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Background: Human genome editing is an area of growing prominence, with many potential therapeutic applications. Sources of data: A project by two UK charities, whose participants included fertility sector patients and practitioners and also people affected by genetic disease and rare disease. Scientiﬁc research into, and wider discussion of, genomics and genome editing. Areas of agreement: There is a need for improved public and professional understanding of genome editing. Areas of controversy: The way genome editing is discussed is often incon- sistent and confusing. Simply deﬁning and explaining the term ‘genome’ can present challenges. Growing points: There are approaches that lend themselves to achieving greater clarity and coherence in discussion of genome editing. Areas timely for developing research: People’s understanding should ideally be able to withstand and evolve alongside current developments in genome editing, rather than being tied ﬁrmly to speciﬁc aspects of genome editing (which may in future be supplanted). Key words: genome editing, public understanding, DNA, CRISPR, fertility, embryo Why talk about genome editing? editing, the deliberate alteration of selected DNA Few topics in biology or medicine have prompted sequences in living cells. Human genome editing 1,2 as much discussion in recent years as genome has many potential therapeutic applications and © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/bmb/article/126/1/5/4985578 by DeepDyve user on 18 July 2022 6 S. Starr, 2018, Vol. 126 is anticipated to be among the most important areas compelling arguments for permitting germline gen- of biomedical innovation in the next 5 years, to ome editing in the clinic—changes to the genome say nothing of the longer-term. that will be inherited by the next generation. Any Patients who could in future beneﬁtfromorother- proposed legal or regulatory change to permit this 8,9 wise be affected by genome editing need a rudimentary should involve thorough public debate. understanding of this subject, as do patients whose involvement is vital if genome editing research is to Involving patients and practitioners proceed. The latter group includes fertility patients, because any research that involves editing the gen- In 2016 and 2017, two UK charities—the Progress omes of human embryos will most likely be dependent Educational Trust (PET) and Genetic Alliance UK— on fertility patients donating surplus embryos follow- carried out a joint project entitled ‘Basic Understanding ing treatment. This was the case with recent research of Genome Editing’, in order to address the need for at the UK’s Francis Crick Institute where the genomes understanding and clear vocabulary in this area. of human embryos were—for the ﬁrst time—edited to Two groups of participants were established for the study the function of a gene during the ﬁrst few days project. One consisted of 14 fertility sector patients of development. and practitioners, and one consisted of 18 people The only alternative to using surplus embryos from affected by—or caring for someone affected by— fertility treatment is to create embryos speciﬁcally for genetic disease or rare disease. Five day-long work- research. It is possible to obtain a licence to do this in shops were conducted with these two groups—two the UK if supernumerary embryos are not available, dedicated workshops per group, plus a larger work- but this still requires the consent of the sperm and egg shop that brought the two groups together. donors from whose gametes the embryos will be cre- During these workshops and during additional ated. Meanwhile, so-called SHEEFs (synthetic human online exercises, participants—whose understand- entities with embryo-like features) are not yet sufﬁ- ing of genome editing was, in all cases, naïve at best— ciently similar to embryos proper to serve as a substi- explored language, imagery and ideas related to the tute (and were they ever to become so, there may be topic. They examined 2 years’ worth of media coverage new ethical and regulatory questions with which to of genome editing, they watched a variety of explana- contend). tory videos, they explored additional material, and Even more than patients, medical practitioners in they heard from—and put questions to—experts in the fertility sector and more generally will increasingly the science and ethics of genome editing. require an understanding of, and clear vocabulary Most gratifyingly, towards the end of the project, with which to discuss, genome editing. Fertility practi- these participants gave their own presentations on tioners will be responsible for talking to patients genome editing, drawing upon what they had learned about the option of donating embryos or gametes, for so far. This provided invaluable insights into their research. Practitioners in various ﬁelds will increas- understanding of the subject, revealing which con- ingly ﬁnd themselves ﬁelding patient questions about cepts andterminology hadprovedtobeeitheranaid genome editing, as it progresses and as its possible or an impediment. uses become more widely reported (or misreported). It became apparent that there was a palpable desire Finally, comprehension of genome editing and a