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Original research article, ethics, patents and genome editing: a critical assessment of three options of technology governance.

• 1 Research Unit “Ethics of Genome Editing”, Institute of Ethics and History of Medicine, University of Tübingen, Tübingen, Germany
• 2 Bioethics Institute Ghent (BIG), Ghent University, Ghent, Belgium

Current methods of genome editing have been steadily realising the once remote possibilities of making effective and realistic genetic changes to humans, animals and plants. To underpin this, only 6 years passed between Charpentier and Doudna’s 2012 CRISPR-Cas9 paper and the first confirmed (more or less) case of gene-edited humans. While the traditional legislative and regulatory approach of governments and international bodies is evolving, there is still considerable divergence, unevenness and lack of clarity. However, alongside the technical progress, innovation has also been taking place in terms of ethical guidance from the field of patenting. The rise of so-called “ethical licensing” is one such innovation, where patent holders’ control over genome editing techniques, such as CRISPR, creates a form of private governance over possible uses of gene-editing through ethical constraints built into their licensing agreements. While there are some immediately apparent advantages (epistemic, speed, flexibility, global reach, court enforced), this route seems problematic for, at least, three important reasons: 1) lack of democratic legitimacy/procedural justice, 2) voluntariness, wider/global coordination, and sustainability/stability challenges and 3) potential motivational effects/problems. Unless these three concerns are addressed, it is not clear if this route is an improvement on the longer, slower traditional regulatory route (despite the aforementioned problems). Some of these concerns seem potentially addressed by another emerging patent-based approach. Parthasarathy proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. This proposal includes the formation of an advisory committee that would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach (over traditional regulation and over the ethical licensing approach mentioned above—speed and stability being central, as well as increased democratic legitimacy). However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising speed of decision-making under the “ethical licensing” approach). This paper seeks to highlight the various advantages and disadvantages of the three main regulatory options—traditional regulation, ethical licensing and Parthasarathy’s approach—before suggesting an important, yet realistically achievable, amendment of TRIPS and an alternative proposal of a WTO ethics advisory committee.

Introduction

Compared to previous techniques of genetic intervention, CRISPR (clustered regularly interspaced short palindromic repeats), and in particular CRISPR-Cas9, has been steadily changing the discourse on gene modification from one of future possibilities to that of emerging realities. There have been a number of promising developments of the CRISPR tools in research (e.g., research on heritable disease (DMD) and infectious disease (HIV); corrections of genetic bases to some heart defects, and to beta thalassaemia). Throughout this time, there have also been developments that have caused concern (e.g., 2015 embryo gene-editing experiments) and, in November 2018, some outrage. To underscore the revolutionary advances in technical capacity, only 6 years passed between Charpentier and Doudna’s 2012 paper outlining the CRISPR-Cas9 technique, and He Jiankui’s case of reproductive human gene-editing ( Jinek et al., 2012 ; Cyranoski and Ledford, 2018 ). He’s gene-editing of twin girls was an attempt to confer immunity to HIV. This case has been significant not only for its extension of gene-editing to humans, but also due to the ethical and legal guidelines ignored in the process ( Feeney, 2019 ).

While the traditional legislative and regulatory approach of governments and international bodies is evolving ( Baylis et al., 2020 ), there is still considerable divergence, unevenness and lack of clarity ( Nordberg et al., 2020 ). Nevertheless, besides in technical progress, innovation has also been taking place in the proposals of new forms of ethical guidance and regulation for gene-editing—from the field of patenting. Guerrini et al. (2017) have noted the rise of so-called ‘ethical licensing’ where institutions, researchers and companies have used their patent control over CRISPR techniques (especially in the case of the foundational patents) to create an emerging form of private governance over some uses of gene-editing. Unlike the partial, ineffective patchwork of uncoordinated and outdated regulatory and legislative systems across different jurisdictions at the international level, the patent system has global scope through the 1994 TRIPS Agreement ( Feeney et al., 2018 ). While there are some immediately apparent advantages (epistemic, speed, flexibility, global reach, and court enforcement), this route seems problematic for, at least, three important reasons: 1) lack of democratic legitimacy/procedural justice, 2) voluntariness, wider/global coordination, and sustainability/stability challenges and 3) potential motivational effects/problems. Unless at least these three concerns are addressed, it is not clear if this route is an improvement on the longer, slower traditional regulatory route.

Some of these concerns seem potentially to be addressed by another emerging patent-based approach. Parthasarathy (2018) proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. Her proposal includes the formation of an advisory committee that would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach over the traditional regulation and ethical licensing approaches—speed and stability being central, as well as increased democratic legitimacy. However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising the speed of decision-making under the ethical licensing approach.

In both patent-based suggestions, it must also be examined whether, or to what degree, this focus lessens the urgency for, or interferes with, the more robust, regulatory/legislative approach. This paper seeks to highlight the various advantages and disadvantages of the three main options—traditional regulation, ethical licensing and Parthasarathy’s approach. We will argue that ethical licensing, if it occurs and the objectives are just and ethical, is to be welcomed. However, this method itself cannot be sufficient as it would just as easily permit unethical objectives. Even if the objectives were ethical, stability and democratic accountability would still be problematic. A prominent concern would also be that this route would slow down the urgency for seeking more traditional regulatory options, whilst at the same time increasing the power of biotechnological companies. Finally, we suggest an additional proposal, entailing an important, but still realistically achievable, amendment of TRIPS and an alternative proposal of a WTO ethics advisory committee that can, and should, be put in place to guide signatory countries worldwide. Throughout, we do not promote this or any patent-related route as the sole, or necessarily optimal, approach to regulating new technologies, such as genome editing, but rather that it may usefully be part of a range of responses, including working alongside forms of traditional regulation. If and where the latter is insufficient, the patent-based route, including our proposal, can be considered beneficial additions to the field.

Background—Technological Progress and Regulatory Inertia?

In the October 2010 issue of Scientific American, an article by Stephen S. Hall entitled “Revolution Postponed” outlined a number of areas that had not progressed as speedily as was predicted during the heady days of the Human Genome Project ( Hall, 2010 ). While such arguments are not particularly accurate or fair—for instance advance in basic research has been immense—there is no doubt as to their accuracy for the decade that immediately followed that article. With major milestones occurring in the 2015 case of CRISPR gene-editing of nonviable human embryos and the 2017 case of the CRISPR correction of the genetic basis of the congenital heart condition hypertrophic cardiomyopathy, only 6 years passed between Charpentier and Doudna’s seminal 2012 paper outlining the CRISPR-Cas9 technique, and the first confirmed case of gene-edited humans ( Jinek et al., 2012 ; Cyranoski and Ledford, 2018 ). In 2018, Jiankui He claimed to have performed germ-line reproductive gene-editing of twin girls—Lulu and Nana—by inserting a variant of the CCR5 gene in an attempt to confer immunity to the human immunodeficiency virus (this was followed with a later claim of a third gene-edited child). Increasing the speed of technical advance puts pressure on ethics and law to catch up.

However, in this case, it was not just areas of ongoing ethical disagreement and still forming ethical values and principles that gave rise to moral unease. It was also the discarding of well-established values and principles that gave rise to moral outrage. From safety concerns and lack of medical necessity to charges of eugenics, He’s case highlighted that we no longer have the silver lining of slow technical progress for further moral reflection before potentially problematic genetic interventions are attempted ( Feeney, 2019 ). While the genome editing techniques of Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) already had potential, CRISPR has revolutionised what was usually termed genetic engineering by making it cheaper, more accurate and more efficient. This is not to suggest that CRISPR-Cas9 is the only gene-editing technique in use. ZFNs and TALENs are still considered as major contemporary forms of genome editing technologies ( Gaj et al., 2013 ; Li et al., 2020 ). Nor, does “more” efficient and accurate mean efficient and accurate (a line is straight or it is not—more straight suggests still not straight).

Nevertheless, the “CRISPR Revolution” has also meant that the ethical discussions over the previous decades, on what changes, if any, we can morally make to humans is less one of future speculation and more one of imminent or current application. Moving beyond well-established clinical research ethics, new ethical issues arise, for instance, in arguments that favour somatic, as opposed to germline, interventions; the latter are arguably problematic insofar as they can affect future generations in unpredictable and irreversible ways ( Ranisch and Ehni, 2020 ). Other concerns include the risk of the use or misuse of the technology for enhancement purposes ( WHO, 2021 ) as well as issues of social justice between those who have their genomes edited, and the rest ( Baylis, 2019 ). Since the Chinese case, claims by a Russian biochemist have raised the prospect of more such interventions in the future ( Kravchenko, 2019 ). Others will surely follow.

While it appears that He was severely sanctioned by the Chinese authorities ( Cyranoski, 2020 ), his case exposed the lack of a clear and coherent international legal or regulatory structure. In fact, the only international ethical instrument with legal force in relation to gene-editing is the Convention on Human Rights and Biomedicine (the Oviedo Convention). However, this only covers countries party to the Council of Europe, and then only those who sign and ratify it. Moreover, this Convention entered into force in 1999, suggesting that there are, at least some, aspects to it that are long out of date, including any consideration of CRISPR or other contemporary genome editing techniques. The Council of Europe’s Committee on Bioethics (DH-BIO) recent examination of Article 13 of the Oviedo Convention in light of gene editing technologies did not embark upon a wider exploration of the ethical and legal issues arising in recent years, confining itself to relatively minor adjustments and clarifications 1 . It is not clear that minor revisions will be sufficient. This is not unique to the Oviedo Convention. As Parthasarathy (2018) notes “when it comes to editing genes in humans and other organisms, the United States and the United Kingdom—along with many other countries—rely on laws and policies that cover existing genetic engineering technologies”. Nordberg et al. (2020) highlight how the current legislative and regulatory framework in Europe incorporates some general principles advanced by the United Nations Educational, Scientific and Cultural Organization (UNESCO). While this may constitute some degree of soft law applicable in the EU arena, Nordberg et al. highlight that some considerable divergence still exists between national regulations and well as lack of clarity regarding the available legal tools.

The lack of clarity on the international level with regarding to the legislative and regulatory options regarding human genome editing is compounded by a lack of empirical work (or lack of rigour in such work) in contemporary discussions. Françoise Baylis et al. (2020) highlight a failure of such discussions to properly acknowledge and accurately portray the existing legislation, regulations, and guidelines on research in human genome editing. Indeed, according to the review of some of the literature by Baylis et al., the expected Chinese reaction to reproductive human genome editing could have ranged from permissive regulation to outright prohibition. However, as the authors observe, there is some degree of consensus in the global setting. With regard to emerging policy on heritable human genome editing, Baylis et al. (2020) found a “broad prevalent agreement” in the international setting which suggests “that development of international consensus on heritable human genome editing is conceivable”. Unsurprisingly, the rough consensus is prohibition. Nevertheless, this international consensus may soon be moving in a new direction that is reflected in a recent Report written largely in response to the gene-edited twins in China. The International Commission on the Clinical Use of Human Germline Genome Editing’s 2020 Heritable Human Genome Editing Report concluded that implanting edited embryos to establish a pregnancy was not justifiable, at this time. Research into heritable human genome editing could proceed, subject to stringent guidelines for carefully progressing toward clinical research and clinical application, such as on monogenetic disorders. In this respect, the Report seeks to offer a translational pathway for the approval of human heritable genome editing in limited cases, where such stringent criteria are met (e.g. where no developmental abnormalities are detected). Furthermore, this could feed into the appropriate WHO governance and monitoring mechanisms for heritable and non-heritable genome editing in clinical use and research in humans. Amongst other things, this would give rise to increasing complexity for legislation and regulation in the different countries—including those that may currently have some form of rough consensus. Outright prohibition is—in one sense—easy: you ban it. But permitting some uses, while temporarily or permanently banning others is not so straightforward and may also break the aforementioned consensus. Noting germline genome editing that is not for reproductive purposes, Baylis et al. (2020) observed a greater international divergence than in the case of its heritable version. As the technology becomes more established, it is plausible, at least, to suggest that some of the initial prohibition standpoints may also soften in the case of heritable changes.

The greater the divergence in international governance (whether in relation to germline or potentially heritable editing), the greater is the risk of unscrupulous actors, companies or indeed states moving genome editing operations to other locations where there are no prohibitions or other restrictions. There may be countries or regions that, while agreeing in principle with a cautious WHO global governance and monitoring mechanism, may not have the local regulatory infrastructure to police rogue actors. Such countries may have legislation in place but no enforcement capability. Similarly, other places may not have the resources to divert to spending time on either legislating on or regulating human genome technologies, let alone enforcing them ( Baylis et al., 2020 ). Other states may be under severe geo-political pressures that creates space for rogue actors to operate. A clinic in Ukraine is purportedly planning to sell CRISPR enhancements ( Knoepfler 2021 ). It is more likely that the Ukrainian government is preoccupied with its conflict with Russia and Russian supporting separatists, than it is eagerly supporting a CRISPR “wild west” in the eastern edge of Europe. It is also not beyond the realms of probability that countries that continue to be at odds with a “western consensus” in terms of military expansionism or vaccine development outside of basic ethical standards, may take entirely regional—not “global”—approaches to human genome governance. A new cold war may arise in the development of human genome editing technologies—a not unlikely prospect given the potential military applications of the technology. “Ethics dumping” may not only be a risk for countries who are unprepared in terms of human genome editing policy—it may be a deliberate political decision ( Schroeder et al., 2019 ).

Appropriately robust and well-balanced international legislation will likely be slow in its development, and subject to persistent moral disagreement ( Nordberg et al., 2020 ). The fact that the Oviedo Convention, now two decades old, is the only international legally binding form of legislation, and applies only within part of Europe, is not exactly confidence inspiring. 2 It is also not clear that old regional/geo-political rivalries will not re-emerge in the heritable, or non-heritable, human genome editing context. Moreover, this may not be confined to monogenic disorders, but cases of therapy vs. enhancement, or other cosmetic treatments, as suggested by the plans of the Ukrainian clinic. The international legislative-regulatory route is far from the finish line, but it should not be abandoned. However, the question of whether other horses should enter the race must also be considered.

A Novel Form of Technology Governance

Legislation to allow governments or international bodies to constrain performance of gene-editing, is not the only way to regulate genome editing. Innovations in the field of patents are giving rise to new forms of (potential) ethical guidance and regulation in gene-editing. The original CRISPR-Cas9 patents were taken out by two groups: the University of California, Berkeley and University of Vienna group of Jennifer Doudna and Emmanuelle Charpentier regarding its use in general, and the MIT/Harvard/Broad Institute group of Feng Zhang regarding its use on eukaryotes in particular, including plants and animals ( Feeney et al., 2018 ). These two groups, and various sub-groups, are issuing licences for CRISPR-Cas9 to various researchers, institutions, and companies across the globe. These licences are crucial as CRISPR is a tool that is fundamental to many areas of research and applications in humans, non-human animals, plants and microorganisms. 3 The technique is used in—and essential to—a vast amount of gene-editing research and many of the patents on this technique are thereby foundational—without licences from the patent holders much work using CRISPR-Cas9 is open to litigation. 4 Accordingly, this puts the patent holders in a significant position of power and control over CRISPR’s uses; a control that can be exerted via the constraints attached to the licences. In addition to the usual patent-related stipulations regarding payment of royalties and exclusivity or non-exclusivity, terms ostensibly based on ethical considerations are emerging in some of the CRISPR-Cas9 licences.

Guerrini et al. (2017) have noted the rise of “ethical licensing” where companies use their patent control over CRISPR techniques to require or forbid certain practices. This is done by having ethical constraints built into their licensing agreements. For instance, Broad’s CRISPR-Cas9 licences forbid the technique from being used in the editing of tobacco plants, with gene drives or for creating “terminator” seeds for agriculture ( Broad Institute, 2017 ). Its licensing practices also forbids its use in human germline modification. All this, even though the local law may otherwise sanction it, or not prohibit it. Similarly, Kevin Esvelt’s (2018a) work on gene drives is focussed on balancing such an environmentally controversial technology by seeking wide community involvement, given the likely impact for all community members. Gene drives (where genetic alterations are spread through a population with increased rates of inheritance) are a good illustration of the future generations concerns in the case of human heritable genome editing. Examples of uses of gene drives include those in mosquitoes, fruit flies, and mice that are CRISPR’d to cause “desirable” changes to spread through a population at higher-than-normal rates of inheritance, in order to control the spread of disease or simply to control the animal population itself. This can have significant potential for widespread, and unanticipated, harms. In the spirit of ethical licensing, Esvelt sees the mobilisation of patent law to be faster than governmental bureaucracy and truly international in its reach (2018a: 30). Esvelt’s advocacy of gene drive technology developed as non-profit, with the particular goal of preventing the profit motive from interfering with public trust, can be promoted with such a leveraging of intellectual property ( Esvelt, 2018b ).

On the face of it, ethical licensing is a potentially welcome initiative. In terms of regulation, rather than having nothing until we have a sufficient consensus, we have a smaller and faster form of ethical decision-making. Moreover, it is the scientists, institutions, and companies at the centre of the CRISPR-Cas9 discovery who are the patent holders. It could be argued that they are ideally placed to better appreciate the potential of their technology, as well as its possible positive and negative uses and, consequently, to devise better, more balanced regulations. There are at least four advantages that can be identified.

• Epistemic—politicians and policy makers are seldom scientific experts, and require numerous civil servants, and other advisors, to support their day-to-day work. They are also susceptible to lobbying and competing and conflicting pressures—e.g., technological safety versus economic benefits. While this does not suggest that those who invent or discover such technological innovations are immune to such conflicting pressures, there may be a better chance that they are better placed to make informed decisions regarding what is possible, realistic, genuinely dangerous, and also better able to balance such competing priorities.

• Speed—Regulation of technology can be slow at the best of times. In cases where a technology is controversial and novel, it can require the input of multiple stakeholders, rival interests, and mutually incompatible groups. The policymakers may include many such incompatible groups making compromise and deal-making an even slower process. Furthermore, the bureaucratic system in place will need to adopt the new policy and enact it, also taking time. On the other hand, control via the terms placed in patent licences can be—relatively speaking—almost immediate.

• Flexibility—This is an advantage similar to speed but still distinct in its own right. Moving at speed in terms of regulation and legislation can be one thing, but it may not include the ability to change course just as speedily if required. When new discoveries are made, or new information arises about an existing patented invention/discovery, there is no slow lag time for revising future licences when one is the patent holder. Even with existing licences, these might contain clauses permitting the patentee to modify the licence terms if new risks or benefits appear.

• Global reach/court enforcement—the traditional international regulatory landscape outlined above does not have any means of global enforcement, nor any firm picture of how one might operate. The only international example is the Oviedo Convention, which cannot even gain ratification from all the counties within the Council of Europe. By contrast, the patent landscape is court-enforced and well-established internationally.

Nevertheless, this route seems problematic for, at least, three important reasons, and unless these are addressed, it is not clear if this route is a real improvement on the longer, slower traditional regulatory route.

Lack of Democratic Legitimacy/Procedural Justice

Firstly, and importantly, ethical licensing lacks the democratic legitimacy and broader consensus that underlies traditional systems of regulation. Of particular concern is the level of power that private governance approaches, such as ethical licensing, can concentrate in the hands of individuals who are not accountable to anyone, besides shareholders. In Feeney et al. (2018) , one concern over patenting foundational technologies, such as CRISPR, was the power it afforded a small group to set the agenda for future research. Perhaps with noble intentions, the “ethical licensing” approach of Broad-Editas is a form of privatised morality—without discussion, debate, public involvement and democratic accountability—that forecloses ethical decision-making on a technology with a wide societal impact. Hilgartner (2018) highlights democratic choice and accountability as crucial in such cases which “shape the technological and social orders that govern our lives”. This, as Hilgartner notes, is a form of configuration power that is also evident in Esvelt’s proposal. While ethical licensing may be welcomed by some, such proposals—and the agenda-setting power they can have—makes “patent policy a matter of profound political importance” ( Hilgartner, 2018 ). The 2013 U.S. Supreme Court ruling that human genes cannot be patented, invalidated key patent claims by Myriad Genetics on both the BRCA1 and BRCA2 genes. Prior to this, Myriad had effectively used its patent control to stop competitors from offering wider and cheaper clinical testing for determining cancer risk—doubtlessly resulting in late diagnosis, illness, unnecessary surgery and death. As Hilgartner notes, despite the ending of its monopoly, Myriad had already amassed an extensive and valuable database on BRCA variants, beyond what its new competitors had access to and therefore “Myriad’s configuration power partially outlived the patents that originally bestowed it”. Similarly, de Graeff et al. (2018) note, that while it is praiseworthy that Editas aims to pursue a socially responsible licensing approach, “leaving the determination of what is “socially responsible” to the sole discretion of the patentee, ethical licensing through private governance raises procedural justice concerns”. One response would be to reform the patent system (so far as possible in the non-ideal context) to reduce the level of exclusivity that patents can grant ( Feeney et al., 2018 ; Feeney, 2019 ). This would constrain the potential for nefarious forms of agenda-setting or configuration power, while—to a greater extent—aligning itself with the socially positive goals of those involved in ethical licensing.

Voluntariness, Wider/Global Coordination and Sustainability/Stability Challenges

Secondly, there is the issue of wider coordination difficulties and likely disagreements between different private actors. This problem is centred on the voluntariness involved in the ethical licensing approach. Nor is the voluntary nature of ethical licensing something that can be easily circumvented—it is a defining characteristic of this approach. In the context of germline editing concerns trumping their current benefits, Guerrini et al. (2017) notes that:

[i]n such instances, the social benefits associated with voluntarily engaging in ethical licensing will spill over beyond those who merely comply with such licenses. These spillover effects may include, for example, increased faith in scientific self-regulation and participation in research. Voluntarily restricting applications can also generate goodwill among the licensing parties and promote institutional leadership that might translate to new, collaborative partnerships (23).

As advocates of virtue ethics will no doubt agree, legal compulsion alone cannot work as effectively without the cultivation of norms and motivations of people to want to comply with such legal requirements, without necessarily having to do so ( Fives, 2013 ). However, while Arneson (2003) sees the potential of informal social norms over the “costly machinery of legal compulsion,” the problem is that norms tend “to sprout up like weeds” (2003: 145). Private governance priorities, if any, will depend on the individual patent holders and there is no reason to assume that all will follow the ethical licensing route or, even if they do, adopt the same scope of ethical licence restrictions. As outlined elsewhere ( Feeney et al., 2018 ), much of the potential application of the currently dominant genome editing technique is built upon a common “foundational” technique of CRISPR-Cas9. This foundational technique is subject to the disputed, overlapping control of two groups (Doudna and Charpentier on one side over its application over DNA, tout court; Zhang on the other over its application on eukaryotic DNA (e.g. plant or animal DNA) and their respective patent claims ( Feeney et al., 2018 ). This now infamous patent dispute has been held up as a pivotal example of how commercial interests can damage scientific collaborations ( Sherkow, 2016 ). Even where “ethical licensing” has been seen to arise with actors in this dispute, there are issues over how long such ethical standpoints last—particularly for a wider group of people, over time in a private arena where profitability, for instance, is an alternative and competing value. As with many other areas, there is also the problematic issue of self-regulation by the patent holders over their own research and commercial activities (e.g. such as when cases of conflict of interest arise). While Contreras (2018) suggests that the option of voluntary solutions is being overly dismissed, the case of Myriad/BRCA alone highlights that any voluntary approach cannot be relied upon ( Hilgartner 2018 ; Feeney, 2019 ).

Potential Motivational Effects/Problems.

In addition to the aforementioned concerns, there is an additional, less obvious issue that can problematise such a reliance on the ethical motivations arising in the private sphere. The sustainability of such voluntary non-profit (“other-regarding”) motivations in a for-profit (incentive-based) environment cannot be assumed. To illustrate, one can review the trend of patent control since the onset of modern genetic interventions, particularly in the USA. The revolutionary developments in recombinant DNA technology by Herbert W. Boyer and Stanley N. Cohen were of significant commercial potential and, patented by Stanford University, generated a sizable source of university funding ( Cook-Deegan and Heaney, 2010 ). However, profit was not the primary goal of the Cohen-Boyer patents, and their licensing decisions largely reflected public service ideals, preventing public harm, and increasing revenue for educational and research purposes ( Feldman et al., 2007 , 1798). Nevertheless, in the intervening years—which included the Bayh-Dole Act (1980) —Peter Lee notes that through “a long (and still ongoing) process of norm contestation, academic culture has become much more receptive to exclusive rights and the commercial exploitation of scientific knowledge” ( Lee, 2013 , 36). This issue is also something that may face similar ethical proposals in the leveraging of private sector motivations for a social or a public good. Norms can indeed sprout up like weeds, but how the local ecology is maintained may well influence the type of weed that is prevalent. This is concerned with the potential interplay between incentives and public-spirited motivations that can be seen with their attempted mutual accommodation in the wider Rawlsian literature. 5 One key complexity that non-ideal theory recognises lies in stronger feasibility constraints than an ideal-theoretical approach to justice would acknowledge—such as what Rawls might consider “unreasonable levels of self-interest” ( Farrelly, 2007 ; Farrelly, 2016 ). In economic theory, Homo oeconomicus is a term used to describe a view of persons as self-interested, rational utility maximisers. While real people (e.g. “pro ethical licensing” members of Broad) may not resemble this image, giving insufficient regard to what “reasonably” self-interested people are like in reality could render unworkable an overly ideal scheme of justice no matter how desirable it might otherwise be ( Brennan and Pettit, 2005 ). While rejecting such an image of purely self-interested people as economists portray, devising institutional arrangements that are not sufficiently economically incentive-compatible is problematic for workable and stable institutions of (genomic) justice ( Brennan and Pettit, 2005 ). People are not knavish and a principle that requires incentives as though we were would be too extreme. Nevertheless, we are not always motivated to an ideal level in order to comply with, or excel upon, socially just institutions (at least not all the time) nor, in so far as we do, could we simply be assumed to continuously do so over time and in all circumstances within which we find ourselves in the normal course of our lives. So far, nothing here seems particularly controversial. It only seems to suggest that the motivations of CRISPR patent-holders (who engage in ethical licensing) may not realistically be assumed to be purely other-motivated, or altruistic, but that they are also in it for commercial profitability, as well as other forms of incentives (such as winning a Nobel Prize).

