use of naturally
occurring inhibitors of its activity. Several labs are also
actively seeking novel, programmable bacterial endonucle-
ases for use in genome-editing procedures. All of these may
have far-reaching implications for clinical applications of
genome editing.
Shock and awe: editing the CCR5 gene
in human embryos
The use of mouse models of human genetic disease to assess
methodologies was a prominent theme at the Summit. How-
ever, in the context of reproductive applications, the effi-
ciency of genome editing in human embryos is currently
the primary area of interest. Such human embryo genome
editing, including base editing, has been reported on several
occasions. Uses have included basic studies of gene func-
tion (Fogarty et al. 2017), and assessments of the feasibility
of using genome editing to correct pathogenic mutations in
human zygotes, whilst avoiding mosaicism, as a means of
preventing the transmission of monogenic diseases (Liang
et al. 2017; Ma et al. 2017). Such interventions are unlawful
in most jurisdictions. Moreover, several reviews of the ethi-
cal acceptability of human germ-line genome editing have
indicated that, even if a safe and efficacious methodology
can be developed, a wide-ranging debate that involves all
stakeholders and publics is a prerequisite of any change to
legislative and governance frameworks (Nuffield Council on
Bioethics 2018; de Wert et al. 2018; National Academies of
Sciences 2017).
It was in this context that the announcement of the
genome-edited Chinese twins had its extraordinary impact.
Many doubted that it could be true, for scientific, ethical
and legal reasons. But Dr Jianqui He, who had been invited
to speak at the Summit before details of the true nature of
his project were available, described on the stage of the
Summit precisely what he had done. This was a scientific
talk, and a session, unlike any I had witnessed before, and I
have written elsewhere about its impact on me (Greenfield
2018a). Briefly, it was a calm presentation, in a high-voltage,
dramatic atmosphere, that revealed the product of a conflu-
ence of both technological and social opportunities. Dr He
described how he had generated human embryos containing
Fearful old world? A commentary on the Second International Summit on human genome editing
deletions of the CCR5 gene, a gene of essentially unknown
function with reported roles in the immune system and cog-
nition. He proceeded to establish pregnancies with edited
embryos, in an attempt to fashion humans with immunity
to HIV infection. The father of the resulting twins is HIV-
positive, but it is unclear whether consent to the procedure
was obtained on the basis that this genomic intervention
was the only way to ensure that his children would not be
infected by the virus. But this claim would be unwarranted,
since there are established protocols for preventing trans-
mission in such cases. Moreover, could Dr He ensure the
safety of the intervention? Almost certainly not, given the
preceding discussion of CRISPR/Cas9 methodologies and
reported uncertainties that persist in respect of their applica-
tion to human embryos. But, HIV infection is stigmatised to
a high degree in Chinese society, suggesting that there may
be a perceived social demand for such an intervention. Some
social scientists in the audience sensed the powerful wheels
of the commercial biotechnology sector beginning to move.
And so, despite most of us thinking of potential applications
of germ-line genome editing in the prevention of disease
transmission, it turns out, if the claims are true, that the
first genuine use was more a public health intervention, a
form of genomic immunisation. The audience was left per-
plexed, amazed and alarmed, probably in equal measure, by
this apparent human experimentation. It will be important,
given the nature of the claims, that all data are appropriately
scrutinised by independent parties. Such scrutiny includes
peer review of a manuscript, although it is unclear whether
any journal will be prepared to publish a paper if appropriate
adherence has not been made to local governance, regulatory
or ethical guidelines.
Does a prudent path forward require broad
societal consensus?
During his talk, George Daley (Harvard Medical School)
discussed pathways to translation, including indications
that warrant reproductive interventions, urging the audi-
ence, with Dr He in mind, not to lose sight of the prom-
ise of genome editing: ‘just because the first steps… are
mis-steps… this should not prevent us from thinking about
plausible and responsible pathways to clinical translations’.