among participants for clarity and coherence in discus- lingua franca with which to discuss the subject are sion of genome editing, and that certain approaches important prerequisites for informed debate. At pre- lend themselves to achieving this. The conduct and sent, in the UK and in many other jurisdictions, the ﬁndings of the project are reported in detail else- only permitted clinical applications of human gen- where, and these ﬁndings have prompted wider dis- 11–13 ome editing are somatic—they involve changes to cussion. Here, we should like to focus on some the genome that will not be inherited by the next key lessons from the project and from other related generation. In the foreseeable future, there may be developments. Downloaded from https://academic.oup.com/bmb/article/126/1/5/4985578 by DeepDyve user on 18 July 2022 How to talk about genome editing, 2018, Vol. 126 7 concrete—a haploid set of chromosomes. The term Understanding the genome can still be used for this purpose today (provided that The ‘editing’ half of the term ‘genome editing’ was it is contextualised appropriately), but it can just as readily understood by most of the participants in the legitimately be used for a wide range of other purposes. project, resonating as it does with the well-established Like other biological terms with the sufﬁx ‘-ome’, metaphor of DNA as text. ‘Editing’ was taken—cor- ‘genome’ connotes totality—a complete set of material. rectly—by most participants to mean a deliberate and At the same time, it connotes singularity—we often speciﬁc alteration to DNA (as distinct from, say, the talk of the genome, the deﬁnite article. However, this haphazard alterations that might result from simple singularity is context-speciﬁc—a cell, an organism exposure of an individual to a mutagenic substance or and a species are all entities that can be said to possess environment). a single genome. Alternatively, these entities can be By contrast, the term ‘genome’ was not very well said to possess multiple genomes, provided that the understood—not even by very engaged genetic disease distinctions between these genomes are speciﬁed (for patients, who might be expected to encounter it fre- example, distinctions between the nuclear and the quently. Participants were not conﬁdent about their mitochondrial genome, or between the germline and grasp of this term, and several were uncertain whether the somatic genome). it referred to something larger than or smaller than a Once the term ‘genome’ encompasses more than gene. Furthermore, there was confusion about whether a single cell (or, in the case of mitochondria, a sin- the genome is the same in different cells of the body. gle structure within a cell), it ceases to correspond This is not necessarily surprising, when one consid- exactly to concrete molecules and begins to acquire ers how counterintuitive use of the term ‘genome’ can a more abstract and idealised character. Because be. The terms ‘gene’ and ‘genome’ originally emerged DNA replication is imperfect, there is inevitably a during heated debates about whether aspects of hered- degree of somatic mosaicism (genetic differences ity were best thought of as concrete and particulate between cells throughout the body) in every individ- (speciﬁc molecules or portions thereof) or as more 23,24 ual. In recent years, it has become possible to 14,15 abstract and hypothetical phenomena. 25,26 verify this fact empirically, although it remains The subsequent ‘modern synthesis’ between major challenging to distinguish true mosaicism from theories of evolution and heredity, and the discovery anomalies attributable to imperfections in genome 17 18 of the function and structure of DNA, brought the sequencing technology. concrete and particulate meanings of the terms ‘gene’ Provided that mosaicism remains within certain and ‘genome’ to the fore. However, these meanings boundaries, it tends to be subsumed within the con- have been problematised and contested anew in the cept of the individual’s genome, which is discussed as era of whole genome sequencing (and now genome though it is replicated ubiquitously and accurately editing), with latter-day deﬁnitions becoming increas- throughout most of the cells of the body. Only when 19–21 ingly complex and contingent. drastically abnormal cells proliferate—when an indi- One way to make sense of this complex history is vidual has cancer—do we say that this individual has to say that the term ‘gene’ can refer to a tangible object one or more additional ‘cancer genomes’. The more (a speciﬁc portion of DNA coding for a molecule, complex truth underlying usage of the term ‘genome’ classically for a protein) but can also refer simultan- is that any genome ascribed toanindividual is either eously to an abstract concept (an inherited instruction an idealised average of many cellular genomes (when to synthesise a molecule or to enact a function via a described in theory), or a set of data from biological molecule). The dialectical tension between these two samples which are assumed to be representative possible meanings of the term ‘gene’ is in turn mani- (when sequenced in practice). fest in the meaning of the term ‘genome’. It is neither possible nor desirable to convey all of When botanist Hans Winkler ﬁrst proposed