However, insofar as such feasibility constraints are taken as limitations on what is realistic in terms of social justice, these limitations themselves must be subjected to critical scrutiny. What is feasible depends greatly on the balance between self-interested and other-interested motivations and, consequently, such feasibility constraints not only form the parameters of what can be done, they are also the consequences of what is done. The concern, akin to that of Titmuss (1971) regarding blood donation, is that this use of incentives would lead to a “crowding out” of social (or other-regarding) preferences, which, while arguably productive in pursuing social justice goals in the short term, would undermine such goals in the longer term. 6 As noted above, the ongoing process of academic norm contestation and movement toward commercial interests, that Lee suggests (2013), may also be a symptom of such “crowding out” dynamics. It may be the case that sometimes the gain from more economic incentives more than compensates for the loss in social preferences. In any case, it seems that the momentum in the context of new gene-editing technologies, such as CRISPR-Cas9, is increasingly toward the ethos of the private sphere, and away from the ethos of (purer) scientific collaboration ( Sherkow, 2016 ). The concern is that this may increasingly “crowd-out” social (other-regarding) preferences and undermine the motivational structure conducive to the potential of “ethical licensing” as a sustainable alternative to the traditional forms of regulation.

Overall, while we note some immediately apparent advantages to the ethical licensing approach (i.e. epistemic, speed, flexibility, global reach, and court enforced), it is not clear that these outweigh the potential problems in terms of lack of democratic legitimacy and procedural justice, problems in maintaining voluntariness, wider/global coordination, and sustainability/stability, particularly with the potential for adverse motivational effects/problems over time. If they do, some response will be needed to address these challenges.

Patents in the Public Sphere?

Some of these concerns seem potentially to be addressed by another emerging patent-based approach. Parthasarathy (2018) proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. Rather than ethical licensing by private actors, Parthasarathy is seeking a more formal, comprehensive and government-administered regulation using the patent system. Citing the EU’s 1998 Directive on the legal protection of biotechnological inventions, as well as other historical examples of government run patent control, a key model was highlighted by the US Congress’ use of the patent system to control the development and commercialisation of atomic weapons in the 1940s. Some relevant technologies would be patentable, some subject to compulsory licences if in the public interest and some excluded from patenting entirely (e.g. atomic weapons). This would be managed by an advisory committee for gene-editing patents—including (in the US case at hand) members of EPA, health sector, commercial sector and others, in conjunction with members from the US Patent Office. This advisory committee would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach (over traditional regulation and over the ethical licensing approach above—speed and stability being central, as well as increased democratic legitimacy, at least via this committee). However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising the speed of decision-making under the ethical licensing approach. The problem here is that this addition to traditional regulation does not seem to improve things from mere reliance on that same traditional regulation itself. The problem of achieving agreement in terms of the ethical, legal and societal implications of such technologies or applications of technologies; in terms of devising the appropriate level of fostering or restriction of such technologies, or parts of such technologies, will be present in this approach, albeit focussed on the aforementioned advisory committee. If the decision-making process is still easier in the committee, the membership of this committee will become the new area of contention. If this is all avoided, by the top-down arrangement of such a committee (whether by government or state body) then there is an issue of a lack of democratic accountability, oversight, and engagement. Whether or not genome editing of humans is to be welcomed, the assessment will entail the same challenges as existing democratically legitimated approaches to creating regulation. If this is short-circuited in some way, then that very democratic legitimacy may be damaged. Given the profound societal impact that can be anticipated, and the strong emotions and reactions that it can provoke, the wider acceptance of this technology could be damaged by the sense that it “slips in by the back door”. This route also loses the dynamic aspects of the ‘private ethical licensing” route—it may require wider levels of compromise, or consensus, that one or a few patent owners can swiftly sidestep, albeit with even greater loss to democratic legitimacy and oversight, as well as the concerns over motivations outlined above.

An International Patent-Based Approach: TRIPS and the WTO

Even with its various problems—speed being the key one - the legislative and regulatory route remains an important, if not the most important, approach in responsible governance of new technologies. One important concern is whether a focus on some patent-based alternative lessens the urgency for, or interferes with, the more robust, regulatory/legislative approach. Adopting either the private governance model or Parthasarathy’s alternative does not seem to be an adequate alternative in this regard. This does not rule out various mixed approaches which may strike viable balances ( Guerrini et al., 2017 ; Sherkow, 2017 ). In fairness, Parthasarathy (2018) does not see her suggestion as a comprehensive alternative to traditional regulation but argues that it should be part of a comprehensive approach. Whatever the combination involved in such a mixed approach, there is no reason to be confined to using the current patent environment as the default framework. In Feeney et al. (2018) , we advanced a number of proposals for relatively realistic, yet substantial, reform of the patent-based environment limiting the ability of the patentee to exclude others from performing work with the patent invention, including restrictions on the technological field in which rights may be exercised and on the types of activity which can be constrained and, importantly, a restriction on the period for which the patentee can impose exclusivity in the first place (44–46). Whatever the various suggestions for realistic reforms of the existing patent landscape may be, the key point is that such reforms may be needed if there is to be a sustainable inclusion of patent-based approaches that will contribute to the traditional regulatory options whilst as the same time, not interfering with this same objective, for instance, by increasing the power of biotechnological companies.

With gene editing, we see two dominant concerns—safety and justice in access. As regards safety, this has two aspects: safety of society as a whole; and, for human editing, safety of the edited individual and her offspring. Safety, with gene editing, has an international dimension since the edited species are at least potentially mobile—they can cross borders, bringing risk to countries beyond those where the gene editing occurs unless export is only of dead or sterile organisms. For fish, birds, pollen, seeds, and many small animals, it may be impossible to prevent border crossing, and for humans the lessons of medical tourism show us that preventing border crossing by edited humans may likewise be impossible. Thus, while, from an international point of view, it may be acceptable to allow countries to make their own decisions regarding gene editing of species which can be prevented from crossing borders alive, for many species we do not have this luxury. Thus, enforceable international regulation seems to be essential, and patent-related governance should be seen only as a, albeit necessary, stop-gap measure.

Ethical licensing, unless mandated by law, can only be an inadequate partial solution as a result of its voluntary nature. Ad hoc national restrictions on patentability, even though these might include constraints on local and international licensing, suffer from the slowness of bureaucracy and the voluntariness of ethical licensing (e.g. a company may choose not to patent in countries with such ad hoc constraints). Nonetheless, even ad hoc patentability constraints would add to the currently inadequate patchwork of international governance.

Revision of TRIPS and of the mandate of the WTO, however, does offer the opportunity to introduce constraints on patentees on a near-global scale without the delays fundamental to international regulation of the performance of gene editing, constraints that could at the same time address the question of justice of access. Thus, a revised TRIPS might allow signatory members to adopt measures proposed ad hoc by a majority of a WTO ethics advisory committee while still allowing other signatory members to avoid imposing such constraints on their national patents. With enough signatory members adopting constraints extending to the activities of patentees and their licensees in other countries, patentees might well be forced to accept constraints globally. 7

Thus, should such a WTO ethics committee recommend X then any country might require that patents should not be granted in their country unless the patentee agrees to X globally and requires its licensees to do the same. X might include not using the technology in a particular way or the granting of non-exclusive licences to the technology available to all in that country, group of countries, or anywhere. Local enforceability of any patent might also be linked to compliance with any future WTO ethics committee recommendation adopted by the country in question. A patentee would then be required to choose between continuing with its existing practices or maintaining local patent enforceability. The patentee could then wait until the need to enforce its patent locally arose before changing its practices.

To deal with “rogue” actors in “rogue” countries, the WTO recommendation might include requiring patentees to grant third parties royalty-free licences not to operate under a patent in a “rogue” country but to sue the “rogue” actors in that country. Thus if Broad were to have a patent in Ukraine, such a licensee might be appointed to sue the “rogue” clinic at its own cost. Of course, any proposal or regulatory approach—patent-based or otherwise—will unlikely eliminate all forms of rogue actors or rogue actions. However, the addition of our proposal to the range of regulatory instruments available should further decrease the room for such actors to successfully operate. 8

In this paper, we argue that gene editing requires regulation and that this ideally would involve enforceable international legislation. However, we accept that the road to such legislation is long and that even after acceptance it would lack adequate flexibility. We consider the ethical licensing approach to be commendable and that it should be encouraged; however, it is insufficient. Parthasarathy’s ad hoc national modification of patent laws is likewise commendable but insufficient. We argue instead for an amendment of TRIPS and the equipping of the WTO with an ethics advisory committee whose majority recommendations can be adopted (or not) by individual WTO signatory countries.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author Contributions

OF conceived of the paper and wrote the first draft of the manuscript. JC and SS added crucial sections to the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

We acknowledge support by Open Access Publishing Fund of University of Tübingen. OF work is supported by the Hans Gottschalk-Stiftung.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

Many thanks to Gardar Árnason for reviewing the final draft and also to the two reviewers for their helpful comments. OF presented an earlier version of this paper at the International Conference Transformative Technologies: Legal and Ethical Challenges of the 21st Century, Banja Luka, Bosnia and Herzegovina. (February 7–8, 2020) and wishes to thank both organisers (especially Igor Milinković) and participants who positively contributed to the current work.

1 The limited revisions include clarifications “on the terms “preventive, diagnostic and therapeutic” and to avoid misinterpretation of the applicability of this provision to “research”. Council of Europe news page: Genome editing technologies: some clarifications but no revision of the Oviedo Convention, June 7, 2021: https://www.coe.int/en/web/human-rights-rule-of-law/-/genome-editing-technologies-some-clarifications-but-no-revision-of-the-oviedo-convention [accessed 22.08.21]. It seems highly implausible to suggest that these few revisions address all the significant advances, and associated ethical and legal implications, over the last decades.

2 We are not here giving any indications regarding the acceptability, or not, of the Oviedo Convention itself; rather we are highlighting that (good or bad) it is still the only show in town with regulatory bite, insofar as it is ratified.

3 We avoid here the many complications that the patent dispute has entailed for those institutions or researchers seeking licences. For more on this, see Feeney et al. 2018 .

4 Basic, non-profit, pure academic research may be exempt from paying royalties or even needing a licence at all. However, even amongst such groups, a fear of litigation is present.

5 Although John Rawls famously stands accused of being too ideal, he does note that any proposal or theory regarding justice must take due account of the “strains of commitment” where people should only be expected to act according to reasonable social rules, including accommodating a reasonable level of self-interest.

6 Benabou and Tirole (2006) note evidence that suggests that the provision of economic rewards and punishments to people in order to foster prosocial behaviour sometimes has a perverse effect of reducing the total contribution those people have been previously providing. They note that a crowding out of “intrinsic motivation” by extrinsic incentives has been observed in a variety of cases. Indeed, provisional evidence even suggests that explicit incentives diminish activity in distinct regions of the brain associated with social preferences ( Bowles and Polanía Reyes, 2009 ). See also Michael Sandel’s chapter on “How markets crowd out morals” in Sandel (2012) : 93–130.

7 Each technology that would be put to such a committee would inevitably raise major lobbying/self-interest concerns in some countries and therefore we suspect that such a committee would have to have delegates from each country or group of countries, eg. grouped according to their level of economic development, geographic location, or population size. Inevitably, these will be political appointees, perhaps supported by a secretariat provided by WTO. Of course, there will be difficulties and challenges here—and with any proposal that seeks to revise TRIPS—we do not attempt to address such issues here.

8 It is worth noting how our proposal should respond to some concerns recently raised by Justine Pila in two papers offering alternative proposals for the regulation of the patenting and licensing of emerging technologies ( Pila 2020a ; Pila 2020b ). In the first paper, Pila argues that the approach of the European Patent Office (EPO) to the interpretation of the morality clause [Article 53(a)] of the European Patent Convention) is “incoherent, unduly restrictive and blind to the regulatory challenges presented by emerging technologies” and that the risk assessment of that clause “necessitates an epistemic and deliberative process aimed at recognizing and confronting the uncertain consequences of new technologies and their implications for society.” ( Pila, 2020a ), 535-6. To do this, she argues, the EPO and the domestic patent offices should introduce a version of the risk assessment model proposed in a brief prepared by the University of the West of England in 2017 for the European Commission and create a “morality and public policy triage system” within those patent offices, i.e. implicitly a system operated by the patent offices themselves. In the later paper, Pila goes on to propose the extension of the “fair, reasonable, and non-discriminatory” (FRAND) licensing system currently operated on a voluntary basis by industry-based standard-setting organizations. Recognising the danger of a voluntary system operated by industry itself, Pila acknowledges that such an extension of the FRAND system should be compulsory for some technologies and that some other means would have to be found for identifying the patents to which such a FRAND-like system would be applied. For medicines, she implicitly identifies the WHO as a possible candidate. ( Pila, 2020b ), 15-8.

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Keywords: genome editing, CRISPR, ethical licensing, patents, governance, TRIPS

Citation: Feeney O, Cockbain J and Sterckx S (2021) Ethics, Patents and Genome Editing: A Critical Assessment of Three Options of Technology Governance. Front. Polit. Sci. 3:731505. doi: 10.3389/fpos.2021.731505

Received: 27 June 2021; Accepted: 07 September 2021; Published: 21 September 2021.

Reviewed by:

Copyright © 2021 Feeney, Cockbain and Sterckx. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Oliver Feeney, [email protected]

This article is part of the Research Topic

Regulation and Governance of Gene Editing Technologies (CRISPR, etc.)

Human Genome Editing: Science, Ethics, and Governance (2017)

Chapter: summary.

Genome editing 2 is a powerful new tool for making precise additions, deletions, and alterations to the genome—an organism’s complete set of genetic material. The development of new approaches—involving the use of meganucleases; zinc finger nucleases (ZFNs); transcription activator-like effector nucleases (TALENs); and, most recently, the CRISPR/Cas9 system—has made editing of the genome much more precise, efficient, flexible, and less expensive relative to previous strategies. With these advances has come an explosion of interest in the possible applications of genome editing, both in conducting fundamental research and potentially in promoting human health through the treatment or prevention of disease and disability. The latter possibilities range from restoring normal function in diseased organs by editing somatic cells to preventing genetic diseases in future children and their descendants by editing the human germline.

As with other medical advances, each such application comes with its own set of benefits, risks, regulatory frameworks, ethical issues, and societal implications. Important questions raised with respect to genome editing include how to balance potential benefits against the risk of unintended

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1 This summary does not include references. Citations for the discussion presented in the summary appear in the subsequent report chapters.

2 The term “genome editing” is used throughout this report to refer to the processes by which the genome sequence is changed by adding, replacing, or removing DNA base pairs. This term is used in lieu of “gene editing” because it is more accurate, as the editing could be targeted to sequences that are not part of genes themselves, such as areas that regulate gene expression.

harms; how to govern the use of these technologies; how to incorporate societal values into salient clinical and policy considerations; and how to respect the inevitable differences, rooted in national cultures, that will shape perspectives on whether and how to use these technologies.

Recognizing both the promise and concerns related to human genome editing, the National Academy of Sciences and the National Academy of Medicine convened the Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations to carry out the study that is documented in this report. While genome editing has potential applications in agriculture and nonhuman animals, this committee’s task was focused on human applications. The charge to the committee included elements pertaining to the state of the science in genome editing, possible clinical applications of these technologies, potential risks and benefits, whether standards can be established for quantifying unintended effects, whether current regulatory frameworks provide adequate oversight, and what overarching principles should guide the regulation of genome editing in humans.

OVERVIEW OF GENOME-EDITING APPLICATIONS AND POLICY ISSUES

Genome-editing methods based on protein recognition of specific DNA sequences, such as those involving the use of meganucleases, ZFNs, and TALENs, are already being tested in several clinical trials for application in human gene therapy, and recent years have seen the development of a system based on RNA recognition of such DNA sequences. CRISPR (which stands for clustered regularly interspaced short palindromic repeats) refers to short, repeated segments of DNA originally discovered in bacteria. These segments provided the foundation for the development of a system that combines short RNA sequences paired with Cas9 (CRISPR associated protein 9, an RNA-directed nuclease), or with similar nucleases, and can readily be programmed to edit specific segments of DNA. The CRISPR/Cas9 genome-editing system offers several advantages over previous strategies for making changes to the genome and has been at the center of much discussion concerning how genome editing could be applied to promote human health. Like the use of meganucleases, ZFNs, and TALENs, CRISPR/Cas9 genome-editing technology exploits the ability to create double-stranded breaks in DNA and the cells’ own DNA repair mechanisms to make precise changes to the genome. CRISPR/Cas9, however, can be engineered more easily and cheaply than these other methods to generate intended edits in the genome.

The fact that these new genome-editing technologies can be used to make precise changes in the genome at a high frequency and with considerable accuracy is driving intense interest in research to develop safe and

effective therapies that use these approaches and that offer options beyond simply replacing an entire gene. It is now possible to insert or delete single nucleotides, interrupt a gene or genetic element, make a single-stranded break in DNA, modify a nucleotide, or make epigenetic changes to gene expression. In the realm of biomedicine, genome editing could be used for three broad purposes: for basic research, for somatic interventions, and for germline interventions.

Basic research can focus on cellular, molecular, biochemical, genetic, or immunological mechanisms, including those that affect reproduction and the development and progression of disease, as well as responses to treatment. Such research can involve work on human cells or tissues, but unless it has the incidental effect of revealing information about an identifiable, living individual, it does not involve human subjects as defined by federal regulation in the United States. Most basic research on human cells uses somatic cells—nonreproductive cell types such as skin, liver, lung, and heart cells—although some basic research uses germline (i.e., reproductive) cells, including early-stage human embryos, eggs, sperm, and the cells that give rise to eggs and sperm. These latter cases entail ethical and regulatory considerations regarding how the cells are collected and the purposes for which they are used, even though the research involves no pregnancy and no transmission of changes to another generation.

Unlike basic research, clinical research involves interventions with human subjects. In the United States and most other countries with robust regulatory systems, proposed clinical applications must undergo a supervised research phase before becoming generally available to patients. Clinical applications of genome editing that target somatic cells affect only the patient, and are akin to existing efforts to use gene therapy for disease treatment and prevention; they do not affect offspring. By contrast, germline interventions would be aimed at altering a genome in a way that would affect not only the resulting child but potentially some of the child’s descendants as well.

A number of the ethical, legal, and social questions surrounding gene therapy and human reproductive medicine provide a backdrop for consideration of key issues related to genome editing. When conducted carefully and with proper oversight, gene therapy research has enjoyed support from many stakeholder groups. But because such technologies as CRISPR/Cas9 have made genome editing so efficient and precise, they have opened up possible applications that have until now been viewed as largely theoretical. Germline editing to prevent genetically inherited disease is one example. Potential applications of editing for “enhancement”—for changes that go beyond mere restoration or protection of health—are another.

Because genome editing is only beginning to transition from basic research to clinical research applications, now is the time to evaluate the full

range of its possible uses in humans and to consider how to advance and govern these scientific developments. The speed at which the science is developing has generated considerable enthusiasm among scientists, industry, health-related advocacy organizations, and patient populations that perceive benefit from these advances. It is also raising concerns, such as those cited earlier, among policy makers and other interested parties to voice concerns about whether appropriate systems are in place to govern the technologies and whether societal values will be reflected in how genome editing is eventually applied in practice.

Public input and engagement are important elements of many scientific and medical advances. This is particularly true with respect to genome editing for potential applications that would be heritable—those involving germline cells—as well as those focused on goals other than disease treatment and prevention. Meaningful engagement with decision makers and stakeholders promotes transparency, confers legitimacy, and improves policy making. There are many ways to engage the public in these debates, ranging from public information campaigns to formal calls for public comment and incorporation of public opinion into policy.

APPLICATIONS OF HUMAN GENOME EDITING

Genome editing is already being widely used for basic science research in laboratories; is in the early stages of development of clinical applications that involve somatic (i.e., nonreproductive) cells; and in the future might be usable for clinical applications involving reproductive cells, which would produce heritable changes.

Basic Science Laboratory Research

Basic laboratory research involving genome editing of human cells and tissues is critical to advancing biomedical science. Genome-editing research using somatic cells can advance understanding of molecular processes that control disease development and progression, potentially facilitating the ability to develop better interventions for affected people. Laboratory research involving genome editing of germline cells can help in understanding human development and fertility, thereby supporting advances in such areas as regenerative medicine and fertility treatment.

The ethical issues associated with basic science research involving genome editing are the same as those that arise with any basic research involving human cells or tissues, and these issues are already addressed by extensive regulatory infrastructures. There are, of course, enduring debates about limitations of the current system, particularly with respect to how it addresses the use of gametes, embryos, and fetal tissue, but the regula-

tions are considered adequate for oversight of basic science research, as evidenced by their longevity. Special considerations may come into play for research involving human gametes and embryos in jurisdictions where such research is permitted; in those cases, the current regulations governing such work will apply to genome-editing research as well. Overall, then, basic laboratory research in human genome editing is already manageable under existing ethical norms and regulatory frameworks at the local, state, and federal levels.

Clinical Uses of Somatic Cell Editing for Treatment and Prevention of Disease and Disability

An example of the application of genome editing to alter somatic (nonreproductive) cells for purposes of treating or preventing disease is a recently authorized clinical trial involving patients whose advanced cancer has failed to respond to such conventional treatments as chemotherapy and radiation. In this study, genome editing is being used to program patients’ immune cells to target the cancer.

Somatic cells are all those present in the tissues of the body except for sperm and egg cells and their precursors. This means that the effects of genome editing of somatic cells are limited to treated individuals and are not inherited by their offspring. The idea of making genetic changes to somatic cells—referred to as “gene therapy”—is not new, and genome editing for somatic applications would be similar. Gene therapy has been governed by ethical norms and subject to regulatory oversight for some time, and this experience offers guidance for establishing similar norms and oversight mechanisms for genome editing of somatic cells.

Somatic genome-editing therapies could be used in clinical practice in a number of ways. Some applications could involve removing relevant cells—such as blood or bone marrow cells—from a person’s body, making specific genetic changes, and then returning the cells to that same individual. Because the edited cells would be outside the body (ex vivo), the success of the editing could be verified before the cells were replaced in the patient. Somatic genome editing also could be performed directly in the body (in vivo) by injecting a genome-editing tool into the bloodstream or target organ. Technical challenges remain, however, to the effective delivery of in vivo genome editing. Gene-editing tools introduced into the body might not find their target gene within the intended cell type efficiently. The result could be little or no health benefit to the patient, or even unintended harm, such as inadvertent effects on germline cells, for which screening would be necessary. Despite these challenges, however, clinical trials of in vivo editing strategies are already under way for hemophilia B and mucopolysaccharidosis I.

The primary scientific and technical, ethical, and regulatory issues associated with the use of somatic gene therapies to treat or prevent disease or disability concern only the individual. The scientific and technical issues of genome editing, such as the as-yet incompletely developed standards for measuring and evaluating off-target events, can be resolved through ongoing improvements in efficiency and accuracy, while the ethical and regulatory issues would be taken into account as part of existing regulatory frameworks that involve assessing the balance of anticipated risks and benefits to a patient.

Overall, the committee concluded that the ethical norms and regulatory regimes developed for human clinical research, gene transfer research, and existing somatic cell therapy are appropriate for the management of new somatic genome-editing applications aimed at treating or preventing disease and disability. However, off-target effects will vary with the platform technology, cell type, target gene, and other factors. As a result, no single standard for somatic genome-editing efficiency or specificity—and no single acceptable off-target rate—can be defined at this time. For this reason, and because, as noted above, somatic genome editing can be carried out in a number of different ways, regulators will need to consider the technical context of the genome-editing system as well as the proposed clinical application in weighing anticipated risks and benefits.

Germline Editing and Heritable Changes

Although editing of an individual’s germline (reproductive) cells has been achieved in animals, there are major technical challenges to be addressed in developing this technology for safe and predictable use in humans. Nonetheless, the technology is of interest because thousands of inherited diseases are caused by mutations in single genes. 3 Thus, editing the germline cells of individuals who carry these mutations could allow them to have genetically related children without the risk of passing on these conditions. Germline genome editing is unlikely to be used often enough in the foreseeable future to have a significant effect on the prevalence of these diseases but could provide some families with their best or most acceptable option for averting disease transmission, either because existing technologies, such as prenatal or preimplantation genetic diagnosis, will not work in some cases or because the existing technologies involve discarding affected embryos or using selective abortion following prenatal diagnosis.

At the same time, however, germline editing is highly contentious precisely because the resulting genetic changes could be inherited by the next

3 OMIM, https://www.omim.org (accessed January 5, 2017); Genetic Alliance, http://www.diseaseinfosearch.org (accessed January 5, 2017).

generation, and the technology therefore would cross a line many have viewed as ethically inviolable. The possibility of making heritable changes through the use of germline genome editing moves the conversation away from individual-level concerns and toward significantly more complex technical, social, and religious concerns regarding the appropriateness of this degree of intervention in nature and the potential effects of such changes on acceptance of children born with disabilities. Policy in this area will require a careful balancing of cultural norms, the physical and emotional well-being of children, parental autonomy, and the ability of regulatory systems to prevent inappropriate or abusive applications.

In light of the technical and social concerns involved, the committee concluded that heritable genome-editing research trials might be permitted, but only following much more research aimed at meeting existing risk/benefit standards for authorizing clinical trials and even then, only for compelling reasons and under strict oversight. It would be essential for this research to be approached with caution, and for it to proceed with broad public input.

In the United States, authorities currently are unable to consider proposals for this research because of an ongoing prohibition on the U.S. Food and Drug Administration’s (FDA’s) use of federal funds to review “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.” 4 In a number of other countries, germline genome-editing trials would be prohibited entirely. If U.S. restrictions on such trials were allowed to expire or if countries without legal prohibitions were to proceed with them, it would be essential to limit these trials only to the most compelling circumstances, to subject them to a comprehensive oversight framework that would protect the research subjects and their descendants, and to institute safeguards against inappropriate expansion into uses that are less compelling or well understood. In particular, clinical trials using heritable genome editing should be permitted only if done within a regulatory framework that includes the following criteria and structures:

• 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 the 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;

4 Consolidated Appropriations Act of 2016, Public Law 114-113 (adopted December 18, 2015).

• availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures;
• ongoing, rigorous oversight during clinical trials 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; and
• reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition.