Many somatic applications of genome editing are now enter-
ing clinical trials, but should such sentiments be a guide
to thinking about germ-line interventions? Wouldn’t they
still be “irresponsible”, as stated in 2015? Daley insisted
that, unlike in 2015, the safety of germ-line interventions
using genome editing was now in sight and that possible
clinical germ-line editing was therefore a topic for urgent
and widespread discussion. He also suggested, reasonably,
that two recent ethical reviews indicated that such germ-line
interventions could be seen as morally permissible in cer-
tain circumstances, if certain conditions are met (Nuffield
Council on Bioethics 2018; National Academies of Sciences
2017).
Nevertheless, I detected some disquiet on the part of
social scientists in the audience on the final day of the sum-
mit; the commitment to broad societal consensus evident in
the 2015 press release was absent, or de-emphasised, in the
final statement of the organisation committee of the second
Summit (http://www8.natio​nalac​ademi​es.org/onpin​ews/
newsi​tem.aspx?Recor​dID=11282​018b). Instead, the 2018
press release states: “germline genome editing could become
acceptable in the future if… risks are addressed and if a
number of additional criteria are met. These criteria include
strict independent oversight, a compelling medical need, an
absence of reasonable alternatives, a plan for long-term
follow-up and attention to societal effects. Even so, public
acceptability will likely vary among jurisdictions, leading to
differing policy responses”. Some pointed out that history
had taught us about the importance of science proceeding
with societal consent, and as such, a consensus was still a
critical objective. How to achieve such consent, of course,
is a question that will challenge different nation states in
different ways, as the press release indicates.
My position on the possibility of human germ-line
interventions has been influenced by my involvement with
the UK Human Fertilisation and Embryology Author-
ity (HFEA), which regulates treatment with, and research
on, human embryos. I have previously pointed out that the
HFEA already regulates two germ-line interventions: mito-
chondrial donation (Greenfield et al. 2017) and preimplan-
tation genetic diagnosis (PGD) (Greenfield 2018b). PGD
is arguably a germ-line intervention that appears not to be
widely recognised as such: it involves procurement of human
gametes, the creation of embryos in vitro (IVF), the biopsy
and genetic testing of all of those embryos and then the dese-
lection of those that fall into the undesired genotypic class,
all in the name of disease prevention. Given this, it seems to
me that whether and how we should employ alternative tech-
niques for achieving the same outcome, namely the birth of
individuals free from inheritable diseases, should be a matter
of mature and calm discussion in the UK moving forward,
since such techniques, such as embryo genome editing, may
meet an unmet clinical need; not least because PGD has its
drawbacks (Steffann et al. 2018). Genome editing, of course,
raises ethical issues that go beyond those raised by interven-
tions such as PGD, but robust regulation could be used to
restrict its application to the least contentious circumstances,
as is the case with PGD. We need to embrace, rather than
fear, broad and inclusive societal debates about such mat-
ters, which eschew overly simplistic tropes and narratives.
My own talk at the Summit emphasised the importance of
creating a shared language in which such conversations can
13
 A. Greenfield
happen. Indeed, it was gratifying to see several sessions at
the Summit dedicated to the topics of public engagement
efforts, broader societal considerations and the need for
democratic governance. Benjamin Hurlbut (Arizona State
University), an historian and ethicist, offered an insightful
discussion of the history of biotechnological innovations,
historical norms and the legitimacy of governance, primarily
in the US. “A commitment to ethics must be a commitment
to infrastructures of participation and deliberation”, he con-
cluded. Hurlbut and colleagues have suggested ways forward
in respect of developing governance of human genome edit-
ing, involving the establishment of a global genome-editing
observatory (Jasanoff and Hurlbut 2018).
Finally, any debate on applications of genome editing,
and genomic technologies more broadly conceived, should
also include an evaluation of the continued importance of
research using animal models and human embryos, in the
name of both feasibility tests of genome-editing interven-
tions and basic research to enhance our knowledge of biolog-
ical mechanisms. We should not let ourselves be distracted
from these broader goals by the unsettling claims concerning
genome-edited twin girls in China, or driven to moral panic
by the inevitable references, or allusions, to the dystopian
vision of Huxley’s Brave New World. I look forward to the
third international summit on genome editing, to be held in
London in 2021.
Funding  This study was funded by Medical Research Council (UK)
(Grant No. MC_U142684167).
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