the the nuances of the term ‘genome’ when discussing term ‘genome’ in 1920, he used it to mean something Downloaded from https://academic.oup.com/bmb/article/126/1/5/4985578 by DeepDyve user on 18 July 2022 8 S. Starr, 2018, Vol. 126 genome editing in public, but it is helpful nonetheless on the site of the desired edit, meaning that the editing to be cognisant of and attentive to these nuances. process does in fact span the genome even if the result- What is most important is simply to ensure at the out- ing edit is minor. setthatone’s audience has some understanding of At the other extreme, there are genome editing what a genome is—this cannot be taken for granted, methods that can be used to delete entire chromo- 30,31 and an explanation may well be necessary. somes. The category ‘genome’ encompasses One way to clarify the meaning of the ‘genome’, chromosomes—including, but not limited to, the despite the fact that it can mean different things in genes on those chromosomes—and so chromosome different contexts, is to say that it contains all of the deletion can also constitute genome editing, provided material or information necessary for the entity to that a speciﬁc chromosome is purposefully deleted in which it belongs—be it a cell, an individual or a a living cell. species—to be (re)created, and for the life of that In the same way that confusing alternatives to entity to be maintained. Researchers increasingly con- the term ‘genome’ currently impede understanding ceptualise the genome as a dynamic rather than a sta- of genome editing, so the same is true of alterna- tic object of study, but the genome can nonetheless be tives to the term ‘editing’. One such variant term is considered static relative to the dynamic process of its ‘modiﬁcation’, which is liable to mislead because being purposefully edited by humans. ‘genetic modiﬁcation’ has long been associated with the introduction of transgenic (foreign) DNA into an organism—this is the common meaning of the Editing the genome widely used phrases ‘GM crops’ and ‘GM food’. Although the meaning of the term ‘genome’ can be By contrast, editing the genome of a human or any challengingly elusive, the corollary of this is that the other organism does not necessarily involve introdu- term is advantageously ﬂexible. Consequently, the term cing any transgenic DNA. Indeed, the question of ‘genome editing’ has wide applicability, and is accur- whether genome editing constitutes ‘genetic modiﬁca- ate in contexts where alternative terms might not be tion’ is a matter of ongoing contention, with a recent accurate. We therefore recommend using the term judicial opinion from the Court of Justice of the ‘genome editing’ exclusively wherever possible. European Union suggesting that genome edited Such consistency is important, at a time when a organisms could be exempt from laws governing gen- plethora of synonyms and near-synonyms for genome etically modiﬁed organisms. It is therefore advisable editing—including ‘gene editing’, ‘genetic editing’ and to avoid speaking of genetic (or gene, or genomic) ‘genomic editing’—circulate and are often used inter- ‘modiﬁcation’ in relation to genome editing. changeably. Participants in the ‘Basic Understanding Another unhelpful alternative to the term ‘editing’ of Genome Editing’ project were confused by this is ‘engineering’. ‘Genetic engineering’ has long been multiplicity of terms, as it was not clear to them near-synonymous with ‘genetic modiﬁcation’,and is whether the distinctions between them were distinc- therefore best avoided for the reasons given above. tions without a difference. This impeded their under- ‘Genome engineering’ is aslightlydifferent case—this standing and undermined their conﬁdence. has become an established term of art in its own right Helpfully, the term ‘genome editing’ can refer to among specialists, one whose possible meanings and an edit made to a single gene or to a part of that gene methods do overlap with those of genome editing. such as a single base pair, because even a change as The term is nonetheless liable to cause confusion, small as this can be said to constitute a change to an simply by virtue of inconsistency. entire genome to which the relevant gene belongs. Additionally, genome editing approaches including Putting CRISPR in its place clustered regularly interspaced short palindromic repeats (CRISPR) may involve much of the genome Genome editing owes much of its current prominence being searched by a guide molecule in order to alight to CRISPR, an approach that has transformed the Downloaded from https://academic.oup.com/bmb/article/126/1/5/4985578 by DeepDyve user on 18 July 2022 How to talk about genome editing, 2018, Vol. 126 9 ﬁeld since it was pioneered in 2012. CRISPR’s advan- append the term ‘Cas9’ to the term ‘CRISPR’ in public tages over earlier approaches to genome editing in discussion by default, rather than doing so only when terms of precision, practicability and affordability there is a reason to be this speciﬁc, narrows unneces- have led to it becoming a near-ubiquitous tool in gen- sarily the technology that is being discussed. etic research, and there is now even a peer-reviewed Just as there are examples of genome editing that journal dedicated solely to articles about CRISPR. are