Even those who will support this recommendation are unlikely to arrive at it by the same reasoning. For those who find the benefits sufficiently compelling, the above criteria represent a commitment to promoting well-being within a framework of due care and responsible science. Those not completely persuaded that the benefits outweigh the social concerns may nonetheless conclude that these criteria, if properly implemented, are strict enough to prevent the harms they fear. It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities. Likewise, physicians and patients will interpret them in light of the specifics of individual cases for which germline genome editing may be considered as a possible option. Starting points for defining some of these concepts exist, such as the definition of “serious disease or condition” used by the FDA. 5 Finally, those opposed to heritable editing may even conclude that, properly implemented, the above criteria are so strict that they would have the effect of preventing all clinical trials involving germline genome editing.

Use of Genome Editing for “Enhancement”

Although much of the current discussion around genome editing focuses on how these technologies can be used to treat or prevent disease and

5 While not drafted with the above criteria in mind, the FDA definition of “serious disease or condition” is “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one” (21 CFR 312.300(b)(1)).

disability, some aspects of the public debate concern other purposes, such as the possibility of enhancing traits and capacities beyond levels considered typical of adequate health. In theory, genome editing for such enhancement purposes could involve both somatic and germline cells. Such uses of the technologies raise questions of fairness, social norms, personal autonomy, and the role of government.

To begin, it is necessary to define what is meant by “enhancement.” Formulating this definition requires a careful examination of how various stakeholders conceptualize “normal.” For example, using genome editing to lower the cholesterol level of someone with abnormally high cholesterol might be considered prevention of heart disease, but using it to lower cholesterol that is in the desirable range is less easily characterized, and would either intervention differ from the current use of statins? Likewise, using genome editing to improve musculature for patients with muscular dystrophy would be considered a restorative treatment, whereas doing so for individuals with no known pathology and average capabilities just to make them stronger but still within the “normal” range might be considered enhancement. And using the technology to increase someone’s muscle strength to the extreme end of human capacity (or beyond) would almost certainly be considered enhancement.

Regardless of the specific definition, there is some indication of public discomfort with using genome editing for what is deemed to be enhancement, whether for fear of exacerbating social inequities or of creating social pressure for people to use technologies they would not otherwise choose. Precisely because of the difficulty of evaluating the benefit of an enhancement to an individual given the large role of subjective factors, public discussion is needed to inform the regulatory risk/benefit analyses that underlie decisions to permit research or approve marketing. Public discussion also is needed to explore social impacts, both real and anticipated, as governance policy for such applications is developed. The committee recommends that genome editing for purposes other than treatment or prevention of disease and disability should not proceed at this time, and that it is essential for these public discussions to precede any decisions about whether or how to pursue clinical trials of such applications.

Public Engagement

Public engagement is always an important part of regulation and oversight for new technologies. As noted above, for somatic genome editing, it is essential that transparent and inclusive public policy debates precede any consideration of whether to authorize clinical trials for indications that go beyond treatment or prevention of disease or disability (e.g., for enhancement). With respect to heritable germline editing, broad participation and

input by the public and ongoing reassessment of both health and societal benefits and risks are particularly critical conditions for approval of clinical trials.

At present, a number of mechanisms for public communication and consultation are built into the U.S. regulatory system, including some designed specifically for gene therapy, whose purview would include human genome editing. In some cases, regulatory rules and guidance documents are issued only after extensive public comment and agency response. Discussion is fostered by the various state and federal bioethics commissions, which typically bring together technical experts and social scientists in meetings that are open to the public. And the National Institutes of Health’s Recombinant DNA Advisory Committee offers a venue for general public discussion of gene therapy, for review of specific protocols, and for transmission of advice to regulators. Other countries, such as France and the United Kingdom, have mechanisms that involve formal polling or hearings to ensure that diverse and informed viewpoints are heard.

PRINCIPLES TO GUIDE THE GOVERNANCE OF HUMAN GENOME EDITING

One of the charges to the committee was to identify principles that many countries might be able to use to govern human genome editing. The principles identified by the committee are detailed in Box S-1 . The committee recommends that any nation considering governance of human genome editing consider incorporating these principles—and the responsibilities that flow therefrom—into its regulatory structures and processes.

RECOMMENDATIONS

In light of the considerations detailed above, the committee made a series of recommendations targeted to basic research and to clinical applications, both somatic and germline. A summary of the key messages in these recommendations is found in Box S-2 .

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Pro and Con: Should Gene Editing Be Performed on Human Embryos?

The most potent use of the new gene editing technique CRISPR is also the most controversial: tweaking the genomes of human embryos to eliminate genes that cause disease. We don’t allow it now. Should we ever?

Pro: Research on Gene Editing in Humans Must Continue

By John Harris

In February of this year, the Human Fertilization and Embryology Authority in the United Kingdom approved a request by the Francis Crick Institute in London to modify human embryos using the new gene editing technique CRISPR-Cas9. This is the second time human embryos have been employed in such research, and the first time their use has been sanctioned by a national regulatory authority. The scientists at the Institute hope to cast light on early embryo development—work which may eventually lead to safer and more successful fertility treatments.

The embryos, provided by patients undergoing in vitro fertilization, will not be allowed to develop beyond seven days. But in theory—and eventually in practice—CRISPR could be used to modify disease-causing genes in embryos brought to term, removing the faulty script from the genetic code of that person’s future descendants as well. Proponents of such “human germline editing” argue that it could potentially decrease, or even eliminate, the incidence of many serious genetic diseases, reducing human suffering worldwide. Opponents say that modifying human embryos is dangerous and unnatural, and does not take into account the consent of future generations. Who is right?

Let’s start with the objection that embryo modification is unnatural, or amounts to playing God. This argument rests on the premise that natural is inherently good. But diseases are natural, and humans by the millions fall ill and die prematurely—all perfectly naturally. If we protected natural creatures and natural phenomena simply because they are natural, we would not be able to use antibiotics to kill bacteria or otherwise practice medicine, or combat drought, famine, or pestilence. The health care systems maintained by every developed nation can aptly be characterized as a part of what I have previously called “a comprehensive attempt to frustrate the course of nature.” What’s natural is neither good nor bad. Natural substances or natural therapies are only better that unnatural ones if the evidence supports such a conclusion.

The matter of consent has been raised by Francis Collins, director of the National Institutes of Health. “Ethical issues presented by altering the germline in a way that affects the next generation without their consent,” he has said, constitute “strong arguments against engaging in” gene editing.

This makes no sense at all. We have literally no choice but to make decisions for future people without considering their consent. All parents do this all the time, either because the children are too young to consent, or because they do not yet exist. George Bernard Shaw and Isadora Duncan knew this. When, allegedly, she said to him “why don’t we make a baby together … with my looks and your brains it cannot fail” she was proposing a deliberate germline determining decision in the hope of affecting their future child. Shaw’s more sober response—“Yes but what if it has my looks and your brains!”—identifies a different possible, but from the child’s perspective equally non-consensual, outcome. Rightly, neither Shaw nor his possible partner thought their decision needed to wait for the consent of the resulting child.

Needless to say, parents and scientists should think responsibly, based on the best available combination of evidence and argument, about how their decisions will affect future generations. However, their decision-making simply cannot include the consent of the future children.

Finally, there’s the argument that modifying genomes is inherently dangerous because we can’t know all the ways it will affect the individual. But those who fear the risks of gene editing don’t take into account the inherent dangers in the “natural” way we reproduce. Two-thirds of human embryos fail to develop successfully, most of them within the first month of pregnancy. And every year, 7.9 million children—6 percent of total births worldwide—are born with a serious defect of genetic or partially genetic origin. Indeed so risky is unprotected sex that, had it been invented as a reproductive technology rather than found as part of our evolved biology, it is highly doubtful it would ever have been licensed for human use.

Certainly we need to know as much as possible about the risks of gene-editing human embryos before such research can proceed. But when the suffering and death caused by such terrible single-gene disorders as cystic fibrosis and Huntington’s disease might be averted, the decision to delay such research should not be made lightly. Just as justice delayed is justice denied, so, too, therapy delayed is therapy denied. That denial costs human lives, day after day.

Con: Do Not Open the Door to Editing Genes in Future Humans

By Marcy Darnovsky

The gene editing tool known as CRISPR catapulted into scientific laboratories and headlines a few short years ago. Fast on its heels came the reemergence of a profoundly consequential controversy: Should these new techniques be used to engineer the traits of future children, who would pass their altered genes to all the generations that follow?

This is not an entirely new question. The prospect of creating genetically modified humans was openly debated back in the late 1990s, more than a decade and a half before CRISPR came on the scene and several years before the human genome had been fully mapped.

It wasn’t long before we saw provocative headlines about designer babies. Princeton mouse biologist Lee Silver, writing in Time magazine in 1999, imagined a fertility clinic of the near future that offered “Organic Enhancement” for everyone, including people with “no fertility problems at all.” He even wrote the ad copy: “Keep in mind, you must act before you get pregnant. Don't be sorry after she's born. This really is a once-in-a-lifetime opportunity for your child-to-be.”

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During the same millennial shift, policymakers in dozens of countries came to a very different conclusion about the genetic possibilities on the horizon. They wholeheartedly supported gene therapies that scientists hoped (and are still hoping) can safely, effectively, and affordably target a wide a range of diseases. But they rejected human germline modification—using genetically altered embryos or gametes to produce a child—and in some 40 countries, passed laws against it.

The issue of human germline modification stayed on a slow simmer during the first decade of the 21st century. But it roared to a boil in April 2015, when researchers at Sun Yat-sen University announced they had used CRISPR to edit the genomes of nonviable human embryos. Their experiment was not very successful in technical terms, but it did focus the world’s attention.

In December 2015, controversy about using CRISPR to produce children was a key agenda item at the International Summit on Human Gene Editing organized by the national science academies of the United States, the United Kingdom, and China. Nearly every speaker agreed that at present, making irreversible changes to every cell in the bodies of future children and all their descendants would constitute extraordinarily risky human experimentation. By all accounts, far too much is unknown about issues including off-target mutations (unintentional edits to the genome), persistent editing effects, genetic mechanisms in embryonic and fetal development, and longer-term health and safety consequences.

Conversations about putting new gene editing tools into fertility clinics need to begin with an obvious but often overlooked point: By definition, germline gene editing would not treat any existing person’s medical needs. At best, supporters can say that it might re-weight the genetic lottery in favor of different outcomes for future people—but the unknown mechanisms of both CRISPR and human biology suggest that unforeseeable outcomes are close to inevitable.

Beyond technical issues are profound social and political questions. Would germline gene editing be justifiable, in spite of the risks, for parents who might transmit an inherited disease? It’s certainly not necessary. Parents can have children unaffected by the disease they have or carry by using third-party eggs or sperm, an increasingly common way to form families. Some heterosexual couples may hesitate to use this option because they want a child who is not just spared a deleterious gene in their lineage, but is also genetically related to both of them. They can do that too, with the embryo screening technique called pre-implantation genetic diagnosis (PGD), a widely available procedure used in conjunction with in vitro fertilization.

PGD itself raises social and ethical concerns about what kind of traits should be selected or de-selected. These questions are particularly important from a disability rights perspective (which means they’re important for all of us). But screening embryos for disease is far safer for resulting children than engineering new traits with germline gene editing would be. Yet this existing alternative is often omitted from accounts of the controversy about gene editing for reproduction.

It is true that a few couples—a very small number—would not be able to produce unaffected embryos, and so could not use PGD to prevent disease inheritance. Should we permit germline gene editing for their sake? If we did, could we limit its use to cases of serious disease risk?

From a policy perspective, how would we draw the distinction between a medical and enhancement purpose for germline modification? In which category would we put short stature, for example? We know that taller people tend to earn more money. So do people with paler skins. Should arranging for children with financially or socially “efficient” varieties of height and complexion be considered medical intervention?

Think back to the hypothetical fertility clinic offering “Organic Enhancement” as a “once-in-a-lifetime opportunity for your child-to-be.” Think back to the 1997 movie Gattaca, about a society in which the genetically enhanced—merely perceived to be biologically superior—are born into the physical reality of those whom we might now call the one percent. These are fictional accounts, but they are also warnings of a possible human (or not so human) future. The kinds of social changes they foresee, once set in motion, could be as difficult to reverse as the genetic changes we’re talking about.

In opening the door to one kind of germline modification, we are likely opening it to all kinds. Permitting human germline gene editing for any reason would likely lead to its escape from regulatory limits, to its adoption for enhancement purposes, and to the emergence of a market-based eugenics that would exacerbate already existing discrimination, inequality, and conflict. We need not and should not risk these outcomes.

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Experts weigh medical advances in gene-editing with ethical dilemmas

Biophysicist He Jiankui addressed the last international summit on human genome editing in Hong Kong in 2018. His experiments in altering the genetic makeup of human embryos was widely condemned by scientists and ethicists at the time, and still casts a long shadow over this week's summit in London. Anthony Wallace/AFP via Getty Images hide caption

Biophysicist He Jiankui addressed the last international summit on human genome editing in Hong Kong in 2018. His experiments in altering the genetic makeup of human embryos was widely condemned by scientists and ethicists at the time, and still casts a long shadow over this week's summit in London.

Hundreds of scientists, doctors, bioethicists, patients, and others started gathering in London Monday for the Third International Summit on Human Genome Editing . The summit this week will debate and possibly issue recommendations about the thorny issues raised by powerful new gene-editing technologies.

The last time the world's scientists gathered to debate the pros and cons of gene-editing — in Hong Kong in late 2018 — He Jiankui, a biophysicist and researcher at Southern University of Science and Technology in Shenzhen, China, shocked his audience with a bombshell announcement . He had created the first gene-edited babies, he told the crowd — twin girls born from embryos he had modified using the gene-editing technique CRISPR.

He, who had trained at Rice University and Stanford, said he did it in hopes of protecting the girls from getting infected with the virus that causes AIDS . (The girls' father was HIV-positive.) But his announcement was immediately condemned as irresponsible human experimentation. Far too little research had been done, critics said, to know if altering the genetics of embryos in this way was safe . He ultimately was sentenced by a Chinese court to three years in prison for violating medical regulations.

In the more than four years since He's stunning announcement, scientists have continued to hone their gene-editing powers.

"A lot has happened over the last five years. It's been a busy period," says Robin Lovell-Badge from the Francis Crick Institute in London, who led the committee convening the new summit.

Doctors have made advances using CRISPR to try to treat or better understand many diseases, including devastating disorders like sickle cell disease , and conditions like heart disease and cancer that are even more common and influenced by genetics.

Jennifer Doudna, a biochemist at the University of California, Berkeley and one of the pioneers in the discovery and use of CRISPR, speaking with reporters at the scientific summit in Hong Kong in 2018. Despite exciting advances, genome-editing still faces technical and ethical challenges, she says. Isaac Lawrence/AFP via Getty Images hide caption

Jennifer Doudna, a biochemist at the University of California, Berkeley and one of the pioneers in the discovery and use of CRISPR, speaking with reporters at the scientific summit in Hong Kong in 2018. Despite exciting advances, genome-editing still faces technical and ethical challenges, she says.

In recent years, scientists have produced new evidence about the risks and possible shortcomings of gene-editing , while also developing more sophisticated techniques that could be safer and more precise.

"We're at an exciting moment for sure with genome-editing," says Jennifer Doudna at the University of California, Berkeley, who helped discover CRISPR. "At the same time, we certainly have challenges."

"We could help a lot of people"

One big remaining challenge and ethical question is whether scientists should ever again try to make gene-edited babies by modifying the DNA in human sperm, eggs or embryos. Such techniques, if successful could help families that have been plagued by devastating genetic disorders.

"There are more than 10,000 single genetic mutations that collectively affect probably hundreds of million of people around the world," says Shoukhrat Mitalipov , a biologist at the Oregon Health and Science University in Portland who's been trying to find ways to safely gene-edit human embryos. "We could help a lot of people."

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But the fear is a mistake could create new genetic diseases that could then be passed down for generations. Some scientists are also concerned about opening a slippery slope to "designer babies" — children whose parents try to pick and choose their traits.

"If we were to allow parents to genetically modify their children, we would be creating new groups of people who are different from each other biologically and some would have been modified in ways that are supposed to enhance them," says Marcy Darnovsky heads the Center for Genetics and Society in San Francisco. "And they would be — unfortunately I think — considered an enhanced race — a better group of people. And I think that could really just super-charge the inequities we already have in our world."

The debate among many scientists seems to have shifted to how to edit a genome safely

Despite those concerns, some critics say the debate over the last five years has shifted from whether a prohibition on inheritable genetic modifications should ever be lifted to what technical hurdles need to be overcome to do it safely — and which diseases doctors might try to eradicate.

As evidence of that, the critics point to the fact that the subject of genetically modifying embryos, sperm or eggs to engineer modifications that would then be passed along to every subsequent generation is the focus of only one of three days of this summit — the first such conference since the CRISPR babies were announced.

"This is quite an ironic outcome," says Sheila Jasanoff is a professor of science and technology studies at Harvard's Kennedy School of Government.

New U.S. Experiments Aim To Create Gene-Edited Human Embryos

"Instead of rejuvenating the calls to say: 'We should be much more careful,' " Jasanoff says, "it was as if the whole scientific community heaved a kind of sigh of relief and said: 'Well, look, of course there are limits. This guy has transgressed the limits. He's clearly outside the limits. And therefore everything else is now open for grabs. And therefore the problem before us now is to make sure that we lay out the guidelines and the rules.'"

Ben Hurlbut , a bioethicist at Arizona State University, agrees.

"There was a time when this was considered taboo," he says. "But since the last summit, there's been a shift from asking the question of 'whether' to asking the question of 'how.' "

It was too easy to scapegoat He, some ethicists say

Hurlbut and others also say scientists have failed to fully come to terms with the high-pressure environment of biomedical research that they say encouraged He to do what he did.

"It just feels easier to condemn He and say all bad resides in his person and he should be ostracized forever as we proceed apace. Not reckoning with what happened and why fosters a certain thoughtlessness, and I would say recklessness," Hurlbut says.

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A Russian Biologist Wants To Create More Gene-Edited Babies

That lack of reckoning with what happened could be dangerous, critics say. It could, they fear, encourage others to try make more gene-edited babies, at a time when the public may never have been more skeptical about scientific experts.

"We have seen in recent years a sense that the experts have taken on too big a role and that they have tried to run roughshod over our our day-to day-lives," says Hank Greely , a longtime Stanford University bioethicist. But whether or not inheritable genetic modifications should be allowed is "ultimately a decision for societies and not a decision for science."

A new lab in Beijing

Meanwhile, He Jiankui appears to be trying to rehabilitate himself after serving his three-year prison sentence. He's set up a new lab in Beijing, is promising to develop new gene-therapies for diseases like muscular dystrophy, is giving scientific presentations , and is trying to raise money.

He's not expected to join the London summit this week, and is no longer talking about creating more gene-edited babies. Still, his activities are raising alarm in the scientific and bioethics communities. He declined NPR's request for an interview. But in a recently published interview with The Guardian the only regret he mentioned was in moving too fast.

"I'm concerned," Lovell-Badge says. "I'm surprised that that he's being allowed to practice science again. It just scares me."

Others agree.

"What he did was atrocious," says Dr. Kiran Musunuru , a professor of medicine at the University of Pennsylvania. "He shouldn't be allowed anywhere near a patient again. He's proven himself to be utterly unqualified."

Lovell-Badge and other organizers of the summit dispute criticisms that scientists are assuming gene-edited babies are inevitable and that the agenda for this week's conference short-changes a debate about the ethical and societal landmines that remain in this field of study.

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Summit leaders say they'll dedicate the last day of the meeting to genetic modifications that can be passed down through generations; panel participants will feature scientists as well as a broad array of watchdog groups, patient advocates, bioethicists, sociologists and others.

Conference organizers say they have good reasons for focusing the first two-thirds of the meeting on the use of gene-editing to treat people who have already been born.

"The summit is a chance to really hear about what's happening in the field that has the greatest potential for improving human health," says R. Alta Charo, a professor emerta of law and bioethics from the University of Wisconsin, who helped organize the summit.

Questions of equity have moved center stage

But those current treatments raise their own ethical concerns — including questions of equity. Will the the current and coming gene therapies be widely available, given how expensive and technologically complicated they can be to create and administer?

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"We're not moving away from the conversation around heritable genome editing, but we are trying to shift some of that focus," says Francoise Baylis , a bioethicist who recently retired from Dalhousie University in Canada and helped plan the meeting. "Really important in this context is the issue of cost, because we have been seeing gene-therapies come onto the market with million-dollar price tags. That's not going to be available to the average person."

The availability of gene-therapy treatments in lower-income countries must be a focus of concern, Baylis says.

"We're going to be asking questions about where are the people who are most likely to be benefit," she says, "and are they going to have access?"

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• genome editing

The Law, Science, and Policy of Genome Editing

Paul Enríquez Online Symposium: Paul Enríquez’s Rewriting Nature: The Future of Genome Editing and How to Bridge the Gap Between Law and Science 102 B.U. L. Rev. Online 42 (2022) PDF | Back to Symposium

Introduction

Genome editing is the most significant breakthrough of our generation. Rewriting Nature [1] explores the intersection of science, law, and policy as it relates to this powerful technology. Since the manuscript went to press, genome-editing developments have continued apace. Researchers have reported encouraging results from the first clinical trials to treat β-thalassemia and Sickle-Cell Disease, [2] the first wheat-crop variety that is resistant to a crippling fungal disease and features no growth or yield deficits, [3] and proof-of-concept data establishing the therapeutic effects of the first clinical trial involving the injection of a therapy directly into the bloodstream of patients suffering from a genetic, neurological disease. [4] Chinese regulators promulgated rules to approve gene-edited crops. [5] These and other developments are testament to the expansive reach and promise of genome editing. Rewriting Nature showcases the technology’s power to transform what we eat, how we provide healthcare, how we confront the challenges of global climate change, who we are as human beings, and more.

One of my goals in writing the book was to help spur robust dialogue and debate about the future of genome editing and the synergistic roles that law, science and public policy can play in promoting or hindering specific uses of the technology. I am grateful to the Boston University Law Review for organizing this symposium on Rewriting Nature and bringing together an extraordinary group of gifted scholars, academics, entrepreneurs, and thinkers, including several members of the National Academy of Sciences, as well as scientists and lawyers to engage in diverse discussions of my book. I am indebted to Professors Rodolphe Barrangou, Naomi Cahn, Dana Carroll, Glenn Cohen, John Conley, Katherine Drabiak, Michele Bratcher Goodwin, Fred Gould, Henry Greely, Gary Marchant, Kevin Outterson, Christopher Robertson, Jacob Sherkow, Sonia Suter, and Allison Whelan for reading the book and contributing their thoughtful insights—during the live event, in print, or both. I am truly honored and humbled by the generous praise they bestow on my work and the collective caliber of insight they bring to the discussion. It is my honor and privilege to share this platform with so many accomplished people who have inspired and taught me a great deal through their work. I am encouraged by the consonance on a vast range of ideas among participants but even more so by the disagreement, as it presents opportunities for engagement and progress. My Essay, thus, focuses on the hard questions and challenges that spring from our disagreements, which allowed me to clarify, refine, and expand on ideas presented in Rewriting Nature and to articulate new ones that point towards future work.

• On Defining Genome Editing

Professor Sherkow’s thoughtful contribution focuses on Chapter 3 of Rewriting Nature , which lays the interpretive and normative groundwork for a working definition of the term “genome editing.” [6] He is skeptical that such a definition is necessary and observes that “the law is quite able to muddle along without a clear definition of a particular thing.” [7]

I concur with the sentiment that definitions can sometimes engender more problems than solutions in some legal contexts, particularly when they are “riddled with vagueness, ambiguity, and incompleteness.” [8] Rewriting Nature explores several of the inherent limitations concerning the use of specific terminology, which may (1) render the meaning of words “malleable” and capable of “evolv[ing] over time and cultures”; (2) be overbroad, so as to make the meaning of words “inherently ambiguous” and difficult to apply uniformly; and (3) trigger the collapse of a definition’s relevance and application to unforeseen circumstances under the weight of undue “stringency” and “rigidity.” [9] I caution at the outset that “no definition is perfect” and recognize that “[n]o one-size-fits-all definition” will ever apply perfectly in every situation. [10]

To support his thesis, Sherkow analogizes the term “genome editing” to the words “family” and “sale.” [11] He notes that “no one seems to be particularly confused” about the meaning of those words in different legal contexts and, therefore, argues that the law is able to “muddle along” without definitions. [12] But Sherkow’s proposition brings to light a fundamental distinction that attenuates the analogy’s scope and application in the legal realm. The terms “family” and “sale” are precisely the type of words that courts are well equipped to construe and interpret based on ordinary meaning and other canons of statutory construction, as well as principles of legislative intent. While judges are unlikely to be fazed by the meaning of the word “sale” in the context of tax, real estate, and commercial laws, [13] there is an inherent challenge for judges, who may fairly be presumed to lack scientific training and to be unfamiliar with a given complex, emerging technology, to construe or infer plain meaning from a scientific term such as genome editing.

The likelihood of confusion over the meaning of such a technical concept is substantial. Without the guiding light of a clear and robust definition grounded in science, judges may follow whatever rules of construction they deem fit or turn to less reliable sources such as general-use dictionaries—which often lack accuracy, specificity, and clarity—in search of an “ordinary” meaning for a specialized concept. [14] This is highly problematic for the reasons I outline in Rewriting Nature . Furthermore, if legal disputes ensue, litigants may introduce evidence of the meaning of genome editing that serves their specific purposes. This opens the door for select “stakeholders to inject self-serving, arbitrary, and subjective interpretations” about the meaning of genome editing. [15]

Courts, of course, are not obligated to follow reference sources, such as dictionaries, and may wholly ignore expert testimony that they deem irrelevant to the inquiry presented. Judicial discretion in these domains contributes to the phenomenon in which courts render interpretations and meanings that eschew scientific evidence. Such occurrences are neither speculative nor hypothetical.

In Nix v. Hedden , [16] the U.S. Supreme Court acknowledged that from the perspective of botany—the scientific discipline that concerns the study of plants—a tomato falls within the definition of “fruit,” a term that refers to the “ripened ovary of a plant and its contents,” including the seeds. [17] Notwithstanding its botanical classification as a fruit, the Court held that a tomato is a vegetable, as a matter of law, because people (1) grow them in gardens among other vegetables and (2) serve them cooked or raw during dinner but not alongside dessert—the way they generally serve fruits. [18] The Court afforded no deference to the scientific meaning of a disputed term and instead relied on the so-called common knowledge of the people at the time to dictate the meaning of fruit. It is not hard to fathom, in light of Nix and similar cases, why scientists and advocates of science-based law and policy are often dismayed when courts ignore relevant scientific evidence and offer jejune legal reasoning as the basis to decide cases with vast repercussions in many areas of society. [19] Absent guidance about the meaning of a scientific concept such as genome editing, courts may churn out a litany of arbitrary decisions featuring broad interpretations and meanings that cannot be reconciled with the particular subtleties and technical context of a given case.

Next, I wish to address Sherkow’s—and, to some extent, Professor Greely’s—comments regarding “universal definitions” [20] that may “fit[ ] all situations.” [21] Sherkow, for instance, grafts a “universality” sine qua non onto my proposed definition of genome editing. But my sense is that he misreads my normative claims. Rewriting Nature features no such universality requirement.

The thrust of my argument is that, due to the increasing reach of the technology across a wide range of disciplines, “[c]ongruity and uniformity on genome-editing terminology [are] sorely needed at this point in time.” [22] Congruity (contextual harmony) [23] and uniformity (consistent treatment) [24] under the law—namely, the harmonious and consistent application of the term—are thus the principal focus of my definitional prescription. Rewriting Nature says nothing about a need for universality (an all-inclusive concept without limit or exception existing under all conditions) [25] in defining genome editing.

Congruity and uniformity breed predictability , which is a quality that the law ought to promote even if outcomes lead to some degree of variation in a given context of a legal dispute. A court may construe or interpret the word “family” liberally to encompass parents, children, siblings, grandparents, cousins, and in-laws and their relatives for purposes of one law regulating family gatherings, but narrowly to refer only to the parent-child relationship for purposes of determining an individual’s qualification as a dependent under a tax law. Such context-dependent degrees of variation, however, would not vitiate the benefits of a robust definition that, for example, anchors “family” to a common denominator that excludes, say, friends and co-workers from the family unit, regardless of the express contextual statutory intent of a specific law or regulation. [26] The definition of “family” may not be universal, but the term can still be uniformly applied to encompass individuals related by blood or marriage in different contexts.

In any event, it is worth reiterating that the book “advocates for the adoption of a (more) uniform definition of genome editing primarily aimed at building a science-based, legal and policy framework to address current and future predicaments within the ambit of genome-editing technologies” and rejects the universal adoption of a rigid, one-size-fits-all definition of genome editing. [27] The definitional prescription concerns efforts to disseminate accurate, science-based information, so as to (1) promote efficient and effective channels of interdisciplinary communication, (2) engage in fruitful discussions grounded on a common understanding of genome editing, and (3) prevent the spread of vagueness, ambiguity, indefiniteness, and confusion in future discussions about genome-editing technologies.

Despite the inherent limitations on specific terminology enumerated in Rewriting Nature , I conclude that such limitations may be largely allayed and overcome by subjecting the proposed definition to rigorous scrutiny and debate. It is true that no one definition may apply perfectly in every situation, but we cannot let the perfect be the enemy of the good. There is value in formulating a robust, science-based definition of genome editing at this early juncture of technological development. Just so, there is no principled reason to avoid subjecting the definition to additional scrutiny as time goes by and the technology continues to develop.

It may be that one option is for the law to “muddle along” without a genome-editing definition for some time. But is it prudent to merely muddle along aimlessly without strategy as courts, policymakers, and society navigate the intersection of law, science, and policy of genome editing? Or would the preferable choice be to confront a complex, foreseeable problem with the benefit of time and widespread input from scientists, interdisciplinary experts, stakeholders, and the public? My sense is that we ought to collectively strive, as a society, to undertake important and difficult dialogues that will promote civic engagement and respectful conversations about science and technology. Sherkow’s and Greely’s thoughtful critiques allowed me an opportunity to clarify some of the things I said and did not say in Rewriting Nature , for which I am grateful.

• Germline Genome Editing and the Constitution

Turning the page on the discussion pertaining to definitions, a number of contributors offered unique perspectives about Rewriting Nature ’s take on germline genome editing (“GGE”) and the Constitution. Professors Suter and Cahn, for example, are skeptical that a subcategory of GGE may potentially give rise to a fundamental right protected by the Constitution. [28] They argue that the “Rehnquist conception of fundamental liberty interests,” which encompasses “[a] rigid and literalist conception of our history and tradition,” excludes forms of assisted reproductive technology (“ART”) such as GGE. [29]

Suter and Cahn refer to the Supreme Court’s two-prong approach articulated in Washington v. Glucksberg , [30] in which the Court concocted a standard to determine whether a fundamental right exists in the Constitution. [31] Under Glucksberg , the asserted right must (1) be “objectively, ‘deeply rooted in this Nation’s history and tradition’” and (2) include a “‘careful description’ of the asserted fundamental liberty interest.” [32] To the extent that the Court may apply a narrow interpretation of Glucksberg as controlling the inquiry of whether a select use of GGE constitutes a cognizable fundamental right under the Constitution today , [33] I am inclined to concur with Suter and Cahn’s analysis because modern GGE constitutes “a nascent biotechnology” not yet proven safe and effective, for which “no deeply rooted history exists.” [34] Rewriting Nature recognizes that contingency.

My analysis and conclusion on this topic, however, ultimately diverge from Suter and Cahn’s perspective because of the structural constitutional jurisprudence erected after Glucksberg . Most notably, my thesis recognizes that Lawrence v. Texas [35] and Obergefell v. Hodges [36] jointly abrogate Glucksberg ’s approach to determining fundamental rights and indeed abandoned the type of rigid application that Suter and Cahn invoke in their analysis. Lawrence , for example, clarified that “[h]istory and tradition are the starting point but not in all cases the ending point of the substantive due process inquiry.” [37] Obergefell subsequently qualified Glucksberg ’s specific breed of substantive due process. Obergefell noted that the definition of rights “in a most circumscribed manner, with central reference to specific historical practices, . . . may have been appropriate for the asserted right” of physician-assisted suicide in Glucksberg but is not the approach the Court has “used in discussing other fundamental rights, including marriage and intimacy.” [38] The Court explained that certain fundamental rights protected by the Constitution “come not from ancient sources alone. They rise, too, from a better informed understanding of how constitutional imperatives define a liberty that remains urgent in our own era.” [39]

Obergefell ’s reasoning thus expressly distinguished the nature of the right under review. On one hand, the Court endorsed Glucksberg ’s narrow holding, which ascribed more weight to historical practices and tradition when striking a purported right of physician-assisted suicide—a right involving, at its core, the termination of life . Conversely, the Court went out of its way to explain that a narrow reading of Glucksberg —one centered exclusively on such reference to historical practices—was not the appropriate analytical framework with which to examine other rights involving marriage and intimacy, which stem from broad protected liberties that are associated with the family-unit sphere and procreation rights.

This nuanced distinction involving fundamental rights—namely, whether the judiciary has implicitly been distinguishing rights associated with the termination of life versus advancement of liberty and autonomy in the procreation and family-unit contexts—is significant for purposes of discussing whether a cognizable right to select uses of GGE may exist under the Constitution. A fundamental right involving parental autonomy to make healthcare decisions and use GGE to rescue one’s child from death and suffering at the hands of congenital disease would be the polar opposite of the asserted right to terminate one’s life that Glucksberg rejected.

The post- Glucksberg line of precedents informs the distinctions that Rewriting Nature draws between a putative right related to specific uses of GGE and the breed of substantive due process articulated in the privacy realm, which includes Roe v. Wade [40] and its progeny. For instance, Roe protects a woman’s constitutional right to terminate her pregnancy. [41] The Court has restricted such a right in recent decades by incorporating an “undue burden” standard into its jurisprudence. [42] My collective reading of these precedents suggests that at least some members of the Court in recent decades have tacitly applied a heightened version of legal scrutiny—perhaps something akin to the strict-scrutiny standard that exclusively applies to government action impinging fundamental rights—in private substantive-due-process cases involving the termination of life, regardless of whether the circumstances arise at an embryonic stage or the point of imminent death. This would explain why cases like United States v. Rutherford [43] and Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach [44] have failed to crystallize certain rights for terminally ill patients. Rewriting Nature hints at this distinction, but I am indebted to Suter and Cahn’s thoughtful essay for prompting me to more clearly articulate this point here.

Elucidation of the heightened standard applicable in termination-of-life cases, as well as the legal treatment afforded to them under the current substantive-due-process framework, further buttress my proposition that Roe and its progeny are largely inapplicable to the GGE context discussed herein. After all, “clinical interventions to cure or ameliorate disease in an embryo—with the intent to save a child from premature death—are at the opposite end of what abortion achieves.” [45] The parents who seek GGE want to rescue their offspring from imminent death caused by harmful genetic mutations, whereas the parents who seek an abortion do not wish to bring the embryo to term. Framing the issue in this context may determine what breed of substantive due process presumably applies to the facts of a given case.

Suter and Cahn’s resistance to my proposed theory discerning among discrete subtypes of substantive due process may explain why they argue that substantive-due-process rights are “on shaky ground” and worry that “[i]f Roe falls,” so too might “other fundamental rights, such as same-sex marriage.” [46] Perhaps Suter and Cahn are right. But I am less convinced than they may be in this regard.

The GGE fundamental-right arguments I advance in Rewriting Nature are largely independent of Roe ’s specific brand of privacy-based substantive due process. Several sections of the book note, for example, that a cognizable right that protects select uses of GGE may encompass a right “in its comprehensive sense” [47] and flow from jurisprudence related to “procreative, parental autonomy, and— to some extent —privacy rights.” [48] The analytical thrust of my proposed framework could, therefore, outlast a potential demise of Roe ’s viability as a constitutional precedent.

On this point, like Suter and Cahn, I too point to comments by Justices of the Supreme Court, who have previously expressed a willingness to overrule certain substantive-due-process precedents. [49] But I would go a step further and discern the specific “species” or subtype of substantive due process inherent in each commentary. To my knowledge, even the most “conservative” jurists have not expressed an appetite for outright overruling procreation-based and parental-autonomy substantive-due-process holdings directly predicated upon Meyer v. Nebraska , [50] Pierce v. Society of Sisters , [51] and Skinner v. Oklahoma [52] —all precedents that, at this point, are very long in the tooth. It is hard to fathom that most, if not nearly all, of the Justices appointed to the Court in recent decades would, for example, uphold a statute impinging on the parental autonomy to decide whether to send children to parochial schools. In a similar vein, when viewed through the termination-of-life prism—rather than the one-size-fits-all, substantive-due-process lens—it seems plausible but, overall, less probable that a panel of Justices would open the door to the States’ annulling some subset of more than 500,000 same-sex marriages. [53]

My argument here stems from the observation that even some individuals who outright reject Roe , Lawrence , and Obergefell would effectively make a substantive distinction between the rights of gay and lesbian couples to marry under Loving and the rights of women to terminate a pregnancy under Roe . Because the former implicates a right within the family-unit sphere (in closer proximity to parental-autonomy precedents) and the latter involves what some may frame as the termination of life (in line with Roe ), the two would presumably share different fates if a particular branch of the doctrine of substantive-due-process tree falls; one branch may fall while others hold up, so long as the tree still stands.

Lastly, Suter and Cahn astutely comment on the evolving composition of the Supreme Court and surmise that “it is highly improbable, at a moment when substantive due process interests seem especially vulnerable, that the Court would recognize a fundamental procreative interest in [ART] and especially to genetically manipulate one’s offspring in a manner that could be heritable to future generations.” [54] I wish to counter this proposition by making two brief points.

First, Suter and Cahn frame the issue as one involving a fundamental right “to genetically manipulate one’s offspring.” [55] The ultimate framing of an issue presented for judicial review plays a pivotal role in the outcome of a given case. In Rewriting Nature , I draw parallels to the questions presented in Glucksberg , Bowers v. Hardwick , [56] and Lawrence to posit that the answer to whether parents have a cognizable right to select uses of GGE under the Constitution would vary under a series of hypothetical statements. [57] Suter and Cahn’s framing mirrors one of those statements, which presumably carries a negative connotation: Is there a right to “genetically modify offspring”?

Parents would better serve their interests by framing the question as one associated with a right to rescue offspring from, in some cases, an imminent death; or more broadly, to make child-healthcare decisions to prevent impending life-threatening disease or death. Again, these questions can evoke the sort of nuanced, substantive-due-process subtype distinctions I discuss in this Essay. More importantly, they play a role in elucidating whether the right in question involves an entirely novel fundamental right (genetic modification) or represents a mere extension of already-existing fundamental rights rooted in parental autonomy and procreation (making child-healthcare decisions).

Second, with regard to the argument that the proposed fundamental right associated with GGE is unlikely to materialize at this moment due to an “increasingly conservative” Supreme Court, admittedly I have no idea what the Court may do in a case that raises the GGE constitutional question under discussion. Nor have I the slightest idea as to the composition of the Court ten or twenty years from now. Above all, we must remember that the GGE constitutional questions raised in the book are on the distant horizon. Rewriting Nature is forward-looking and seeks to explore these issues early on so that we have ample time to contemplate the benefits and potential downsides associated with uses of the technology.

In the end, I think Suter and Cahn make an excellent point that ought not to be overlooked, which is that these issues do not arise in a vacuum of science, law, and policy. Rewriting Nature acknowledges that the composition of the Court at a particular point in time would be an important factor to consider. [58] Perhaps I am too sanguine, but part of me generally resists the urge to think of these issues along political lines. I will offer one last comment on this point.

The current COVID-19 pandemic has led to an increase in the political polarization of vaccine mandates. The Court has been called on to resolve disputes about such mandates. [59] Regardless of how each Justice has come down in favor or against a vaccine mandate in a given context, all Justices are nevertheless fully vaccinated. [60] They have availed themselves of a scientific breakthrough—a messenger ribonucleic acid (“mRNA”)-based vaccine—to protect their lives. So too have most representatives in Congress, regardless of political affiliation. The point is that many of these issues, including vaccinations, can certainly be political and become politicized. But it does not have to be so. Judges are human, after all. They have surprised legal experts by voting in unexpected ways in myriad cases—Kennedy in Lawrence , [61] O’Connor in Grutter v. Bollinger , [62] Gorsuch in Bostock v. Clayton County , [63] Roberts in NFIB v. Sebelius , [64] to name a few—and will continue to do so.

Regardless of political association, I am confident that judges are unified in protecting the lives of children. My hope is that precedent, science, as well as tempered, science-based law and policy—not politics—will be the driving forces that shape the future of GGE. I have no principled reason to believe that, at some point in the future, judges would summarily dismiss the pleas of desperate parents and haphazardly oppose a safe and effective treatment that can spare the life of a child because they are bound to blindly follow a particular constitutional ideology. My sincere hope is that by the time that future comes, Rewriting Nature will have at least contributed to jumpstarting relevant science-based discussions about those future issues surrounding genome editing.

III.   Countering Skepticism of Scientific Progress

Professor Drabiak offers a different critique of my proposed approach to GGE. She is doubtful that GGE will ever be safe and effective. Based on a presumption of “unknown factors” associated with GGE, she argues that parents lack the authority to make decisions that can “substantially limit [a] child’s life path.” [65] She further argues for a “right to an open future,” which would limit parental authority to consent to GGE medical interventions or, in the alternative, a “right to genomic integrity” that would forbid carrying out “intentional germline modifications.” [66]

Drabiak’s essay offers a provocative viewpoint that induced me—and probably other symposium participants—to think about GGE from another angle. It is clear, however, that we approach law and science differently.

From my perspective as a scientist, the most unexpected of her arguments is perhaps the assertion that GGE “will never be safe and effective.” [67] The “never-will” proposition in this regard deals in absolutes and is laden with the type of “value judgment” [68] that she ascribes to the scientific community when it points to incremental advances in basic research as the basis for its optimism about a given technology. Optimism, however, is clearly distinguishable from hype. The former is grounded on promising results from empirical research, which spotlight areas of improvement and future research directions. The latter is unsupported by evidence, replete with deceptive simplicity, [69] and prone to manipulation by parties with ulterior motives.

The principle underlying the never-will assertion further concerns me because it implies an unwillingness to consider new evidence that may disprove a given hypothesis. That is antithetical to the scientific method and would all but foreclose an open dialogue about the potential benefits and harms of developing and using any nascent technology. As Professor Barrangou articulated, science and technology are here to help humanity solve big problems that call for big solutions. [70] Averring that GGE will never be “safe and effective” would be akin to claims that interoceanic aviation would never have been safe, or even possible, because the 1903 Wright Flyer covered a ground distance of 120 feet. [71] The same holds true about the once-nascent technology that brought us the mRNA vaccines against SARS-CoV-2, the virus that causes COVID-19. And let’s not forget in vitro fertilization (“IVF”), which since 1978 has led to the birth of more than eight million babies. [72]

Safety and efficacy are relative terms. GGE is no different than other therapeutic contexts in that regard. The U.S. Food and Drug Administration’s (“FDA”) determination that a drug is safe, for example, does not indicate a complete absence of risk or potential harm. Safety means that the therapeutic “benefits of the drug outweigh the risks.” [73]

Adherence to a “never-will” principle would have precluded virtually every modern-era, technological advance in telecommunications, space travel, human medicine, transportation, and more. We should not be skeptical of robust scientific evidence. Scientists, however, must ground their optimism about a given technology firmly in scientific facts to avoid misinterpretation of scientific progress. On that point, Rewriting Nature warns that GGE is “not yet ready for primetime” [74] and that any experiments in the human germline at this time would be “premature” and pose risks not outweighed by potential benefits. [75] Ultimately, we must not lose sight of the fact that GGE is a promising, nascent biotechnology that will continue to develop and improve in years to come.

Still, my most substantive disagreement with Drabiak concerns her discussion of the rights to “an open future” and “genomic integrity.” [76] The rights are tentative and lack specificity; they appear to enshrine an ideal but are rife with obstacles that would preclude their application in the law. The rights also leave me wondering about their source of origin, presumptive limits, constituent elements, how they would be implemented, what mechanisms of enforcement would be available, and how they would interact with other related rights. The language associated with the framing of these rights leads me to assume, perhaps incorrectly, that they derive from human-rights treaties. Accordingly, I wonder about the kinds of obstacles Drabiak foresees in efforts to incorporate them into domestic law, and whether they would be self-executing.

I further question what it means to have an amorphous right that protects “genomic integrity.” Drabiak explains that the right “preclude[s] intentional germline modifications.” [77] But does this mean the right suggests that a purported sanctity (inviolability) of the human germline must be protected? If so, does it follow that we have a duty to maintain the integrity of genomic loci that trigger human disease and death? I am not persuaded that the integrity of a genome featuring a deleterious mutation that causes, for example, Tay-Sachs disease or Cystic Fibrosis is worthy of protection under a fundamental right.

If we equate this presumed germline-integrity argument with a right to bodily integrity, how should we reconcile said right against the constitutionally recognized principle of parental autonomy to make decisions on behalf of children, including granting or withholding consent for medical care? Suppose a toddler with a severe form of aortic stenosis, a congenital heart defect that may lead to congestive heart failure, needs a heart transplant. Assuming the parents opt in favor of the surgery, would that decision render them infringers of the child’s right to bodily integrity? The likely answer under the law of parental autonomy to direct offspring medical-care decisions is no. It is therefore hard to reconcile this concept against a right to “germline integrity” solely because the treatment is molecular in nature and occurs at an embryonic stage. I admit I do not quite understand the logic dictating that at some point in the future, if and when the technology is safe and effective, preventing offspring death and suffering with the use of GGE constitutes an “infringe[ment] upon the dignity and rights of the future child.” [78]

The right to an “open future” is similarly ambiguous. Revisiting the aortic-stenosis hypothetical above, under Drabiak’s proposal, parents who choose the heart-transplant procedure would likely violate the child’s rights because a heart transplant carries significant risks, including death, and is not ever completely safe and effective. The parents could not consent to the transplant because it constitutes an intervention that may “substantially limit their child’s life path.” [79] But would not parents also violate the “open-future” right if they do nothing and allow congestive heart failure itself to limit the child’s life path?

Medical-care decisions of this sort are deeply personal. At a minimum, however, a safe and effective medical intervention performed at the molecular level, which cures or protects a child from serious illness or death, cannot ipso facto violate any children’s rights. As Rewriting Nature notes, implied consent is logically embedded in the parental autonomy to make medical-care decisions regarding the use of therapeutic GGE intervention. [80] Surely, the child whose corrected germline once bore a deleterious mutation that causes Tay-Sachs disease would not grow up wishing her parents did nothing to spare her from a life-threatening disease, death, and suffering.

• On the Nexus of Genome Editing and Administrative Law

Professor Greely’s creative and forward-looking essay contributes a wealth of perspectives, ranging from human genome editing and art to law and regulation, and constitutes a resource for a myriad of future paper topics. [81] I wish to tackle two brief points warranting clarification—one about the regulation of crops in this Section and another about GGE in the concluding Section.

Greely, Professor Gould, and I agree that a regulatory system for crops should focus on the product at issue, rather than the process by which it was created. [82] I also agree that regulation should be commensurate with the degree of risk inherent in each product derived from genome editing. Greely’s view that my “basic position is that if no meaningful differences exist between non-regulated and regulated crops, neither should be regulated,” [83] however, oversimplifies my stance about the future regulatory scheme for genome-edited crops.

A significant portion of my analysis and recommendations about the regulation of crops in Rewriting Nature are guided by the Chapter 7 hypothetical embodiment, which contemplates the making of a fungus-resistant banana crop using recombinant DNA-free genome editing that features a single-point mutation in a receptor protein. [84] Based on the specific facts concerning that embodiment, a mutant crop that has zero foreign DNA and is—but for the single-residue substitution—genetically identical to its naturally occurring counterpart should not be subject to onerous regulations applicable to crops derived from older genetic-engineering techniques. [85] My regulatory prescription for the deregulation of such crops devoid of foreign DNA, therefore, extends exclusively to that fact pattern. The choice to cabin a regulatory analysis to that embodiment was deliberate, so as to allow substantive and nuanced discussion of regulation of that crop. I did not expand on the many other possible types of gene-edited crops due to space constraints and other factors. But Rewriting Nature alludes that a different regulatory scheme would be applicable to crops featuring other types of genetic modifications. [86] And I have further discussed some of these distinctions in greater detail in previous works. [87] To make clear, I neither advocate nor endorse a simplistic one-size-fits-all approach to the regulation of crops.

Suter and Cahn, for their part, embrace much of Rewriting Nature ’s proposed GGE regulatory framework. They also strengthen my arguments by placing them “in the context of other potential regulatory structures.” [88] I embrace their feedback in full as it provides additional support for a robust GGE regulatory framework based on science, ethics, and the free market. I only wish to focus briefly on their suggestion that, because the FDA does not specialize in reproductive technologies, it may be useful to look to other administrative agencies such as the UK Human Fertilisation and Embryology Authority, the UK regulatory agency for fertility treatment and research. Although many before us have proposed the creation of a new agency in the United States to oversee matters of reproductive technology, Suter and Cahn’s essay persuades me to contemplate this matter further in future works. The idea is provocative and interests me because it calls for a “metanationalist” [89] approach to ART regulation. Certainly, it would be beneficial to inspect and study comparative international law to address the issue of future GGE regulation, which has become a “global problem” in the wake of the 2018 birth of the first gene-edited babies in China. [90]

Additional Perspectives and Future Directions

This final Section addresses miscellaneous commentary, reflects on the progress made, and contemplates perspectives about the future of genome editing.

Although Greely endorses my approach to GGE, he contends I make an important error by “dismiss[ing] preimplantation genetic diagnosis” (“PGD”) as an alternative to GGE intervention. [91] To be clear, I do not advance the proposition that PGD is an unsuitable alternative for GGE in some contexts. Nor do I mean to imply that certain heterozygous couples who might potentially carry a faulty allele cannot successfully avail themselves of PGD to conceive a healthy child. [92] To the contrary, both GGE and PGD are methods that could, and likely will, be used side-by-side. My comments about the limitations of PGD relate mostly to homozygous parents—namely, couples in which each parent carries an allele with deleterious genetic mutations that guarantee the onset of genetic disease in their offspring—and concern the practicability of using PGD to help such couples conceive healthy children.

For this category of homozygous parents carrying a faulty allele, GGE is virtually the only way to conceive an otherwise healthy, biologically related child. [93] That is because every fertilized embryo available for implantation features the faulty alleles (because each parent carries a copy of said allele). No amount of PGD in that scenario would allow the parents to screen among embryos for one without the faulty alleles. For them, PGD is not a viable alternative to conceive healthy offspring. This contrasts with the case of a heterozygous couple who could, in theory, screen for embryos without faulty alleles. The problem is that the heterozygous couple would potentially need to produce and screen many embryos, which can be expensive and lead to otherwise “good” embryos being discarded. In that sense, GGE would benefit even the heterozygous parents because they would potentially need to produce fewer embryos. After performing GGE, they could then screen a subset of embryos prior to implantation.

Professor Carroll participated in the 1975 Asilomar Conference on Recombinant DNA and the recent International Summits on Human Genome Editing in 2015 and 2018 and, thus, brings a wealth of experience to the discussion. His essay reflects a thoughtful and measured approach to human GGE. While he agrees with my general GGE approach, he notes that it is difficult for him to understand why I might leave a door open for potential GGE cosmetic modifications but, at the same time, foreclose editing the human germline to modify some disabilities. [94]

Carroll refers to the proposed four-tiered, normative framework in Chapter 11, which distinguishes among permissible and impermissible uses of GGE technologies. [95] My response to Carroll’s question embarks from the recognition of a special history of irrational discrimination against some minority groups on the basis of race, gender, sexual orientation, specific disabilities, and other protected categories under the law. [96] Such past discrimination strongly counsels against sanctioning GGE to modify traits associated with protected groups, regardless of whether the modifications are technologically feasible. Unlike certain therapeutic GGE interventions for which evidence exists to establish safety and efficacy in the near future, cosmetic uses of GGE are not technologically feasible at this time and raise fewer concerns about unlawful discrimination against protected classes.