not CRISPR, so there are examples of CRISPR Participants in the ‘Basic Understanding of Genome that are not genome editing. In fact, CRISPR research Editing’ project were confused by a current tendency predates genome editing research by a number of to use the term ‘CRISPR’ as though it is a synonym years—the term ‘CRISPR’ originally refers to a natur- for genome editing. In truth CRISPR is not a syno- ally occurring phenomenon, ﬁrst observed in bacteria nym but a synecdoche for genome editing, and a in 1987, which defends these bacteria against potentially misleading one at that. The approaches invading viruses. It is this natural phenomenon that that preceded CRISPR are not obsolete, but remain has been adapted into an ingenious approach to gen- important in the present day (notwithstanding their ome editing. limitations). More recently, researchers have created a real-time For example, transcription activator-like effector ﬁlm of a CRISPR process at the molecular scale. nucleases (TALENs) is an earlier genome editing The paper where this was described has proved popu- approach that has been used recently in the UK to lar, but also makes it clear that in order to create reverse advanced leukaemia in two infants, an the ﬁlm, researchers had to contrive a situation which achievement that has been widely reported and took CRISPR outside the auspices of genome editing— lauded. Another earlier approach, zinc ﬁnger rather than alter DNA sequences in living cells, they nucleases (ZFNs), has been used recently in a altered sequences within fragments of puriﬁed DNA clinical trial in the USA—to treat Hunter syndrome— attached to a surface. The resulting ﬁlm documented where genome editing components were, for the ﬁrst only part of the ‘editing’ process—DNA was cut, but time, introduced directly into a patient’s body (rather was not then repaired—which further disqualiﬁes this than being used on cells or tissues removed from a example of CRISPR from being considered ‘genome patient or donor’s body and then reintroduced into the editing’. patient). A ﬁnal distinction that can give rise to confusion CRISPR was not the ﬁrst word in genome editing, is that not all CRISPR editing is necessarily genome nor is it likely to be the last. At one juncture, it seemed editing. CRISPR (and other approaches) can also be that the successor to CRISPR might be an approach used for epigenome editing, and this too has poten- 45,46 named NgAgo (Natronobacterium gregoryi tial therapeutic applications. The term ‘epigen- Argonaute), but the paper where this was proposed ome’ is as challenging to deﬁne as the term ‘genome’ was eventually retracted when other researchers were (if not more so), and we will not attempt to do so unable to replicate its ﬁndings. Instead, a more here—sufﬁce to say that ‘editing’ epigenomes involves plausible successor to CRISPR has emerged in the altering the pattern of gene expression in living cells, form of ‘base editing’ , which has already been used without making any alterations to the DNA sequences in research to edit the genomes of human embryos. in those cells. If ‘CRISPR’ is a popular but misleading synecdoche for genome editing, then this is even more true of Conclusions ‘CRISPR/Cas9’. Cas9 (CRISPR associated protein 9) is the nuclease (the ‘cutting’ molecule) most commonly The story of genome editing is not complete but rather used in CRISPR genome editing, but work is ongoing is still unfolding and is liable to take unexpected turns. with alternative nucleases (such as Cpf1 ) and it is Seemingly promising avenues may transpire to be culs- not inconceivable that Cas9 could be supplanted as de-sac, while areas which seem arcane and unimport- the nuclease of choice in future. A current tendency to ant may transpire to be tremendously signiﬁcant. Downloaded from https://academic.oup.com/bmb/article/126/1/5/4985578 by DeepDyve user on 18 July 2022 10 S. Starr, 2018, Vol. 126 Genome Editing’ project, and to the Wellcome Trust for fund- Patients and practitioners need to be furnished with ing the project (grant reference number 202675/Z/16/A). This an understanding of genome editing that can with- article is developed from a presentation given by the author at stand and evolve alongside these sorts of develop- the Progress Educational Trust conference ‘Crossing Frontiers: ments, rather than being tied ﬁrmly to CRISPR (still Moving the Boundaries of Human Reproduction’,heldin less CRISPR/Cas9). London on 8 December 2017. When discussing genome editing in public, atten- tion should be given in the ﬁrst instance not to Conﬂict of interest statement CRISPR, but instead to addressing the following The authors have no potential conﬂicts of interest. three questions in the following order of priority. � What is a genome? References � What is genome editing? � What can genome editing be used for? 1. Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med 2015;21:121–31. It is important not just to prioritise but to reiterate 2. Prakash V, Moore M, Yáñez-Muñoz RJ. Current pro- one’s explanations. 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British Medical Bulletin – Oxford University Press
Published: Jun 1, 2018
Keywords: genome editing; genome; fertility; crispr
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