Consider a set of parents seeking to perform GGE to edit an embryo’s race and eye color. Rewriting Nature explains that there is no constitutional justification to modify an embryo’s race because the law already prohibits racial discrimination. [97] Having green eyes, however, is not associated with a protected class under the law. GGE aimed at eye-color modifications may give rise to ethical, access, and other equitable considerations but, so long as the technology is safe and effective to use, such interventions may warrant a less restrictive approach because (1) they are distant in the future and (2) do not raise serious concerns of insidious discrimination. The nature of the GGE intervention sought should, therefore, dictate whether a specific GGE use ought to be banned or regulated. Rewriting Nature proposes a framework to assist in making those important distinctions among GGE subtypes. The framework is flexible. In the disability realm, for example, it counsels against modifying traits related to certain protected disabilities such as deafness, while recognizing that GGE associated with disabilities closely linked to therapeutic conditions (such as diabetes and congenital cardiovascular disease) may be permissible. [98]

This brings me to Professors Goodwin and Whelan’s contribution, which fits neatly within a growing body of law and social-science literature focused on the intersection of genetics, clinical ethics, and social equality. [99] I welcome and embrace their essay in full and am delighted to see that it fills an important gap in the conversation. I devote some space in Rewriting Nature to issues of social inequality, inequity, and institutional discrimination, but I do not explore topics of fairness, cost, and access to genome-editing technologies with any sufficient depth. The advent of genome editing and its application to myriad facets of society raise an alarming potential to exacerbate healthcare disparities between privileged and nonprivileged communities. Goodwin and Whelan forecast that the incidence of some diseases among “wealthy, largely White, populations will decrease, while those in historically marginalized or vulnerable populations will remain unchanged or even worsen.” [100] Sadly, I agree. But I am encouraged by the work being done by scholars, community leaders, and regulators to build networks and support the institutional infrastructure that will ameliorate social inequality as healthcare-related technologies continue to develop.

Lastly, I want to acknowledge the significant contributions of Professors Barrangou, Cohen, Conley, Gould, and Marchant. [101] Gould and Barrangou—as did Greely—sagaciously noted the importance of focusing on nonhuman uses of genome editing, which can arguably exert a greater impact on society in the long run. Gould’s discussion about “omics” technologies and the increased use of artificial intelligence and data science in crop breeding added context to Rewriting Nature ’s push to adopt science-based regulatory frameworks that focus on products, rather than the processes through which they are derived. Barrangou provided compelling arguments for deploying genome-editing tools to modify trees and forests, which could help ameliorate the impacts of the global climate-change crisis. Conley and Marchant added a much-needed soft-law perspective to the conversation and put the spotlight on the development of new informal mechanisms of international governance for emerging technologies. Finally, Cohen focused his perspicacious remarks on the nexus of normativity and the theory of a jurisprudence of scientific empiricism, which Rewriting Nature introduces as a theoretical structural framework to address questions of science in law. There is much to share about that theory, its underlying mechanisms, and methodology in future work.

My deepest thanks to the Boston University Law Review for making this symposium possible and to all participants, whose superb insights elevated the quality of the discourse. Conversations such as these are precisely what is needed to close the gap between law and science and pave the road ahead for genome-editing technologies. I look forward to many engaging and lively discussions in years to come.

[1] Paul Enríquez, Rewriting Nature: The Future of Genome Editing and How to Bridge the Gap Between Law and Science (2021).

[2] Haydar Frangoul, David Altshuler, M. Domenica Cappellini, Yi-Shan Chen, Jennifer Domm, Brenda K. Eustace, Juergen Foell, Josu de la Fuente, Stephan Grupp, Rupert Handgretinger, Tony W. Ho & Antonis Kattamis, Andrew Kernytsky, Julie Lekstrom-Himes, Amanda M. Li, Franco Locatelli, Markus Y. Mapara, Mariane de Montalembert, Damiano Rondelli, Akshay Sharma, Sujit Sheth, Sandeep Soni, Martin H. Steinberg, Donna Wall, Angela Yen, Selim Corbacioglu, CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β -Thalassemia , 384 N. Eng. J. Med. 252, 258-59 (2021).

[3] Shengnan Li, Dexing Lin, Yunwei Zhang, Min Deng, Yongxing Chen, Bin Lv, Boshu Li, Yuan Lei, Yanpeng Wang, Long Zhao, Yueting Liang, Jinxing Liu, Kunling Chen, Zhiyong Liu, Jun Xiao, Jin-Long Qiu & Caixia Gao, Genome-Edited Powdery Mildew Resistance in Wheat Without Growth Penalties , 602 Nature 455, 460 (2022).

[4] Julian D. Gillmore, Ed Gane, Jorg Taubel, Justin Kao, Marianna Fontana, Michael L. Maitland, Jessica Seitzer, Daniel O’Connell, Kathryn R. Walsh, Kristy Wood, Jonathan Phillips, Yuanxin Xu, Adam Amaral, Adam P. Boyd, Jeffrey E. Cehelsky, Mark D. McKee, Andrew Schiermeier, Olivier Harari, Andrew Murphy, Christos A. Kyrasous, Brian Zambrowicz, Randy Soltys, David E. Gustein, John Leonard, Laura Sepp-Lorenzino & David Lebwohl, CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis , 385 N. Eng. J. Med. 493, 499-501 (2021).

[5] Dominique Patton, China to Allow Gene-Edited Crops in Push for Food Security , Reuters (Jan. 25, 2022, 3:41 PM), https://www.reuters.com/world/china/china-drafts-new-rules-allow-gene-edited-crops-2022-01-25/.

[6] See Jacob S. Sherkow, Writing Definitions in Rewriting Nature : Lessons from FDA Law , 102 B.U. L. Rev. Online 22, 22-23 (2022).

[7] Id. at 23.

[8] Enríquez, supra note 1, at 83.

[9] Id. at 74-75.

[10] Id. at 74, 89.

[11] Sherkow, supra note 6, at 23.

[12] See id. at 23.

[14] See Enríquez, supra note 1, at 83-91 (describing the problems associated with overreliance on dictionaries as sources of ordinary meaning while noting the ambiguity and lack of clarity of dictionary definitions of genome editing).

[15] Id. at 91.

[16] 149 U.S. 304 (1893).

[17] Id. at 307; see also Enríquez, supra note 1, at 87-89 (discussing Nix ).

[18] Nix , 149 U.S. at 307.

[19] Despite Nix ’s holding, the botanical definition of a fruit remains unchanged nearly one hundred and thirty years later. But so too does the legal treatment of tomatoes as vegetables under U.S. trade law remain unchanged. See Harmonized Tarif Schedule of the United States Revision 2 (2022), USITC Pub. 5293, § 2, ch. 7 (Feb. 2022), https://hts.usitc.gov/current [https://perma.cc/UXJ3-FR7Y].

[20] See Sherkow, supra note 6, at 24, 25, 28.

[21] Henry T. Greely, Rewriting (Non-Human) Nature , 102 B.U. L. Rev. Online 16, 18 (2022).

[22] Enríquez, supra note 1, at 73.

[23] See Congruous , Merriam-Webster, https://www.merriam-webster.com/dictionary /congruous [https://perma.cc/48PL-GFJE] (last visited Mar. 9, 2022) (defining the term as “being in agreement, harmony, or correspondence”; “conforming to the circumstances or requirements of a situation; appropriate”; and “marked or enhanced by harmonious agreement among constituent elements”).

[24] See Uniform , Merriam-Webster, https://www.merriam-webster.com/dictionary /uniform [https://perma.cc/K3XN-H86T] (last visited Mar. 9, 2022) (defining the term, in relevant part, as being “consistent in conduct or opinion,” such as in the “ uniform interpretation of laws”).

[25] See Universal , Merriam-Webster, https://www.merriam-webster.com/dictionary /universal [https://perma.cc/P3D4-3ZGD] (last visited Mar. 9, 2022) (defining the term as “including or covering all or a whole collectively or distributively without limit or exception”; “present or occurring everywhere”; and “existent or operative everywhere or under all conditions”).

[26] For purposes of this Essay, we need not engage in an exercise of defining the term family. Suffice it to note that, unlike “family,” the term genome editing lacks an “ordinary” meaning.

[27] E.g. , Enríquez, supra note 1, at 73, 75, 89.

[28] See Sonia M. Suter & Naomi R. Cahn, Regulating Technology as We Rewrite Nature , 102 B.U. L. Rev. Online 29, 30 (2022).

[29] Id. at 31.

[30] 521 U.S. 702 (1997).

[31] Id. at 720-21.

[33] It is, however, quite unlikely that the Court would grant certiorari to address that question today.

[34] Enríquez, supra note 1, at 337.

[35] 539 U.S. 558 (2003).

[36] 576 U.S. 644 (2015).

[37] Lawrence , 539 U.S. at 572 (quoting Sacramento v. Lewis, 523 U.S. 833, 857 (1998) (Kennedy, J., concurring)).

[38] Obergefell , 576 U.S. at 671.

[39] Id. at 671-72.

[40] 410 U.S. 113 (1973).

[41] Id. at 154 (“[T]he right of personal privacy includes the abortion decision.”).

[42] See, e.g. , Planned Parenthood of Se. Pa. v. Casey, 505 U.S. 833, 876 (1992) (plurality opinion) (“[T]he undue burden standard is the appropriate means of reconciling the State’s interest with the woman’s constitutionally protected liberty.”).

[43] 442 U.S. 544, 559 (1979) (holding that the FDA can preclude terminally ill cancer patients from obtaining a drug not recognized as “safe and effective”).

[44] 495 F.3d 695, 713 (D.C. Cir. 2007) (holding that there is no such right of access to experimental drugs that have not been proven safe and effective).

[45] Enríquez, supra note 1, at 346 (emphasis added).

[46] Suter & Cahn, supra note 28, at 32.

[47] Obergefell v. Hodges, 576 U.S. 644, 671 (2015).

[48] See, e.g. , Enríquez, supra note 1, at 331, 337, 338 (emphasis added).

[49] See, e.g. , id. at 353 n.76; Suter & Cahn, supra note 28, at 32 n.24.

[50] 262 U.S. 390 (1923).

[51] 268 U.S. 510 (1925).

[52] 316 U.S. 535 (1942). Skinner held that the right to procreate was both a fundamental right and liberty protected under the Constitution. See id. at 541. Thus, while the Court’s majority struck down the Oklahoma sterilization statute under equal-protection grounds, it also hinted at the application of substantive due process. The concurring opinions expressly invoked due process. See id. at 544-45 (Stone, C.J., concurring); id. at 546 (Jackson, J., concurring). In any event, Justices have recognized that the right to procreate under Skinner provides support to other rights protected under substantive due process. See, e.g. , Obergefell , 576 U.S. at 674-75 (linking the right to procreate to the later-recognized right to marry); id. at 691 (Roberts, C.J., dissenting) (same).

[53] A recent May 2020 study reported there were an estimated 513,000 married, same-sex couples in the United States. See Christy Mallory & Brad Sears, The Economic Impact of Marriage Equality Five Years After Obergefell v. Hodges, UCLA Sch. of L. Williams Inst. (May 2020), https://williamsinstitute.law.ucla.edu/publications/econ-impact-obergefell-5-years/ [https://perma.cc/JN7K-ZG9P].

[54] Suter & Cahn, supra note 28, at 32.

[56] 478 U.S. 186 (1986).

[57] See Enríquez, supra note 1, at 347.

[58] See id. at 353 n.76.

[59] See Biden v. Missouri, 142 S. Ct. 647 (2022); Nat’l Fed’n of Indep. Bus. v. Dep’t of Lab., Occupational Safety & Health Admin., 142 S. Ct. 661 (2022).

[60] Jessica Gresko & Mark Sherman, High Court Confirms Justices Have Received COVID-19 Booster , AP News (Jan. 4, 2022), https://apnews.com/article/coronavirus-pandemic-joe-biden-us-supreme-court-health-centers-for-disease-control-and-prevention-85207706b48cc76147a17d7a476fd9c6.

[61] 539 U.S. 558 (2003).

[62] 539 U.S. 306 (2003).

[63] 140 S. Ct. 1731 (2020).

[64] 567 U.S. 519 (2012).

[65] Katherine Drabiak, Framing Germline Modifications of Human Embryos , 102 B.U. L. Rev. Online 7, 15 (2022).

[67] Id. at 12 (citing George J. Annas, Lori B. Andrews & Rosario M. Isasi, Protecting the Endangered Human: Toward an International Treaty Prohibiting Cloning and Inheritable Alterations , 28 Am. J.L. & Med. 151, 154-78 (2002) (“[M]any believe that . . . inheritable genetic alternations at the embryo level will never be safe because they will always be inherently unpredictable in their effects on the children and their offspring.”)).

[68] Id. at 7, 10, 14.

[69] See Enríquez, supra note 1, at 386 n.72.

[70] Rodolphe Barrangou, Boston University Law Review Online Virtual Discussion on Rewriting Nature (Nov. 5, 2021).

[71] 1903 Wright Flyer , Smithsonian Nat’l Air & Space Museum, https://airandspace.si.edu/collection-objects/1903-wright-flyer/nasm_A19610048000 (last visited Mar. 11, 2022).

[72] Bart CJM Fauser, Towards the Global Coverage of a Unified Registry of IVF Outcomes , 38 Reproductive Biomedicine Online 133, 133 (2019).

[73] 21 U.S.C. § 355-1(a)(1).

[74] Enríquez, supra note 1, at 161, 337. See also Paul Enríquez, Genome Editing and the Jurisprudence of Scientific Empiricism , 19 Vand. J. Ent. & Tech. L. 603, 666 (2017).

[75] Enríquez, supra note 1, at 276.

[76] Drabiak, supra note 65, at 15 & n.47 (referencing Dena S. Davis’s theory of a right to an open future).

[77] Id. at 15.

[80] Enríquez, supra note 1, at 368.

[81] See generally Greely, supra note 21.

[82] See, e.g. , Enríquez, supra note 1, at 256.

[83] Greely, supra note 21, at 20.

[84] See Enríquez, supra note 1, at 252-53.

[86] See, e.g. , id. at 254-56.

[87] See, e.g. , Paul Enríquez, CRISPR GMOs , 18 N.C. J.L. & Tech. 432, 538 n.536 (2017).

[88] Suter & Cahn, supra note 28, at 33.

[89] Paul Enríquez, Deconstructing Transnationalism: Conceptualizing Metanationalism as a Putative Model of Evolving Jurisprudence , 43 Vand. J. Transnat’l L. 1265, 1269, 1303-10 (2010).

[90] See Paul Enríquez, Editing Humanity: On the Precise Manipulation of DNA in Human Embryos , 97 N.C. L. Rev. 1147, 1152-53 (2019).

[91] Greely, supra note 21, at 17.

[92] In this context, I use “faulty allele” to refer to an allele that features a genetic mutation associated with the onset of a genetic disorder or disease.

[93] See Enríquez, supra note 1, at 364. I suppose one alternative would be to perform GGE on each of the parental gametes, rather than on the fertilized embryo. But that is beyond the scope of the subject of GGE in human embryos contemplated in that section.

[94] Dana Carroll, Rewriting Nature: The Case of Heritable Human Genome Editing , 102 B.U. L. Rev. Online 1, 6 (2022).

[95] Enríquez, supra note 1, at 360-78.

[96] See id. at 368.

[98] See id. at 370-71.

[99] See, e.g. , Laura Hercher & Anya E.R. Prince, Gene Therapy’s Field of Dreams: If You Build It, Will We Pay? , 97 N.C. L. Rev. 1463 (2019).

[100] Allison M. Whelan & Michele Goodwin, Will the Past Be Prologue? Race, Equality, and Human Genetics , 102 B.U. L. Rev. Online 37, 39 (2022).

[101] Boston University Law Review Online Virtual Discussion on Rewriting Nature (Nov. 5, 2021).

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Faculty Scholarship

Perspectives on gene editing.

This article was originally published in the Harvard Gazette on January 9, 2019.

Medicine is at a turning point, on the cusp of major change as disruptive technologies such as gene, RNA, and cell therapies enable scientists to approach diseases in new ways. The swiftness of this change is being driven by innovations such as  CRISPR gene editing , which makes it possible to correct errors in DNA with relative ease.

Progress in this field has been so rapid that the dialogue around potential ethical, societal, and safety issues is scrambling to catch up.

This disconnect was brought into stark relief at the  Second International Summit on Human Genome Editing , held in Hong Kong in November, when exciting updates about emerging therapies were eclipsed by a disturbing announcement. He Jiankui, a Chinese researcher, claimed that he had edited the genes of two human embryos, and that they had been brought to term.

There was immediate outcry from scientists across the world, and He was subjected to intense social pressure, including the removal of his affiliations, for having allegedly disregarded ethical norms and his patients’ safety.

Yet as I. Glenn Cohen  ’03, faculty director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School , has said, gene editing comes in many varieties, with many consequences. Any deep ethical discussion needs to take into account those distinctions.

Human genome editing: somatic vs. germline

The germline editing He claimed to have carried out is quite different from the somatic gene therapies that are currently changing the frontiers of medicine. While somatic gene editing affects only the patient being treated (and only some of his or her cells), germline editing affects all cells in an organism, including eggs and sperm, and so is passed on to future generations. The possible consequences of that are difficult to predict.

Somatic gene therapies involve modifying a patient’s DNA to treat or cure a disease caused by a genetic mutation. In one clinical trial, for example, scientists take blood stem cells from a patient, use CRISPR techniques to correct the genetic mutation causing them to produce defective blood cells, then infuse the “corrected” cells back into the patient, where they produce healthy hemoglobin. The treatment changes the patient’s blood cells, but not his or her sperm or eggs.

Germline human genome editing, on the other hand, alters the genome of a human embryo at its earliest stages. This may affect every cell, which means it has an impact not only on the person who may result, but possibly on his or her descendants. There are, therefore, substantial restrictions on its use.

Germline editing in a dish can help researchers figure out what the health benefits could be, and how to reduce risks. Those include targeting the wrong gene; off-target impacts, in which editing a gene might fix one problem but cause another; and mosaicism, in which only some copies of the gene are altered. For these and other reasons, the scientific community approaches germline editing with caution, and the U.S. and many other countries have substantial policy and regulatory restrictions on using germline human genome editing in people.

But many scientific leaders are asking: When the benefits are believed to outweigh the risks, and dangers can be avoided, should science consider moving forward with germline genome editing to improve human health? If the answer is yes, how can researchers do so responsibly?

CRISPR pioneer Feng Zhang of the Broad Institute of Harvard and MIT responded immediately to He’s November announcement by calling for a moratorium on implanting edited embryos in humans. Later, at a public event on “Altering the Human Genome” at the Belfer Center at Harvard Kennedy School (HKS), he explained why he felt it was important to wait:

“The moratorium is a pause. Society needs to figure out if we all want to do this, if this is good for society, and that takes time. If we do, we need to have guidelines first so that the people who do this work can proceed in a responsible way, with the right oversight and quality controls.”

Professors at the University’s schools of medicine, law, business, and government saw He’s announcement as a turning point in the discussion about heritable gene therapies and shared their perspectives on the future of this technology with the Gazette.

Here are their thoughts, issue by issue:

Aside from the safety risks, human genome editing poses some hefty ethical questions. For families who have watched their children suffer from devastating genetic diseases, the technology offers the hope of editing cruel mutations out of the gene pool. For those living in poverty, it is yet another way for the privileged to vault ahead. One open question is where to draw the line between disease treatment and enhancement, and how to enforce it, considering differing attitudes toward conditions such as deafness.

Robert Truog , director of the Center for Bioethics at Harvard Medical School (HMS), provided context:

“This question is not as new as it seems. Evolution progresses by random mutations in the genome, which dwarf what can be done artificially with CRISPR. These random mutations often cause serious problems, and people are born with serious defects. In addition, we have been manipulating our environment in so many ways and exposing ourselves to a lot of chemicals that cause unknown changes to our genome. If we are concerned about making precise interventions to cure disease, we should also be interested in that.

“To me, the conversation around Dr. He is not about the fundamental merits of germline gene editing, which in the long run will almost certainly be highly beneficial. Instead, it’s about the oversight of science. The concern is that with technologies that are relatively easy to use, like CRISPR, how does the scientific community regulate itself? If there’s a silver lining to this cloud, I think it is that the scientific community did pull together to be critical of this work, and took the responsibility seriously to use the tools available to them to regulate themselves.”

When asked what the implications of He’s announcement are for the emerging field of precision medicine, Richard Hamermesh, faculty co-chair of the Harvard Business School/Kraft Precision Medicine Accelerator, said:

“Before we start working on embryos, we have a long way to go, and civilization has to think long and hard about it. There’s no question that gene editing technologies are potentially transformative and are the ultimate precision medicine. If you could precisely correct or delete genes that are causing problems—mutating or aberrant genes—that is the ultimate in precision. It would be so transformative for people with diseases caused by a single gene mutation, like sickle cell anemia and cystic fibrosis. Developing safe, effective ways to use gene editing to treat people with serious diseases with no known cures has so much potential to relieve suffering that it is hard to see how anyone could be against it.

“There is also commercial potential and that will drive it forward. A lot of companies are getting venture funding for interesting gene therapies, but they’re all going after tough medical conditions where there is an unmet need—[where] nothing is working—and they’re trying to find gene therapies to cure those diseases. Why should we stop trying to find cures?

“But anything where you’re going to be changing human embryos, it’s going to take a long time for us to figure out what is appropriate and what isn’t. That has to be done with great care in terms of ethics.”

George Q. Daley  is dean of HMS, the Caroline Shields Walker Professor of Medicine, and a leader in stem cell science and cancer biology. As a spokesperson for the organizing committee of the Second International Summit on Human Genome Editing, he responded swiftly to He’s announcement in Hong Kong. Echoing those remarks, he said:

“It’s time to formulate what a clinical path to translation might look like so that we can talk about it. That does not mean that we’re ready to go into the clinic—we are not. We need to specify what the hurdles would be if one were to move forward responsibly and ethically. If you can’t surmount those hurdles, you don’t move forward.

“There are stark distinctions between editing genes in an embryo to prevent a baby from being born with sickle cell anemia and editing genes to alter the appearance or intelligence of future generations. There is a whole spectrum of considerations to be debated. The prospect includes an ultimate decision that we not go forward, that we decide that the benefits do not outweigh the costs.”

Asked how to prevent experiments like He’s while preserving academic freedom, Daley replied:

“For the past 15 years, I have been involved in efforts to establish international standards of professional conduct for stem cell research and its clinical translation, knowing full well that there could be—and has been—a growing number of independent practitioners directly marketing unproven interventions to vulnerable patients through the internet. We advocated so strongly for professional standards in an attempt to ward off the risks of an unregulated industry. Though imperfect, our efforts to encourage a common set of professional practices have been influential.

“You can’t control rogue scientists in any field. But with strongly defined guidelines for responsible professional conduct in place, such ethical violations like those of Dr. He should remain a backwater, because most practitioners will adhere to generally accepted norms. Scientists have a responsibility to come together to articulate professional standards and live by them. One has to raise the bar very high to define what the standards of safety and efficacy are, and what kind of oversight and independent judgment would be required for any approval.

“We have called for an ongoing international forum on human genome editing, and that could take many shapes. We’ve suggested that the national academies of more countries come together—the National Academy of Sciences in the U.S. and the Royal Society in the U.K. are very active here—because these are the groups most likely to have the expertise to convene these kinds of discussions and keep them going.”

Cohen , speaking to the legal consequences of germline human genome editing, said:

“I think we should slow down in our reaction to this case. It is not clear that the U.S. needs to react to Dr. He’s announcement with regulation. The FDA [Food and Drug Administration] already has a strong policy on germline gene editing in place. A rider in the Consolidated Appropriations Act of 2016—since renewed—would have blocked the very same clinical application of human germline editing He announced, had it been attempted in the U.S.

“The scientific community has responded in the way I’d have liked it to. There is a difference between ‘governance’ and ‘self-governance.’ Where government uses law, the scientific community uses peer review, public censure, promotions, university affiliations, and funding to regulate themselves. In China, in Dr. He’s case, you have someone who’s (allegedly) broken national law and scientific conventions. That doesn’t mean you should halt research being done by everyone who’s law-abiding.

“Public policy or ethical discussion that’s divorced from how science is progressing is problematic. You need to bring everyone together to have robust discussions. I’m optimistic that this is happening, and has happened. It’s very hard to deal with a transnational problem with national legislation, but it would be great to reach international consensus on this subject. These efforts might not succeed, but ultimately they are worth pursuing.”

Professor  Kevin Eggan  of Harvard’s Department of Stem Cell and Regenerative Biology said, “The question we should focus on is: Will this be safe and help the health of a child? Can we demonstrate that we can fix a mutation that will cause a terrible health problem, accurately and without the risk of harming their potential child? If the answer is yes, then I believe germline human genome editing is likely to gain acceptance in time.

“There could be situations where it could help a couple, but the risks of something going wrong are real. But at this point, it would be impossible to make a risk-benefit calculation in a responsible manner for that couple. Before we could ever move toward the clinic, the scientific community must come to a consensus on how to measure success, and how to measure off-target effects in animal models.

“Even as recently as this past spring and fall, the results of animal studies using CRISPR—the same techniques Dr. He claimed to have used—generated a lot of confusion. There is disagreement about both the quality of the data and how to interpret it. Until we can come to agreement about what the results of animal experiments mean, how could we possibly move forward with people?

“As happened in England with mitochondrial replacement therapy, we should be able to come to both a scientific and a societal consensus of when and how this approach should be used. That’s missing.”

According to Catherine Racowsky, professor of obstetrics, gynecology and reproductive biology at Brigham and Women’s Hospital, constraints on the use of embryos in federally funded research pose barriers to studying the risks and benefits of germline editing in humans. She added:

“Until the work is done, carefully and with tight oversight, to understand any off-target effects of replacing or removing a particular gene, it is inappropriate to apply the technology in the clinical field. My understanding of Dr. He’s case is that there wasn’t a known condition in these embryos, and by editing the genes involved with HIV infection, he could also have increased the risks of susceptibility to influenza and West Nile viruses.

“We need a sound oversight framework, and it needs to be established globally. This is a technology that holds enormous promise, and it is likely to be applied to the embryo, but it should only be applied for clinical purposes after the right work has been done. That means we must have consensus on what applications are acceptable, that we have appropriate regulatory oversight, and, perhaps most importantly, that it is safe. The only way we’re going to be able to determine that these standards are met is to proceed cautiously, with reassessments of the societal and health benefits and the risks.”

Asked about public dialogue around germline human genome editing,  George Church , Robert Winthrop Professor of Genetics at HMS, said:

“With  in vitro  fertilization (IVF), ‘test tube babies’ was an intentionally scary term. But after Louise Brown, the first IVF baby, was born healthy 40 years ago, attitudes changed radically. Ethics flipped 180 degrees, from it being a horrifying idea to being unacceptable to prevent parents from having children by this new method. If these edited twins are proven healthy, very different discussions will arise. For example, is a rate of 900,000 deaths from HIV infection per year a greater risk than West Nile virus, or influenza? How effective is each vaccine?”

Science, technology, and society

Sheila Jasanoff , founding director of the Science, Technology, and Society program at HKS, has been calling for a “global observatory” on gene editing, an international network of scholars and organizations dedicated to promoting exchange across disciplinary and cultural divides. She said:

“The notion that the only thing we should care about is the risk to individuals is very American. So far, the debate has been fixated on potential physical harm to individuals, and not anything else. This is not a formulation shared with other countries in the world, including practically all of Europe. Considerations of risk have equally to do with societal risk. That includes the notion of the family, and what it means to have a ‘designer baby.’

“These were not diseased babies Dr. He was trying to cure. The motivation for the intervention was that they live in a country with a high stigma attached to HIV/AIDS, and the father had it and agreed to the intervention because he wanted to keep his children from contracting AIDS. AIDS shaming is a fact of life in China, and now it won’t be applied to these children. So, are we going to decide that it’s OK to edit as-yet-to-be children to cater to this particular idea of a society?

“It’s been said that ‘the genie is out of the bottle’ with germline human genome editing. I just don’t think that’s true. After all, we have succeeded in keeping ‘nuclear’ inside the bottle. Humanity doesn’t lack the will, intelligence, or creativity to come up with ways for using technology for good and not ill.

“We don’t require students to learn the moral dimensions of science and technology, and that has to change. I think we face similar challenges in robotics, artificial intelligence, and all kinds of frontier fields that have the potential to change not just individuals but the entirety of what it means to be a human being.

“Science has this huge advantage over most professional thought in that it has a universal language. Scientists can hop from lab to lab internationally in a way that lawyers cannot because laws are written in many languages and don’t translate easily. It takes a very long time for people to understand each other across these boundaries. A foundational concept for human dignity? It would not be the same thing between cultures.

“I would like to see a ‘global observatory’ that goes beyond gene editing and addresses emerging technologies more broadly.”

To learn more:

Technology and Public Purpose project, Belfer Center for Science and International Affairs, Harvard Kennedy School of Government,  https://www.belfercenter.org/tapp/person

Concluding statement from the Second International Summit on Human Genome Editing.  http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b

A global observatory for gene editing: Sheila Jasanoff and J. Benjamin Hurlbut call for an international network of scholars and organizations to support a new kind of conversation.  https://www.nature.com/articles/d41586-018-03270-w

Building Capacity for a Global Genome Editing Observatory: Institutional Design.  http://europepmc.org/abstract/MED/29891181

Glenn Cohen’s blog: How Scott Gottlieb is Wrong on the Gene Edited Baby Debacle.  http://blog.petrieflom.law.harvard.edu/2018/11/29/how-scott-gottlieb-is-wrong-on-the-gene-edited-baby-debacle/

Gene-Editing: Interpretation of Current Law and Legal Policy.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651701/

Forum: Harvard T.H. Chan School of Public Health event on the promises and challenges of gene editing, May 2017:  https://theforum.sph.harvard.edu/events/gene-editing/

Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies: http://petrieflom.law.harvard.edu/events/details/2019-petrie-flom-center-annual-conference

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• Open access
• Published: 11 September 2020

Human germline editing in the era of CRISPR-Cas: risk and uncertainty, inter-generational responsibility, therapeutic legitimacy

• Sebastian Schleidgen   ORCID: orcid.org/0000-0002-7564-8675 1 ,
• Hans-Georg Dederer 2 ,
• Susan Sgodda 3 ,
• Stefan Cravcisin 2 ,
• Luca Lüneburg 2 ,
• Tobias Cantz   ORCID: orcid.org/0000-0002-1382-9577 3 &
• Thomas Heinemann   ORCID: orcid.org/0000-0002-8316-7054 4  

BMC Medical Ethics volume  21 , Article number:  87 ( 2020 ) Cite this article

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Clustered Regularly Interspaced Short Palindromic Repeats-associated (CRISPR-Cas) technology may allow for efficient and highly targeted gene editing in single-cell embryos. This possibility brings human germline editing into the focus of ethical and legal debates again.

Against this background, we explore essential ethical and legal questions of interventions into the human germline by means of CRISPR-Cas: How should issues of risk and uncertainty be handled? What responsibilities arise regarding future generations? Under which conditions can germline editing measures be therapeutically legitimized? For this purpose, we refer to a scenario anticipating potential further development in CRISPR-Cas technology implying improved accuracy and exclusion of germline transmission to future generations. We show that, if certain concepts regarding germline editing are clarified, under such conditions a categorical prohibition of one-generation germline editing of single-cell embryos appears not to be ethically or legally justifiable.

These findings are important prerequisites for the international debate on the ethical and legal justification of germline interventions in the human embryo as well as for the harmonization of international legal standards.

Peer Review reports

Ever since the publication of Friedmann and Roblin’s article “Gene Therapy for Human Genetic Disease?” in 1972 [ 1 ], the possibility as well as permissibility of modifying human deoxyribonucleic acid (DNA) is subject to intense debates in ethics and law. Three problems regarding germline therapies have been consistently discussed in ethics and law: (i) questions of risk and uncertainty related to the technology and its application, (ii) interference with the human germline and responsibility towards future generations, and (iii) the legitimization of genome editing measures with regard to the concepts of therapy and enhancement. Since these questions point toward conceptual issues yet to be clarified, there is wide consensus that germline editing in human beings at present cannot be justified.

The introduction of CRISPR-Cas has stirred up again normative debates on human germline editing. This technology spread rapidly in biomedical research as it allows for a comparatively easy, efficient and precise targeted editing of the human genome [ 2 , 3 ]. For this purpose, a CRISPR-associated protein 9 (Cas9) is guided by custom-made short ribonucleic acid (RNA)-sequences (guideRNAs) to specific genomic loci where it acts as molecular scissors inducing DNA breaks. The resulting DNA cleavage activates a cellular repair mechanism (non-homologous end-joining) that seeks to reassemble the clipped DNA ends. This results in rejoining the DNA ends but may also lead to, e.g., DNA insertions or deletions. However, when adding a defined DNA-repair template, an insertion of this sequence results in precise genetic edits at the given DNA-site (homology driven repair) [ 4 , 5 ]. Exploiting these mechanisms, gene editing via CRISPR-Cas has become rapidly available for numerous approaches ranging from cell culture and in vivo applications to the manipulation of early human embryos. The first report of CRIPSR-Cas mediated editing of human embryos was published in 2016 [ 6 , 7 ]. In November 2018, the birth of twin girls allegedly carrying an intentionally modified gene of the chemokine receptor type 5 (CCR5) was announced [ 8 ].

Besides modifying a few nucleotides of a given DNA sequence, CRISPR-Cas can also be used for introducing larger elements, i.e. transgene cassettes, to specific DNA loci. Such cassettes may consist of one or more genes controlled by independent promotor sequences, and could be used to co-introduce a DNA recombinase system that physically removes the gene(s) located in the cassette if this very promotor is activated [ 9 , 10 ]. This may allow for the removal of a transgene cassette from, e.g., developing germ cells if it contains a recombinase system controlled by a germ cell-specific promotor. Such a design would confine the edited genome to the treated individual, leaving, however, future generations unaffected (so-called “one-generation germline therapy”).

In the following, we examine potential implications of the CRISPR-Cas technology for an evaluation of the three major ethical and legal problem complexes regarding human germline editing, i.e. questions of risk and uncertainty, inter-generational responsibility, and therapeutic legitimacy. For this purpose, we use cystic fibrosis (CF) as a clinical example for a frequent autosomal recessive genetically transmitted disease and re-analyze the ethical and legal arguments regarding genome editing in single-cell human embryos with CRISPR-Cas mediated treatment. This hypothetical situation can count as realistic insofar as it includes advances in the development of CRISPR-Cas that have so far not been accomplished but are currently intensively studied and may be available in the future [ 11 , 12 ]. Using this approach, we show that if the accuracy of CRISPR-Cas mediated genome editing can be improved and germline transmission to future generations be excluded, the editing of human single-cell embryos appears to be no matter of categorical arguments, but rather one of safety aspects.

Risk and uncertainty

Ethical and legal arguments so far.

CRISPR-Cas, although raising hopes and expectations regarding the safe and effective treatment of severe, hitherto incurable hereditary human diseases, has provoked intense ethical and legal debates with a view to possible risks associated with the technology. At present, CRISPR-Cas does not work sufficiently precise, leading to so-called off-target effects, i.e. unintended changes in non-target locations of the genome with unknown effects on treated cells [ 6 , 13 , 14 , 15 ]. If applied in human single-cell embryos, it is stated from an ethical point of view, such edited embryos would bear unacceptable risks because of such off-target effects. On the other hand, it is argued that these risks would not speak against germline editing, but rather in favor of further research with the aim of risk minimization [ 16 , 17 , 18 ].

These arguments have been put forward in the context of germline interventions long before the advent of CRISPR-Cas. Risk assumptions prompted many national regulators to ban or restrict human germline modification. For example, the German legislature prohibited any artificial modification of germline cells [ 19 ] because, from the legislator’s perspective, any such treatment would, initially, require experiments on human beings [ 20 ]. Such experiments, however, would have to be considered irresponsible in view of potentially irreversible consequences for the involved individuals. Similarly, in the United States, the National Institutes of Health (NIH) based their decision not to fund “any use of gene-editing technologies in human embryos” [ 21 ] on the consideration that “[t]he concept of altering the human germline in embryos for clinical purposes” raises “serious and unquantifiable safety issues” [ 21 ].

Such decisions by national legislators or regulators Footnote 1 may have been guided by requirements arising from constitutional law or international human rights law. In Germany, e.g., fundamental rights such as the right to life and physical integrity [ 23 ] are not only negative rights, but rather impose positive obligations on the government to protect human life and physical integrity against, e.g., risks arising from new technologies [ 24 ]. The European Court of Human Rights (ECtHR), for instance, has firmly established the doctrine of positive obligations arising from human rights [ 25 ]. On the other hand, the concept of positive obligations arising from fundamental rights has, for example, not gained acceptance in US constitutional law doctrine or jurisprudence [ 26 ].

With the recent advancements of the CRISPR-Cas technology, however, it seems within reach that risks for the life and health of human embryos as well as uncertainties regarding long-term effects for edited embryos and their descendants arising from germline interventions can be minimized to an acceptable level. Footnote 2 Ever since its discovery, great effort has been put into further improving the accuracy of CRISPR-Cas [ 28 ]. In the following scenario 1, we assume that due to substantial improvements in CRISPR-Cas technology the risks of accidentally altering the germline could be considered negligible.

Scenario 1: gene editing at the endogenous CF-related gene locus

In scenario 1, CRISPR-Cas is used to edit the CF-underlying defect at the endogenous gene locus (cystic fibrosis transmembrane conductance regulator, CFTR) in all in vitro generated human embryos descending from a CF-carrier couple (see Fig.  1 a). As such single-cell embryos cannot be diagnosed without being destroyed, all alleles, whether mutation carrying or not, are remodeled to the wildtype sequence of the functionally normal gene. Editing the endogenous gene locus entails that all correlated cells of the developing embryo produce the wildtype form of CFTR and, thus, that the embryo and all future offspring develop healthy (see Fig. 1 b).

Scenario 1. Hereditary outcomes of CRISPR-Cas mediated correction at the CFTR site (WT: wild-type allele; M: mutant allele)

When in vitro fertilization procedures including intracytoplasmic sperm injection (ICSI) or other sophisticated techniques are applied in couples suffering from infertility, a given amount of genetic damage of the isolated gametes as well as of the developing embryo during in vitro propagation needs to be considered, even if no genomic interventions are pursued. Scenario 1 rests on the core assumption that due to improvements of the CRISPR-Cas technology risks arising from off-target effects of the genomic intervention would have only a minor impact. This means that the overall risk of genome editing interventions would not significantly deviate from the risks arising from the mutation rate of routinely used complex procedures in assisted reproduction medicine, defined as the rate of genetic sequence variations during fertilization and the first steps of embryonic development. If this risk level was considered sufficiently small, our assumption undermines, first, arguments concerning risks for off-target effects and, second, arguments in favor of preferring preimplantation genetic diagnosis (PGD) and subsequent selection of embryos as already available safe alternative over genome editing in human embryos.

Remaining concerns

Assuming the overall risk of the intervention in scenario 1 is scoring within the risks arising from the mutation rate of normal reproduction or already established assisted reproduction procedures, the question arises of whether existing regulations referring to unacceptable risks of germline interventions would have to be adjusted. For instance, both the German Federal Constitutional Court [ 29 ] and the ECtHR [ 30 ] have held that governments are obliged to observe future development in the sciences. Accordingly, the German legislator as well as the contracting parties to the European Convention of Human Rights may be under the obligation to revisit their national prohibitions of human germline modifications and, ultimately, to revoke the ban or allow for exceptions if prior assumptions of risk are refuted by new scientific insights or technological progress. In particular, with regard to scenario 1, it could be argued that the positive obligation to take life and health protecting measures is not triggered any longer by gene editing, if the rate of unintended effects of genome editing by use of CRISPR-Cas is within the mutation rate of assisted reproduction during complex in vitro fertilization procedures. Consequently, as far as the prohibition of human germline editing is based on the argument of unacceptable risks to human life and health of the embryo and its offspring, national legislators might be legally obliged to revoke absolute bans on human germline interventions. In addition, one may hold that this is supported by international human rights law. According to Article 15(1)(b) of the International Covenant on Economic, Social and Cultural Rights (ICESCR) [ 31 ], states must recognize everyone’s right “to enjoy the benefits of scientific progress and its applications”. Hence, if our core assumptions proved true, i.e. the overall risk of genome editing interventions did not significantly add to the risks arising from the mutation rate of assisted reproduction during in vitro fertilization procedures, and, hence, this form of therapy was scientifically feasible, states could be considered to be under the positive obligation to make such therapies available to patients. Retaining a prohibition of germline therapies might, furthermore, also be regarded as a violation of everyone’s right “to the enjoyment of the highest attainable standard of physical and mental health” (Article 12(1) ICESCR).

From an ethical point of view, the question arises why, if at all, any of the risks related to the technical intervention should be considered, provided that they score within the risks occurring in assisted reproduction during in vitro fertilization procedures. On this view, the assumption reflects the frequently presented argument that reducing known risks to a certain degree would make the application of genome editing measures unproblematic [ 32 ]. However, what this calls for is a clarification of the underlying epistemic as well as normative values. What is required, both in ethics and law, are adequate points of reference for regarding the overall risk, e.g. the rate of unintended off-target effects, as sufficiently low. One possibility, as implied in scenario 1, consists in referring to the mutation rate occurring in assisted reproduction procedures already established as a morally and epistemically appropriate point of reference for determining risks of genome editing measures as sufficiently small. Another possibility would be to establish alternative thresholds for morally or legally irrelevant risks of harm, for instance the threshold of non-detectability of risk effects. Both approaches come at the cost of difficulties to be solved, e.g. of falling victim to the fallacy of regarding non-detectable effects as irrelevant [ 33 ].

Even if the overall risk of a CRISPR-Cas mediated germline intervention lies within the risks of already established assisted reproduction procedures, and is, therefore, considered acceptable, negative long-term consequences, in particular for the edited embryo as well as its offspring, cannot be ruled out entirely. Hence, scenario 1 does not release from developing an ethically as well as legally acceptable strategy for coping with uncertainty.

In situations of uncertainty, an application of the so-called precautionary principle often is proposed. From a legal perspective, it may be safe to say that the principle entitles the legislator in a situation of scientific uncertainty to assume that harm is possible and to enact respective laws aiming at protection [ 34 ]. In philosophical terms, however, it is still largely unclear what the precautionary principle implies. Although manifold versions of the principle exist, Sandin has demonstrated that almost any version can be summed up under the abstract formula: “If there (1) is a threat, which is (2) uncertain, then (3) some kind of action (4) is mandatory” [ 35 ].

Thus, the principle comprises four dimensions. The threat (1) and uncertainty (2) dimensions establish the conditions of its application. The former specifies the potentially negative consequences which call for its application. The latter specifies the nature and extent of (scientific) uncertainty regarding the occurrence of these consequences in the sense of necessary conditions for its application. Threat (1) and uncertainty (2) dimensions are also reflected in legal doctrine on the precautionary principle. According to the European Commission, for instance, it applies only if scientists are able to identify, at least, the possibility of negative effects [ 34 ]. This is in line with the CJEU’s case-law [ 36 ] which explicitly held that “where, following an assessment of available information, the possibility of harmful effects on health is identified but scientific uncertainty persists, provisional risk management measures […] may be adopted” [ 37 ]. Footnote 3

The action (3) and command dimensions (4) are concerned with establishing precautionary measures. Whereas the former determines the required decision strategy, the latter defines the degree to which pursuing the proposed action is prescribed (e.g. as obligatory, permissible, etc.). In legal terms, e.g., the precautionary principle “justifies the adoption of restrictive measures, provided they are non-discriminatory and objective […and] proportionate and no more restrictive […] than is required to achieve the […] level of […] protection chosen” [ 37 ].

Ultimately, with a view to our scenario 1 and the assumption of the interventions’ overall risk lying within the mutation rate of established assisted reproduction procedures, all four dimensions of the precautionary principle would have to be specified to make the principle applicable.

Responsibility towards future generations

Even if risks and uncertainties associated with genome editing in single-cell embryos could be minimized to an acceptable level, the question remains of whether it is ethically and legally justified to transfer these genetic alterations to future generations. Several objections have been raised, e.g., that it would be morally unacceptable to artificially manipulate the germline as the “heritage of humanity”, Footnote 4 or that human germline editing would, if not for therapeutic purposes, undermine future individuals’ autonomy [ 39 ].

None of such categorical arguments, whether they are considered valid or not, will be solved or explained away by making use of CRISPR-Cas as presented in scenario 1. However, CRISPR-Cas may also allow for “one-generation germline editing” leaving future generations unaffected.

Scenario 2: “one-generation germline therapy”

In scenario 2, embryos descending from a CF-carrier couple are not genetically modified at the endogenous CFTR gene. Rather, a more complex transgene cassette is introduced into a particular genomic locus. Such “safe harbor sites” allow for a stable integration of transgenes, while an interference with regulatory DNA-sequences or a transactivation of neighboring genes is avoided. The inserted transgene cassette can comprise more than one module, allowing for the expression of the CFTR wild-type sequence under the transcriptional control of its physiological promoter, and the expression of a DNA-recombinase under the transcriptional control of a germline-specific promoter (see Fig.  2 a). Furthermore, the entire transgene cassette is flanked by specific recognition sites that allow for a removal of the cassette in all germ-line cells upon transcriptional activation of the DNA-recombinase. As a result, the endogenous CFTR gene locus is unaltered, while at the same time the additional wildtype-CFTR transgene is available in all somatic cells and the developing embryo is phenotypically cured of CF (see Fig. 2 b). Its offspring, however, would not carry the transgene cassette as it is physically removed in all germ cells and, with the exception of a slight footprint in form of a few additional functionally inactive DNA nucleotides after recombination, remains unaffected from genome editing. As regards overall risk assessment, we assume for this scenario: first, the footprint in the genetic safe harbor site would not have functional consequences and, therefore, would not result in non-negligible risks. Second, future developments of gene editing tools will allow for highly efficient and precise insertion of transgenes and the overall risk of such genome editing interventions would not significantly deviate from the risks arising from the mutation rate of other complex procedures in assisted reproduction medicine.

Scenario 2. “One-generation genome editing” (AAVS1: Adeno-Associated Virus Integration Site 1; WT: wild-type allele; M: mutant allele)

Scenario 2 overcomes the normative problem of passing on genetic modifications in the germline of individual human beings to future generations and exposing future human beings, i.e. descendants of edited embryos, to unknown, possibly negative long-term effects without their consent, as well as affecting the human gene pool and, thus, humanity as a whole.

On the other hand, in scenario 2, the specific ethical issue is whether not passing on an edited genome to individuals of future generations needs justification. As the phenotype-correcting gene sequence is self-removing in germ cells, potential benefits of the intervention are limited to the edited embryo. Its descendants, however, are exposed to the risk of developing CF. To answer the question of whether this needs justification, first, the meaning of “exposing” descendants has to be clarified: is “exposing” to be understood intentionally and, hence, as an action calling for ethical evaluation? Only if this is answered in the affirmative it can be asked whether exposing future individuals to the risk of developing diseases like CF can be justified and, hence, be understood as a responsible action. Again, answering this question is possible, for instance, in view of the (potential) well-being of future individuals or the degree of naturalness of edited embryos.

From a legal perspective, at first sight, a “one-generation germline therapy” could be considered to be in conformity with the right to life and health of future human beings as long as adverse long-term effects of germline therapies cannot be ruled out. However, any legal restriction of germline therapies to “one-generation therapies” could conflict with the positive obligation of the State to protect human life and health [ 23 , 24 ]. If germline therapy of, e.g., CF had to be considered safe for future generations according to science and technology, the legislator’s positive obligation to protect human life and health might transform into a legislative duty to permit such therapeutic germline modifications, e.g. for the treatment of CF patients, even beyond “one-generation” therapies [ 40 ]. In other words, with a view to its positive obligation to protect human life and health, the legislator might be precluded from permitting human germline editing under the restrictive technical conditions of scenario 2 only since, in that scenario, offspring of the edited embryo might still suffer from CF.

However, the conclusiveness of this inference depends on whether the State’s positive obligation to protect human life and health extends to future human beings, e.g. to future CF patients, at all. In addition, the problem of consent of future generations as well as of effects on the human gene pool and, hence, on humanity as such, would remain unsolved. In light of these remaining concerns, it might be considered not be contrary to the State’s positive obligation to protect human life and health, but within the State’s possibilities of decision-making, if the legislator confined the permissibility of germline therapies to “one-generation therapies” for the time being.

Therapeutic legitimacy

Our prior considerations and scenarios suggest that categorical objections to human germline interventions may be overcome both scientific-technically and ethical-legally. If categorical prohibitions (to ban human germline editing completely) or dictates (to permit human germline editing in any case) cannot be convincingly established, the question arises under which conditions human germline editing might be considered legitimate in individual cases.

Ethical perspective: arguments and criteria for legitimizing germline editing interventions

The legitimacy of medical interventions into the physical integrity of human subjects usually relies on the informed and self-determined consent of the subjects concerned. Since consent cannot be obtained from single-cell embryos, the justification of genetic interventions is often discussed by reference to their (potential for) sufficient therapeutic benefit. Yet, looking at the germline editing procedures of scenarios 1 and 2 as a whole, it could be argued that they qualify as preventive rather than therapeutic measures. Ultimately, only in 25% of the embryos a genetic mutation would be corrected, 50% would lose carrier status while being phenotypically unchanged, and 25% would be left with the very same genetic sequence. If, however, individual embryos are considered legitimizing germline editing measures refers to the assumption that these embryos may benefit from the very genetic intervention. Hence, the (potential) therapeutic benefit is considered as key argument. Therefore, we discuss some of the presuppositions of focusing on therapeutic benefit in the context of germline editing measures as presented in our scenarios. We will conclude that, under certain conditions and with respect to individual embryos, it is possible to speak of such measures as preemptive therapies , i.e. as anticipative therapy without (knowledge of) existing pathologies (as known, e.g., from contexts like prophylactic mastectomy in cases of breast cancer gene [BRCA] mutations).

When referring to therapeutic benefit, it could be stated that legitimacy of human germline editing measures depends on a secured genetic diagnosis substantiating an individuals’ medical need (i.e. the expectation of her manifesting a relevant genetic disease), as well as the availability of an established gene therapy. On these grounds, referring to the publicly available information, the recently announced modification of CCR5 in human embryos with the aim of preventing the developing individuals from infection with human immunodeficiency virus (HIV) [ 8 ] could hardly be justified as therapeutic intervention. In fact, the developing embryos would not have been carrying a considerable risk for an HIV infection, if (washed) sperm was used from an HIV-positive father in an assisted reproduction setting. Hence, beside the fact that in this case gene editing was apparently performed without appropriate prior risk and safety assessments conducted by independent regulatory bodies, seemingly no medical need for the intervention was given [ 8 ].

However, germline editing does not seem to be justified by sole reference to (potential) therapeutic benefit in our scenarios either since no genetic diagnosis of CF can be performed in the individual single-cell embryos without destroying the respective zygotes. Thus, it is not knowable whether a certain embryo carries a diseased CF gene and, hence, would benefit from germline therapy. Rather, as shown in Fig. 1 b, only probabilities can be given for the developing embryos either being healthy, healthy carriers of CF, or actually diseased. Consequently, it is questionable whether such genome editing interventions, without knowing the CF genotype in the individual single-cell embryos, can be considered therapeutic measures at all, or rather represent actions beyond therapeutic intention, and if so, how such actions may be legitimized. One way of answering this question would be to analyze the concepts of disease and diagnosis in terms of whether they may be adapted to situations like our scenarios and, hence, would allow for justifying genetic interventions in zygotes affected by certain diseases with a certain probability. A second type of argument could be based on re-analyzing regarding to whom genome editing interventions have to be justified or, in other words, who is to be regarded as patient: either the focus of justification is primarily on future parents (1), or it is primarily on the embryos or future children (2) [ 41 ]. If (1) is assumed, our scenarios seem to be similar to cases of selective reproduction [ 42 ] leading to considerations of reproductive autonomy, the value and meaning of genetic parenthood as well as possible alternatives to germline editing. If, however, (2) is held, according to an alternative concept of therapy , it is, certain conditions satisfied, plausible to label germline editing as (preemptive) therapy [ 41 , 43 ].

Understanding germline editing in single-cell embryos as preemptive therapy in individuals requires two conditions being satisfied: First, the respective unedited zygote and the embryo resulting from the intervention must be regarded as ontologically identical ( identity condition ). Second, the intervention under consideration must promise (the potential for) sufficient overall benefit for an individual developing from an edited embryo ( benefit condition ).

The identity condition may seem trivial at first sight. It is, however, of particular importance in the context of germline editing in single-cell embryos, since CRISPR-Cas mediated changes in the genome of a zygote apply to all future cells in the developing embryo. Hence, the genetic make-up of the edited embryo differs in all subsequently developing cells from that of the unedited zygote as do the “normalized” physiological functions resulting from the genetic intervention. Therefore, germline edited individuals would have life conditions quite different from individuals developing from nonedited embryos. Against this background, it could be questioned (in contrast to most common medical contexts) whether the two entities under consideration are in fact identical. If they were not, however, the corresponding germline intervention could be neither regarded nor justified as a (preemptive) therapy. For any plausible concept of individual therapy necessarily relies on the assumption that individuals before and after an intervention are ontologically identical. Otherwise, it would be, e.g., logically impossible to justify an intervention in a certain individual by reference to its (potential) therapeutic benefit for this very individual.

The benefit condition, in turn, gains importance from the fact that (potential) benefits for individuals developing from edited embryos seem to be the only relevant normative aspect in the context of appropriate, i.e. justified medical decision-making regarding germline interventions in individual human embryos. For other normative claims usually relevant for medical decision-making, e.g. the consideration of patient autonomy through informed consent, are impossible to meet.

Following these considerations for an alternative concept of therapy, we may consider germline editing interventions as preemptive therapies with respect to their (potential) benefits for individuals developing from edited embryos (benefit condition), if the respective unedited zygotes and edited embryos are identical (identity condition). To support this claim, it has been suggested to specify the identity condition by reference to Parfit’s Origin View [ 43 ], according to which “[…] each person has this distinctive necessary property: that of having grown from the particular pair of cells from which this person in fact grew” [ 44 ]. Furthermore, it has been proposed to refine the benefit condition in view of a relative account of harm, according to which an individual is being harmed, if it is (possibly) worse off than it would have been in case of a certain action being taken [ 43 ]. Consequently, (sufficient) therapeutic benefit consists in avoiding such harm at the very least.

Parfit’s Origin View indeed suggests identity of the unedited zygotes and the edited embryos in our scenarios. Moreover, the individuals developing from the edited embryos can be held (possibly) worse off if the editing intervention had not been applied, and at least not harmed if the editing was applied (regardless of whether the edited zygote actually was healthy, a healthy carrier, or suffering from CF). Accordingly, it seems to be legitimate holding our scenarios as examples of (preemptive) therapy and, hence, to justify germline editing of a CFTR defect with regard to its (potential) therapeutic benefits.

However, both Parfit’s Origin View as well as relative accounts of harm have been contested [ 45 , 46 , 47 , 48 ]. As regards the former, it could be argued, e.g., that Parfit’s approach is ignoring decisive aspects of identity. In particular, interventions in the genome of embryos and their impact on the lives of edited individuals would make it difficult to understand unedited zygotes and edited embryos as qualitatively identical. As regards the latter, in view of our scenarios, the question arises, for instance, whether highly invasive genetic interventions in a human embryo can be adequately justified by reference to (sufficient) therapeutic benefit regarded as, at the very least, avoidance of harm. In contrast to many other medical interventions, e.g. oncological treatments, this is an issue precisely because a distinct diagnosis is lacking. The (necessary) renunciation of any reference to diagnosis in combination with the revised concept of therapeutic benefit in the alternative concept of therapy comes at the cost of therapeutically justifying germline editing in human single-cell embryos even though, like in our scenarios, 50% of the treated embryos would be phenotypically healthy without such intervention (and 25% even genotypically) (see Fig. 1 b). Thus, the alternative concept of therapy, opponents could state, does not solve the problem of lacking diagnostic possibilities when deciding about germline interventions in single-cell embryos, but rather points toward the importance of diagnosis for justifying such measures.

In addition, it could be asked more generally whether the mere therapeutic intention to germline edit embryos possibly suffering from CF may be sufficient to adequately justify such interventions. These issue calls for further analysis of the alternative concept of therapy as well as the normative function of therapeutic intentions for an adequate justification of germline interventions like in our scenarios. Nevertheless, at least it seems possible that under certain theoretical assumptions both scenarios can be legitimized with regard to (sufficient) therapeutic benefit.

As regards scenario 1, however, the question arises whether passing on genomes to the offspring of edited embryos may also be justified as individual preemptive therapy. It is a trivial fact that the offspring of edited embryos cannot be identical with the unedited zygotes from which their parents developed. Hence, the identity condition is not satisfied for the offspring of edited embryos; passing on genomes to future individuals may not be justified by reference to a concept of preemptive therapy. Thus, insofar germline interventions can be justified as therapies at all, interventions as in scenario 2 seem preferable over interventions as in scenario 1.

In cases where germline editing measures are legitimate in view of their (potential) therapeutic benefit, the question arises of how to detect and deal with actually occurring side-effects in ethically acceptable ways. Postnatal monitoring of edited persons has been proposed, raising, however, important questions of whether, e.g., the individuals concerned are restrained regarding their autonomy, as well as organizational questions, for instance, of who (edited persons, their descendants) should be monitored in what time frames (5 years, 10 years, lifetime), and what monitoring measures would need to be applied by whom (state authorities, private institutions, parents) [ 49 ]. Here, too, decisive differences between the two scenarios occur: whereas scenario 1 may also require monitoring descendants of edited embryos, scenario 2 at most requires monitoring edited individuals. This also seems to make scenario 2 prima facie favorable over scenario 1.

Legal perspective: what are the requirements for legitimate germline editing interventions?

From a legal perspective, as long as arguments for a categorical prohibition of human germline editing or, conversely, for an unrestricted permissibility of germline therapies cannot be convincingly established, the legitimacy of such interventions should depend on whether certain strict substantive and procedural requirements are met. In fact, reactions regarding the recent announcement of the birth of genome edited twins [ 8 ] have clearly shown the need for normative standards to be strictly complied with in cases of human germline therapies. The object and purpose of such strict substantive and procedural requirements would be the protection of life and health (or physical integrity respectively) and related rights to self-determination of edited embryos, the resulting human beings and its descendants as well as of mothers carrying edited embryos. The lawmaker would have to balance these legal concerns in light of the precautionary principle while taking into account the interests of the international community of states regarding the human genome as “heritage of humanity” [ 38 ]. Against this background, for the time being, the following substantive and procedural requirements seem not to be excessively restrictive or unproportional and may, therefore, considered justified.

Concerning substantive requirements, it should be laid down, e.g., that germline interventions are limited to the treatment or prevention of certain serious, hitherto incurable hereditary diseases (such as CF) only and that germline interventions for other, e.g. enhancing or eugenic, Footnote 5 purposes are to be prohibited. Relevant serious diseases could be defined in an abstract way or classified in a list of either exhaustive (i.e. static) or exemplary (i.e. dynamic) character. Compiling and updating such lists might be the legislators’ task or, on the basis of legislatively delegated powers, the task of an administrative authority or of a special committee composed of relevant stakeholders (e.g. scientists, ethicists, lawyers, medical doctors, patient groups).

An additional substantive requirement should be that (preemptive) therapeutic effects, i.e. the cure or prevention of hereditary diseases, are unambiguous and the overall advantage for embryos’ and their offspring’s health is unequivocal. The latter should imply that there are also no negative side effects such as a higher susceptibility to other kinds of diseases.

The permissibility of germline interventions should depend, in addition, on the criterion of necessity. For example, human germline modification might not be necessary in this regard, if an equally effective (preemptive) therapy is available being less intrusive, i.e. not requiring intervening into the germline [ 51 ]. Furthermore, with regard to unpredictable long-term effects, a particular germline therapy affecting future generations could be considered unnecessary if a “one-generation therapy” (scenario 2) was available.

Moreover, any clinical application of germline editing should be preceded by rigorous preclinical scientific testing and evaluation using in vitro and in vivo animal models. A current legislative hindrance of clinical trials would be, at least in the EU, that both the EU’s Clinical Trials Directive 2001/20/EC and the new EU’s Clinical Trials Regulation (EU) No. 536/2014 prohibit “gene therapy clinical trials […] which result in modifications to the subject’s germline genetic identity” (Article 90(2) Regulation (EU) No. 536/2014; similarly Article 9(6)(2) Directive 2001/20/EC). However, any form of germline editing in clinical trials would necessarily modify the genetic identity of the respective trial subjects. In line with its positive obligations to protect human life and health, the Union legislator, therefore, might be obliged to review and possibly modify the prohibition laid down in the Clinical Trials Regulation so as to permit clinical germline therapy trials, if they could result in safe therapies as in our scenarios 1 and 2.

In addition, germline interventions, as does any therapeutic intervention, require consent. Obviously, however, embryos are not able to consent to germline interventions [ 52 ]. Instead, (future) parents of such embryos could consent to germline treatment. Consent of mothers carrying genetically modified embryos to term will be of particular importance [ 53 ]. A more difficult regulatory issue might be whether consent of future generations is required [ 53 ] and who should express consent, if, for instance, one-generation genome editing was not applicable. For this purpose, a kind of “trustee” or “custodian” could be established. Since germline editing might affect, albeit over a long period of time, the human gene pool as a whole, such a “trustee” or “custodian” might have to be an international body. These considerations and difficulties speak in favor of only permitting measures as in scenario 2.

The aforementioned substantive requirements would have to be accompanied by procedural requirements. For whether the former are met would have to be reviewed by one or more administrative authorities within the framework of a particular administrative procedure. For the time being, any individual germline intervention should be subject to the requirement of prior authorization. Part of such an authorization procedure could be, e.g., the involvement of an ethics committee with the task to carry out a thorough risk-benefit analysis.

With a view to (international) transparency and traceability, it is advisable to list all authorized germline editing treatments in a registry. In addition, tight monitoring programs should be established in order to survey and control long-term effects of germline interventions.

Conclusions

Scenario 2 represents a situation in which a clinical application of CRISPR-Cas mediated genome editing interventions in single-cell embryos may be feasible in ethical and legal terms. If the risks of genome interventions can be minimized, future generations excluded from genome editing, and the purpose of the intervention confined to therapeutic measures, there are good reasons to consider the intervention being justified in principle. Further developments on the basis of CRISPR-Cas may provide the means to accomplish the first two requirements. On the other hand, ethical and legal considerations may direct further research on CRISPR-Cas into improving accuracy and elaborating measures to avoid germline transmission to future generations.

Our scenarios reveal a number of questions, which need to be considered from both an ethical and a legal perspective. First, as regards issues of risk and uncertainty, it has to be clarified what risks can legitimately count as acceptable risks. Criteria for the threshold of acceptable risks might be, for instance, that risks are scoring within the risks associated with other established reproductive procedures or that mutations are non-detectable. In any case, arguments for the statutory prohibition of germline interventions would be possibly substantially weakened, if the question of safety was resolved [ 54 ]. As far as consequences of germline editing remain uncertain, the precautionary principle entitles states to take preventive measures. However, the exact conditions for applying the precautionary principle as well as adequate precautionary measures have yet to be specified in the context of human germline editing.

Second, as regards responsibilities towards future generations, avoiding any transmission of edited genomes should be persuaded prima facie [ 55 ]. Nevertheless, it needs to be clarified whether, and if so in what meaning and consequence, constitutional or international human rights may trigger a positive obligation of the State to protect, e.g., human life and health even of future, not yet existing individuals. From an ethical perspective, it has to be examined whether passing on edited genomes to future generations is to be justified at all, for instance in view of future individuals’ well-being. Similarly, it has to be clarified whether not passing on a modified genome to future generations is to be justified in cases where descendants of edited embryos could have benefitted from the intervention.

Third, if no categorical arguments speak against human germline editing, the necessary legitimacy requirements need to be considered. From a legal perspective, several procedural and substantive prerequisites would have to be laid down by law (see Table 1 ).

Answering the question of ethical legitimization means considering the conditions under which a germline editing intervention can be understood as (preemptive) therapy, thus legitimizing them. These findings are important prerequisites for the international debate on the ethical and legal justification of germline interventions in the human embryo as well as for the harmonization of international legal standards.

Availability of data and materials

Not applicable.

For an overview of regulatory approaches to germline editing in various states see [ 14 , 22 ].

Cf., however, the recent judgment of the Court of Justice of the European Union (CJEU) concerning mutagenesis through genome editing techniques, in which the Court held (with a view to current knowledge as stipulated by the referring national court) that “the risks linked to the use of those new techniques/methods of mutagenesis [such as CRISPR-Cas] might prove to be similar to those which result from the production and release of a [genetically modified organism] through transgenesis” [ 27 ].

Interestingly, in [ 27 ], i.e. in its judgment on mutagenesis through genome editing, the Court did not adhere to its own standards when it self-reliantly considered, without referring to any scientific source, that the precautionary principle was applicable due to “risks for the environment or human health linked to the use of new techniques/methods of mutagenesis [such as CRISPR-Cas] […that] might be similar to those which result from the production and release of a [genetically modified organism] through transgenesis”.

Cf [ 38 ]., according to which the “human genome” is “the heritage of humanity” (albeit “[i]n a symbolic sense” only).

In that regard, it is interesting to note that the European Union (EU) Charter of Fundamental Rights has established an explicit “prohibition of eugenic practices” in its Article 3(2)(b) [ 50 ], which may be understood as a bioethical consensus among the EU Member States. In fact, the German legislator, e.g., had already warned as early as in 1989 that dangers of abuse of germline interventions, in particular, for purposes of “human breeding”, were obvious [ 20 ].

Abbreviations

Chemokine Receptor Type 5

Court of Justice of the European Union

Cystic Fibrosis Transmembrane Conductance Regulator

Clustered Regularly Interspaced Short Palindromic Repeats-associated

deoxyribonucleic acid

European Court of Human Rights

European Union

Human Immunodeficiency Viruses

International Covenant on Economic, Social and Cultural Rights

National Institutes of Health

Preimplantation Genetic Diagnosis

ribonucleic acid

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Acknowledgements

We would like to thank Barbara Advena-Regnery, Dustin Gooßens, Gregor Frenken, Sebastian Gierschick, Kristian Köchy, Ralf Müller-Terpitz, Michael Ott, Peter Schröder-Bäck as well as Rainer Schweizer for their support with regard to content and methodological matters.

This study was carried out as part of the research project “REALiGN-HD: Revisited Ethical And Legal Concepts For Precise Genome Engineering Approaches of Hereditary Diseases”, funded by the German Federal Ministry of Education and Research (grant number 01GP1616A-C). The German Federal Ministry of Education and Research did not participate in any form in designing the study, collecting, analyzing, interpreting data or in writing the manuscript.

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Schleidgen, S., Dederer, HG., Sgodda, S. et al. Human germline editing in the era of CRISPR-Cas: risk and uncertainty, inter-generational responsibility, therapeutic legitimacy. BMC Med Ethics 21 , 87 (2020). https://doi.org/10.1186/s12910-020-00487-1

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What are the Ethical Concerns of Genome Editing?

Most of the ethical discussions related to genome editing center around human germline because editing changes made in the germline would be passed down to future generations.

The debate about genome editing is not a new one but has regained attention following the discovery that CRISPR has the potential to make such editing more accurate and even "easy" in comparison to older technologies.

Bioethicists and researchers generally believe that human genome editing for reproductive purposes should not be attempted at this time, but that studies that would make  gene therapy  safe and effective should continue. 1 , 2  Most stakeholders agree that it is important to have continuing public deliberation and debate to allow the public to decide whether or not germline editing should be permissible. As of 2014, there were about 40 countries that discouraged or banned research on germline editing, including 15 nations in Western Europe, because of ethical and safety concerns. 3  There is also an international effort led by the US, UK, and China to harmonize regulation of the application of genome editing technologies. This effort officially launched in December 2015 with the  International Summit on Human Gene Editing  in Washington, DC. For more information on this summit, see  What's happening right now?

NHGRI uses the term "genome editing" to describe techniques used to modify DNA in the genome. Other groups also use the term "gene editing." In general, these terms are used interchangeably.

Ethical Considerations

Due to the possibility of off-target effects (edits in the wrong place) and mosaicism (when some cells carry the edit but others do not), safety is of primary concern. Researchers and ethicists who have written and spoken about genome editing, such as those present at the  International Summit on Human Gene Editing,  generally agree that until germline genome editing is deemed safe through research, it should not be used for clinical reproductive purposes; the risk cannot be justified by the potential benefit. Some researchers argue that there may never be a time when genome editing in embryos will offer a benefit greater than that of existing technologies, such as  preimplantation genetic diagnosis (PGD)  and  in-vitro fertilization (IVF) . 4

However, scientists and bioethicists acknowledge that in some cases, germline editing can address needs not met by PGD. This includes when both prospective parents are  homozygous  for a disease-causing variant (they both have two copies of the variant, so all of their children would be expected to have the disease); cases of polygenic disorders, which are influenced by more than one gene; and for families who object to some elements of the PGD process. 5 , 6

Some researchers and bioethicists are concerned that any genome editing, even for therapeutic uses, will start us on a slippery slope to using it for non-therapeutic and  enhancement  purposes, which many view as controversial. Others argue that genome editing, once proved safe and effective, should be allowed to cure genetic disease (and indeed, that it is a moral imperative). 6  They believe that concerns about enhancement should be managed through policy and regulation.

Lastly, commenters on the issue are concerned that the use of genome editing for reproductive purposes will be regulated differently inside and outside of the U.S., leading to uses considered objectionable to the American public. These arguments cite the largely self-regulated environments of the reproductive clinics that offer PGD and IVF 7 , 8  and the existing differences in regulations among different countries. 9

Informed Consent

Some people worry that it is impossible to obtain informed consent for germline therapy because the patients affected by the edits are the embryo and future generations. The counterargument is that parents already make many decisions that affect their future children, including similarly complicated decisions such as PGD with IVF. Researchers and bioethicists also worry about the possibility of obtaining truly informed consent from prospective parents as long as the risks of germline therapy are unknown. 10

Justice and Equity

As with many new technologies, there is concern that genome editing will only be accessible to the wealthy and will increase existing disparities in access to health care and other interventions. Some worry that taken to its extreme, germline editing could create classes of individuals defined by the quality of their engineered genome.

Genome-Editing Research Involving Embryos

Many people have moral and religious objections to the use of human embryos for research. Federal funds cannot be used for any research that creates or destroys embryos. In addition, NIH does not fund any use of gene editing in human embryos. (See:  U.S. and NIH regulations and perspective )

While NIH will not fund gene editing in human embryos at this time, many bioethical and research groups believe that research using gene editing in embryos is important for myriad reasons, including to address scientific questions about human biology, as long as it is not used for reproductive purposes at this time. 11 , 12  Some countries have already allowed genome-editing research on nonviable embryos (those that could not result in a live birth), and others have approved genome-editing research studies with viable embryos. 13 , 14  In general, research that is conducted in embryos could use viable or nonviable embryos leftover from IVF, or embryos created expressly for research. Each case has its own moral considerations.

[1] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[2] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[3] Araki, M., & 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

[4] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:10.1038/519410a

[5] Hampton, T. (2016). Ethical and Societal Questions Loom Large as Gene Editing Moves Closer to the Clinic. JAMA, 315(6), 546-548. doi:10.1001/jama.2015.19150

[6] Savulescu, J., Pugh, J., Douglas, T., & Gyngell, C. (2015). The moral imperative to continue gene editing research on human embryos. Protein Cell, 6(7), 476-479. doi:10.1007/s13238-015-0184-y

[7] Ishii, T. (2017). Germ line genome editing in clinics: the approaches, objectives and global society. Brief Funct Genomics, 16(1), 46-56. doi:10.1093/bfgp/elv053

[8] Park, A. (2016). UK Approves First Studies Using New Gene Editing Technique. Time Health.

[9] Araki, M., & 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

[10] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:doi:10.1038/519410a

[11] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[12] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[13] Callaway, E. (2016). UK scientists gain licence to edit genes in human embryos. Nature News, 530(7588), 18. doi:doi:10.1038/nature.2016.19270

[14] Cyranoski, D., & Reardon, S. (2017). Chinese scientists genetically modify human embryos. Nature News. doi:doi:10.1038/nature.2015.17378

Last updated: August 3, 2017

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• 10 April 2024

How to supercharge cancer-fighting cells: give them stem-cell skills

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A CAR T cell (orange; artificially coloured) attacks a cancer cell (green). Credit: Eye Of Science/SPL

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Bioengineered immune cells have been shown to attack and even cure cancer , but they tend to get exhausted if the fight goes on for a long time. Now, two separate research teams have found a way to rejuvenate these cells: make them more like stem cells .

Both teams found that the bespoke immune cells called CAR T cells gain new vigour if engineered to have high levels of a particular protein. These boosted CAR T cells have gene activity similar to that of stem cells and a renewed ability to fend off cancer . Both papers were published today in Nature 1 , 2 .

The papers “open a new avenue for engineering therapeutic T cells for cancer patients”, says Tuoqi Wu, an immunologist at the University of Texas Southwestern in Dallas who was not involved in the research.

Reviving exhausted cells

CAR T cells are made from the immune cells called T cells, which are isolated from the blood of person who is going to receive treatment for cancer or another disease. The cells are genetically modified to recognize and attack specific proteins — called chimeric antigen receptors (CARs) — on the surface of disease-causing cells and reinfused into the person being treated.

But keeping the cells active for long enough to eliminate cancer has proved challenging, especially in solid tumours such as those of the breast and lung. (CAR T cells have been more effective in treating leukaemia and other blood cancers.) So scientists are searching for better ways to help CAR T cells to multiply more quickly and last longer in the body.

Cutting-edge CAR-T cancer therapy is now made in India — at one-tenth the cost

With this goal in mind, a team led by immunologist Crystal Mackall at Stanford University in California and cell and gene therapy researcher Evan Weber at the University of Pennsylvania in Philadelphia compared samples of CAR T cells used to treat people with leukaemia 1 . In some of the recipients, the cancer had responded well to treatment; in others, it had not.

The researchers analysed the role of cellular proteins that regulate gene activity and serve as master switches in the T cells. They found a set of 41 genes that were more active in the CAR T cells associated with a good response to treatment than in cells associated with a poor response. All 41 genes seemed to be regulated by a master-switch protein called FOXO1.

The researchers then altered CAR T cells to make them produce more FOXO1 than usual. Gene activity in these cells began to look like that of T memory stem cells, which recognize cancer and respond to it quickly.

The researchers then injected the engineered cells into mice with various types of cancer. Extra FOXO1 made the CAR T cells better at reducing both solid tumours and blood cancers. The stem-cell-like cells shrank a mouse’s tumour more completely and lasted longer in the body than did standard CAR T cells.

Master-switch molecule

A separate team led by immunologists Phillip Darcy, Junyun Lai and Paul Beavis at Peter MacCallum Cancer Centre in Melbourne, Australia, reached the same conclusion with different methods 2 . Their team was examining the effect of IL-15, an immune-signalling molecule that is administered alongside CAR T cells in some clinical trials. IL-15 helps to switch T cells to a stem-like state, but the cells can get stuck there instead of maturing to fight cancer.

The team analysed gene activity in CAR T cells and found that IL-15 turned on genes associated with FOXO1. The researchers engineered CAR T cells to produce extra-high levels of FOXO1 and showed that they became more stem-like, but also reached maturity and fought cancer without becoming exhausted. “It’s the ideal situation,” Darcy says.

Stem-cell and genetic therapies make a healthy marriage

The team also found that extra-high levels of FOXO1 improved the CAR T cells’ metabolism, allowing them to last much longer when infused into mice. “We were surprised by the magnitude of the effect,” says Beavis.

Mackall says she was excited to see that FOXO1 worked the same way in mice and humans. “It means this is pretty fundamental,” she says.

Engineering CAR T cells that overexpress FOXO1 might be fairly simple to test in people with cancer, although Mackall says researchers will need to determine which people and types of cancer are most likely to respond well to rejuvenated cells. Darcy says that his team is already speaking to clinical researchers about testing FOXO1 in CAR T cells — trials that could start within two years.

And Weber points to an ongoing clinical trial in which people with leukaemia are receiving CAR T cells genetically engineered to produce unusually high levels of another master-switch protein called c-Jun, which also helps T cells avoid exhaustion. The trial’s results have not been released yet, but Mackall says she suspects the same system could be applied to FOXO1 and that overexpressing both proteins might make the cells even more powerful.

Nature 628 , 486 (2024)

doi: https://doi.org/10.1038/d41586-024-01043-2

Doan, A. et al. Nature https://doi.org/10.1038/s41586-024-07300-8 (2024).

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Chan, J. D. et al. Nature https://doi.org/10.1038/s41586-024-07242-1 (2024).

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Should We Change Species to Save Them?

When traditional conservation fails, science is using “assisted evolution” to give vulnerable wildlife a chance.

Credit... Photo illustration by Lauren Peters-Collaer

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By Emily Anthes

Photographs by Chang W. Lee

This story is part of a series on wildlife conservation in Australia, which Emily Anthes reported from New York and Australia, with Chang W. Lee.

• Published April 14, 2024 Updated April 16, 2024

For tens of millions of years, Australia has been a playground for evolution, and the land Down Under lays claim to some of the most remarkable creatures on Earth.

It is the birthplace of songbirds, the land of egg-laying mammals and the world capital of pouch-bearing marsupials, a group that encompasses far more than just koalas and kangaroos. (Behold the bilby and the bettong!) Nearly half of the continent’s birds and roughly 90 percent of its mammals, reptiles and frogs are found nowhere else on the planet.

Australia has also become a case study in what happens when people push biodiversity to the brink. Habitat degradation, invasive species, infectious diseases and climate change have put many native animals in jeopardy and given Australia one of the worst rates of species loss in the world.

In some cases, scientists say, the threats are so intractable that the only way to protect Australia’s unique animals is to change them. Using a variety of techniques, including crossbreeding and gene editing, scientists are altering the genomes of vulnerable animals, hoping to arm them with the traits they need to survive.

“We’re looking at how we can assist evolution,” said Anthony Waddle, a conservation biologist at Macquarie University in Sydney.

It is an audacious concept, one that challenges a fundamental conservation impulse to preserve wild creatures as they are. But in this human-dominated age — in which Australia is simply at the leading edge of a global biodiversity crisis — the traditional conservation playbook may no longer be enough, some scientists said.

“We’re searching for solutions in an altered world,” said Dan Harley, a senior ecologist at Zoos Victoria. “We need to take risks. We need to be bolder.”

The extinction vortex

The helmeted honeyeater is a bird that demands to be noticed, with a patch of electric-yellow feathers on its forehead and a habit of squawking loudly as it zips through the dense swamp forests of the state of Victoria. But over the last few centuries, humans and wildfires damaged or destroyed these forests, and by 1989, just 50 helmeted honeyeaters remained, clinging to a tiny sliver of swamp at the Yellingbo Nature Conservation Reserve.

Intensive local conservation efforts, including a captive breeding program at Healesville Sanctuary, a Zoos Victoria park, helped the birds hang on. But there was very little genetic diversity among the remaining birds — a problem common in endangered animal populations — and breeding inevitably meant inbreeding. “They have very few options for making good mating decisions,” said Paul Sunnucks, a wildlife geneticist at Monash University in Melbourne.

In any small, closed breeding pool, harmful genetic mutations can build up over time, damaging animals’ health and reproductive success, and inbreeding exacerbates the problem. The helmeted honeyeater was an especially extreme case. The most inbred birds left one-tenth as many offspring as the least inbred ones, and the females had life spans that were half as long, Dr. Sunnucks and his colleagues found.

Without some kind of intervention, the helmeted honeyeater could be pulled into an “extinction vortex,” said Alexandra Pavlova, an evolutionary ecologist at Monash. “It became clear that something new needs to be done.”

A decade ago, Dr. Pavlova, Dr. Sunnucks and several other experts suggested an intervention known as genetic rescue , proposing to add some Gippsland yellow-tufted honeyeaters and their fresh DNA to the breeding pool.

The helmeted and Gippsland honeyeaters are members of the same species, but they are genetically distinct subspecies that have been evolving away from each other for roughly the last 56,000 years. The Gippsland birds live in drier, more open forests and are missing the pronounced feather crown that gives helmeted honeyeaters their name.

Genetic rescue was not a novel idea. In one widely cited success, scientists revived the tiny, inbred panther population of Florida by importing wild panthers from a separate population from Texas.

But the approach violates the traditional conservation tenet that unique biological populations are sacrosanct, to be kept separate and genetically pure. “It really is a paradigm shift,” said Sarah Fitzpatrick, an evolutionary ecologist at Michigan State University who found that genetic rescue is underused in the United States.

Crossing the two types of honeyeaters risked muddying what made each subspecies unique and creating hybrids that were not well suited for either niche. Moving animals between populations can also spread disease, create new invasive populations or destabilize ecosystems in unpredictable ways.

Genetic rescue is also a form of active human meddling that violates what some scholars refer to as conservation’s “ ethos of restraint ” and has sometimes been critiqued as a form of playing God.

“There was a lot of angst among government agencies around doing it,” said Andrew Weeks, an ecological geneticist at the University of Melbourne who began a genetic rescue of the endangered mountain pygmy possum in 2010. “It was only really the idea that the population was about to go extinct that I guess gave government agencies the nudge.”

Dr. Sunnucks and his colleagues made the same calculation, arguing that the risks associated with genetic rescue were small — before the birds’ habitats were carved up and degraded, the two subspecies did occasionally interbreed in the wild — and paled in comparison with the risks of doing nothing.

And so, since 2017, Gippsland birds have been part of the helmeted honeyeater breeding program at Healesville Sanctuary. In captivity there have been real benefits, with many mixed pairs producing more independent chicks per nest than pairs composed of two helmeted honeyeaters. Dozens of hybrid honeyeaters have now been released into the wild. They seem to be faring well, but it is too soon to say whether they have a fitness advantage.

Monash and Zoos Victoria experts are also working on the genetic rescue of other species, including the critically endangered Leadbeater’s possum, a tiny, tree-dwelling marsupial known as the forest fairy. The lowland population of the possum shares the Yellingbo swamps with the helmeted honeyeater; in 2023, just 34 lowland possums remained . The first genetic rescue joey was born at Healesville Sanctuary last month.

The scientists hope that boosting genetic diversity will make these populations more resilient in the face of whatever unknown dangers might arise, increasing the odds that some individuals possess the traits needed to survive. “Genetic diversity is your blueprint for how you contend with the future,” Dr. Harley of Zoos Victoria said.

Targeting threats

For the northern quoll, a small marsupial predator, the existential threat arrived nearly a century ago, when the invasive, poisonous cane toad landed in eastern Australia. Since then, the toxic toads have marched steadily westward — and wiped out entire populations of quolls, which eat the alien amphibians.

But some of the surviving quoll populations in eastern Australia seem to have evolved a distaste for toads . When scientists crossed toad-averse quolls with toad-naive quolls, the hybrid offspring also turned up their tiny pink noses at the toxic amphibians.

What if scientists moved some toad-avoidant quolls to the west, allowing them to spread their discriminating genes before the cane toads arrived? “You’re essentially using natural selection and evolution to achieve your goals, which means that the problem gets solved quite thoroughly and permanently,” said Ben Phillips, a population biologist at Curtin University in Perth who led the research.

A field test, however, demonstrated how unpredictable nature can be. In 2017, Dr. Phillips and his colleagues released a mixed population of northern quolls on a tiny, toad-infested island. Some quolls did interbreed , and there was preliminary evidence of natural selection for “toad-smart” genes.

But the population was not yet fully adapted to toads, and some quolls ate the amphibians and died, Dr. Phillips said. A large wildfire also broke out on the island. Then, a cyclone hit. “ All of these things conspired to send our experimental population extinct,” Dr. Phillips said. The scientists did not have enough funding to try again, but “all the science lined up,” he added.

Advancing science could make future efforts even more targeted. In 2015, for instance, scientists created more heat-resistant coral by crossbreeding colonies from different latitudes . In a proof-of-concept study from 2020, researchers used the gene-editing tool known as CRISPR to directly alter a gene involved in heat tolerance.

CRISPR will not be a practical, real-world solution anytime soon, said Line Bay, a biologist at the Australian Institute of Marine Science who was an author of both studies. “Understanding the benefits and risks is really complex,” she said. “And this idea of meddling with nature is quite confronting to people.”

But there is growing interest in the biotechnological approach. Dr. Waddle hopes to use the tools of synthetic biology, including CRISPR, to engineer frogs that are resistant to the chytrid fungus, which causes a fatal disease that has already contributed to the extinction of at least 90 amphibian species.

The fungus is so difficult to eradicate that some vulnerable species can no longer live in the wild. “So either they live in glass boxes forever,” Dr. Waddle said, “or we come up with solutions where we can get them back in nature and thriving.”

Unintended consequences

Still, no matter how sophisticated the technology becomes, organisms and ecosystems will remain complex. Genetic interventions are “likely to have some unintended impacts,” said Tiffany Kosch, a conservation geneticist at the University of Melbourne who is also hoping to create chytrid-resistant frogs . A genetic variant that helps frogs survive chytrid might make them more susceptible to another health problem , she said.

There are plenty of cautionary tales, efforts to re-engineer nature that have backfired spectacularly. The toxic cane toads, in fact, were set loose in Australia deliberately, in what would turn out to be a deeply misguided attempt to control pest beetles.

But some environmental groups and experts are uneasy about genetic approaches for other reasons, too. “Focusing on intensive intervention in specific species can be a distraction,” said Cam Walker, a spokesman for Friends of the Earth Australia. Staving off the extinction crisis will require broader, landscape-level solutions such as halting habitat loss, he said.

Moreover, animals are autonomous beings, and any intervention into their lives or genomes must have “a very strong ethical and moral justification” — a bar that even many traditional conservation projects do not clear, said Adam Cardilini, an environmental scientist at Deakin University in Victoria.

Chris Lean, a philosopher of biology at Macquarie University, said he believed in the fundamental conservation goal of “preserving the world as it is for its heritage value, for its ability to tell the story of life on Earth.” Still, he said he supported the cautious, limited use of new genomic tools, which may require us to reconsider some longstanding environmental values.

In some ways, assisted evolution is an argument — or, perhaps, an acknowledgment — that there is no stepping back, no future in which humans do not profoundly shape the lives and fates of wild creatures.

To Dr. Harley, it has become clear that preventing more extinctions will require human intervention, innovation and effort. “Let’s lean into that, not be daunted by it,” he said. “My view is that 50 years from now, biologists and wildlife managers will look back at us and say, ‘Why didn’t they take the steps and the opportunities when they had the chance?’”

Emily Anthes is a science reporter, writing primarily about animal health and science. She also covered the coronavirus pandemic. More about Emily Anthes

Chang W. Lee has been a photographer for The Times for 30 years, covering events throughout the world. He is currently based in Seoul. Follow him on Instagram @nytchangster . More about Chang W. Lee

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The ability of gene editing technology to precisely modify DNA offers unprecedented opportunities to address pressing challenges and improve the quality of life for humans, animals, and the environment. Explain.

Topic: Achievements of Indians in science & technology; indigenization of technology and developing new technology.

5. The ability of gene editing technology to precisely modify DNA offers unprecedented opportunities to address pressing challenges and improve the quality of life for humans, animals, and the environment. Explain. (250 words)

Difficulty level: Easy

Reference: Insights on India.

Why the question: The question is part of the static syllabus of General studies paper – 3 and mentioned as part of Mission-2024 Secure timetable. Key Demand of the question: To write about the gene editing technology is with its potential applications in various fields. Directive word:  Explain –  Clarify the topic by giving a detailed account as to how and why it occurred, or what is the particular context. You must be defining key terms where ever appropriate, and substantiate with relevant associated facts. Structure of the answer: Introduction:  Start with what you understand by Gene editing technology. Body: In the first part, write about the process of gene editing technology with a brief diagram. Next, write about the possible advantages of Gene editing and cite examples to substantiate. Next, write about the limitations of the above. Conclusion: Conclude by summarising.

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Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing

Misganaw asmamaw.

1 Division of Biochemistry, Department of Biomedical Sciences, College of Medicine and Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia

Belay Zawdie

2 Division of Biochemistry, Department of Biomedical Sciences, Institute of Health, Jimma University, Jimma, Ethiopia

Clustered regularly interspaced short palindromic repeat (CRISPR) and their associated protein (Cas-9) is the most effective, efficient, and accurate method of genome editing tool in all living cells and utilized in many applied disciplines. Guide RNA (gRNA) and CRISPR-associated (Cas-9) proteins are the two essential components in CRISPR/Cas-9 system. The mechanism of CRISPR/Cas-9 genome editing contains three steps, recognition, cleavage, and repair. The designed sgRNA recognizes the target sequence in the gene of interest through a complementary base pair. While the Cas-9 nuclease makes double-stranded breaks at a site 3 base pair upstream to protospacer adjacent motif, then the double-stranded break is repaired by either non-homologous end joining or homology-directed repair cellular mechanisms. The CRISPR/Cas-9 genome-editing tool has a wide number of applications in many areas including medicine, agriculture, and biotechnology. In agriculture, it could help in the design of new grains to improve their nutritional value. In medicine, it is being investigated for cancers, HIV, and gene therapy such as sickle cell disease, cystic fibrosis, and Duchenne muscular dystrophy. The technology is also being utilized in the regulation of specific genes through the advanced modification of Cas-9 protein. However, immunogenicity, effective delivery systems, off-target effect, and ethical issues have been the major barriers to extend the technology in clinical applications. Although CRISPR/Cas-9 becomes a new era in molecular biology and has countless roles ranging from basic molecular researches to clinical applications, there are still challenges to rub in the practical applications and various improvements are needed to overcome obstacles.

Genome editing is a type of genetic engineering in which DNA is deliberately inserted, removed, or modified in living cells. 1 The name CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) refers to the unique organization of short, partially repeated DNA sequences found in the genomes of prokaryotes. CRISPR and its associated protein (Cas-9) is a method of adaptive immunity in prokaryotes to defend themselves against viruses or bacteriophages. 2 Japanese scientist Ishino and his team accidentally found unusual repetitive palindromic DNA sequences interrupted by spacers in Escherichia coli while analyzing a gene for alkaline phosphatase first discovered CRISPR in 1987. However, they did not ascertain its biological function. In 1990, Francisco Mojica identifies similar sequences in other prokaryotes and he named CRISPR, yet the functions of these sequences were a mystery. 3 Later on in 2007, a CRISPR was experimentally conferred as a key element in the adaptive immune system of prokaryotes against viruses. During the adaptation process, bacterial cells become immunized by the insertion of short fragments of viral DNA (spacers) into a genomic region called the CRISPR array. Hence, spacers serve as a genetic memory of previous viral infections. 4 The CRISPR defense mechanism protects bacteria from repeated viral attacks via three basic stages: adaptation (spacer acquisition), crRNA synthesis (expression), and target interference. CRISPR loci are an array of short repeated sequences found in chromosomal or plasmid DNA of prokaryotes. Cas gene is usually found adjacent to CRISPR that codes for nuclease protein (Cas protein) responsible to destroy or cleave viral nucleic acid. 5

Before the discovery of CRISPR/Cas-9, scientists were relied on two gene-editing techniques using restriction enzymes, zinc finger nucleases (ZFN) and Transcription activator-like effector nucleases (TALENs). 6 ZFN has a zinc finger DNA binding domain used to bind a specific target DNA sequence and a restriction endonuclease domain used to cleave the DNA at the target site. TALENs are also composed of DNA binding domain and restriction domain like ZFN but their DNA binding domain has more potential target sequence than the ZFN gene-editing tool. In both cases, the difficulty of protein engineering, being expensive, and time-consuming were the major challenges for researchers and manufacturers. 6 , 7 The development of a reliable and efficient method of a gene-editing tool in living cells has been a long-standing goal for biomedical researchers. After figuring out the CRISPR mechanism in prokaryotes, scientists understood that it could have beneficial use in humans, plants, and other microbes. It was in 2012 that Doudna, J, and Charpentier, E discovered CRISPR/Cas-9 could be used to edit any desired DNA by just providing the right template. 8 Since then, CRISPR/Cas-9 becomes the most effective, efficient, and accurate method of genome editing tool in all living cells and utilized in many applied disciplines. 9 Thus, this review aims to discuss the mechanisms of genome editing mediated by CRISPR/Cas-9 and to highlight its recent applications as one of the most important scientific discoveries of this century, as well as the current barriers to the transformation of this technology.

Components of CRISPR/Cas-9

Based on the structure and functions of Cas-proteins, CRISPR/Cas system can be divided into Class I (type I, III, and IV) and Class II (type II, V, and VI). The class I systems consist of multi-subunit Cas-protein complexes, while the class II systems utilize a single Cas-protein. Since the structure of type II CRISPR/Cas-9 is relatively simple, it has been well studied and extensively used in genetic engineering. 10 Guide RNA (gRNA) and CRISPR-associated (Cas-9) proteins are the two essential components in CRISPR/Cas-9 system. The Cas-9 protein, the first Cas protein used in genome editing was extracted from Streptococcus pyogenes (SpCas-9). It is a large (1368 amino acids) multi-domain DNA endonuclease responsible for cleaving the target DNA to form a double-stranded break and is called a genetic scissor. 11 Cas-9 consists of two regions, called the recognition (REC) lobe and the nuclease (NUC) lobe. The REC lobe consists of REC1 and REC2 domains responsible for binding guide RNA, whereas the NUC lobe is composed of RuvC, HNH, and Protospacer Adjacent Motif (PAM) interacting domains. The RuvC and HNH domains are used to cut each single-stranded DNA, while PAM interacting domain confers PAM specificity and is responsible for initiating binding to target DNA. 12 Guide RNA is made up of two parts, CRISPR RNA (crRNA) and trans-activating CRISPR RNA (tracrRNA). The crRNA is an 18–20 base pair in length that specifies the target DNA by pairing with the target sequence, whereas tracrRNA is a long stretch of loops that serve as a binding scaffold for Cas-9 nuclease. In prokaryotes, the guide RNA is used to target viral DNA, but in the gene-editing tool, it can be synthetically designed by combining crRNA and tracrRNA to form a single guide RNA (sgRNA) in order to target almost any gene sequence supposed to be edited. 11

Mechanisms of CRISPR/CAS-9 Genome Editing

The mechanism of CRISPR/Cas-9 genome editing can be generally divided into three steps: recognition, cleavage, and repair. 13 The designed sgRNA directs Cas-9 and recognizes the target sequence in the gene of interest through its 5ʹcrRNA complementary base pair component. The Cas-9 protein remains inactive in the absence of sgRNA. The Cas-9 nuclease makes double-stranded breaks (DSBs) at a site 3 base pair upstream to PAM. 14 PAM sequence is a short (2–5 base-pair length) conserved DNA sequence downstream to the cut site and its size varies depending on the bacterial species. The most commonly used nuclease in the genome-editing tool, Cas-9 protein recognizes the PAM sequence at 5ʹ-NGG-3ʹ (N can be any nucleotide base). Once Cas-9 has found a target site with the appropriate PAM, it triggers local DNA melting followed by the formation of RNA-DNA hybrid, but the mechanism of how Cas-9 enzyme melts target DNA sequence was not clearly understood yet. Then, the Cas-9 protein is activated for DNA cleavage. HNH domain cleaves the complementary strand, while the RuvC domain cleaves the non-complementary strand of target DNA to produce predominantly blunt-ended DSBs. Finally, the DSB is repaired by the host cellular machinery. 11 , 15

Double-Stranded Break Repair Mechanisms

Non-homologous end joining (NHEJ), and homology-directed repair (HDR) pathways are the two mechanisms to repair DSBs created by Cas-9 protein in CRISPR/Cas-9 mechanism. 16 NHEJ facilitates the repair of DSBs by joining DNA fragments through an enzymatic process in the absence of exogenous homologous DNA and is active in all phases of the cell cycle. It is the predominant and efficient cellular repair mechanism that is most active in the cells, but it is an error-prone mechanism that may result in small random insertion or deletion (indels) at the cleavage site leading to the generation of frameshift mutation or premature stop codon. 17 HDR is highly precise and requires the use of a homologous DNA template. It is most active in the late S and G2 phases of the cell cycle. In CRISPR-gene editing, HDR requires a large amount of donor (exogenous) DNA templates containing a sequence of interest. HDR executes the precise gene insertion or replacement by adding a donor DNA template with sequence homology at the predicted DSB site. 16 , 17

Applications of CRISPR/CAS-9

In just a few years of its discovery, the CRISPR/Cas-9 genome editing tool has already being explored for a wide number of applications and had a massive impact on the world in many areas including medicine, agriculture, and biotechnology. In the future, researchers hope that this technology will continue to advance for treating and curing diseases, develop more nutritious crops, and eradicating infectious diseases. 18 Highlights for some of the recent CRISPR/Cas-9 applications and clinical trials being investigated are discussed below.

Role in Gene Therapy

More than 6000 genetic disorders have been known so far. But the majority of the diseases lack effective treatment strategies. 19 Gene therapy is the process of replacing the defective gene with exogenous DNA and editing the mutated gene at its native location. It is the latest development in the revolution of medical biotechnology. From 1998 to August 2019, 22 gene therapies including the novel CRISPR/Cas-9 have been approved for the treatment of human diseases. 20

Since its discovery in 2012, CRISPR/Cas-9 gene editing has held the promise of curing most of the known genetic diseases such as sickle cell disease, β-thalassemia, cystic fibrosis, and muscular dystrophy. 21 , 22 CRISPR/Cas-9 for targeted sickle cell disease (SCD) therapy and β-thalassemia have been also applied in clinical trials. 23 SCD is an autosomal recessive genetic disease of red blood cells, which occurs due to point mutation in the β-globin chain of hemoglobin leading to sickle hemoglobin (HbS). During the deoxygenation process, HbS polymerization leads to severe clinical complications like hemolytic anemia. 24 Either direct repairing the gene of hemoglobin S or boosting fetal γ-globin are the two main approaches that CRISPR/Cas-9 is being used to treat SCD. 25 However, the most common method used in a clinical trial is based on the approach of boosting fetal hemoglobin. First bone marrow cells are removed from patients and the gene that turns off fetal hemoglobin production, called B-cell Lymphoma 11A (BCL11A) is disabled with CRISPR/Cas-9. Then, the gene-edited cells are infused back into the body. 26 BCL11A is a 200 base pair gene found on chromosome 2 and its product is responsible to switch γ-globin into the β-globin chain by repressing γ-globin gene expression. 27 Once this gene is disabled using CRISPR/Cas-9, the production of fetal hemoglobin containing γ-globin in the red blood cells will increase, thereby alleviating the severity and manifestations of SCD. 28

Scientists have been also investigating CRISPR/Cas-9 for the treatment of cystic fibrosis. The genetic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene decreases the structural stability and function of CFTR protein leading to cystic fibrosis. 29 CFTR protein is an anion channel protein regulated by protein kinase-A, located at the apical surface of epithelial cells of the lung, intestine, pancreas, and reproductive tract. 30 Although there is no cure for cystic fibrosis, symptom-based therapies (such as antibiotics, bronchodilators, and mucus thinning medications) and CFTR modulating drugs have become the first-line treatments to relieve symptoms and reduce the risk of complications. 31 Currently, gene manipulation technologies and molecular targets are also being explored. The use of CRISPR/Cas-9 technology for genome editing has great potential, although it is in the early stages of development. 32 In 2013, researchers culture intestinal stem cells from two cystic fibrosis patients and corrected the mutation at the CFTR locus resulting in the expression of the correct gene and full function of the protein. Since then, the potential utility of the application of CRISPR/Cas-9 for cystic fibrosis was established. 33 Furthermore, Duchenne muscular dystrophy (DMD), which is caused by a mutation in the dystrophin gene and characterized by muscle weakness, has been successfully corrected by CRISPR/Cas-9 in patient-induced pluripotent stem cells. 34 Despite considerable efforts, the treatment available for DMD remains supportive rather than curative. Currently, several therapeutic approaches (gene therapy, cell therapy, and exon skipping) have been investigated to restore the expression of dystrophin in DMD muscles. 35 , 36 Deletion/excision of intragenic DNA and removing the duplicated exon by CRISPR/Cas-9 are the new and promising approaches in correcting the DMD gene, which restores the expression of dystrophin protein. 37

Moreover, the latest researches show that the CRISPR/Cas-mediated single-base editing and prime editing systems can directly install mutations in cellular DNA without the need for a donor template. The CRISPR/Cas-base editor and prime editor system do not produce DSB, which reduces the possibility of indels that are different from conventional Cas-9. 38 So far, two types of base editors have been developed: cytosine base editor (CBE) and adenine base editor (ABE). 39 The CBE is a type of base editor composed of cytidine deaminase fused with catalytically deficient or dead Cas-9 (dCas-9). It is one of the novel gene therapy strategies that can produce precise base changes from cytidine (C) to thymidine (T). 40 However, the target range of the CBE base editor is still restricted by PAM sequences containing G, T, or A bases. Recently, a more advanced fidelity and efficiency base editor called nNme2-CBE (discovered from Neisseria meningitides ) with expanded PAM compatibility for cytidine dinucleotide has been developed in both human cells and rabbits embryos. 41 The ABE uses adenosine deaminase fused to dCas-9 to correct the base-pair change from adenosine (A) to guanosine (G). 38 Overall, single-base editing through the fusion of dCas-9 to cytidine deaminase or adenosine deaminase is a safe and efficient method to edit point mutations. But both base editors can only fix four-transition mutations (purine to purine or pyrimidine to pyrimidine). 42 To overcome this shortcoming, the most recent member of the CRISPR genome editing toolkit called Prime Editor (PE) has been developed to extend the scope of DNA editing beyond the four types of transition mutations. 43 PE contains Cas-9 nickase fused with engineered reverse transcriptase and multifunctional primer editing guide RNA (pegRNA). The pegRNA recognizes the target nucleotide sequence; the Cas-9 nickase cuts the non-complementary strand of DNA three bases upstream from the PAM site, exposing a 3ʹ-OH nick of genomic DNA. The reverse transcriptase then extends the 3ʹ nick by copying the edit sequence of pegRNA. Hence, PE not only corrects all 12 possible base-to-base transitions, and transversion mutations but also small insertion and deletion mutations in genetic disorders. 44

Therapeutic Role of CRISPR/Cas-9

The first CRISPR-based therapy in the human trial was conducted to treat patients with refractory lung cancer. Researchers first extract T-cells from three patient’s blood and they engineered them in the lab through CRISPR/Cas-9 to delete genes ( TRAC , TRBC , and PD-1 ) that would interfere to fight cancer cells. Then, they infused the modified T-cells back into the patients. The modified T-cells can target specific antigens and kill cancer cells. Finally, no side effects were observed and engineered T-cells can be detected up to 9 months of post-infusion. 45 CRISPR/Cas-9 gene-editing technology could also be used to treat infectious diseases caused by microorganisms. 46 One focus area for the researchers is treating HIV, the virus that leads to AIDS. In May 2017, a team of researchers from Temple University demonstrated that HIV-1 replication can be completely shut down and the virus eliminated from infected cells through excision of HIV-1 genome using CRISPR/Cas-9 in animal models. 47 In addition to the approach of targeting the HIV-genome, CRISPR/Cas-9 technology can also be used to block HIV entry into host cells by editing chemokine co-receptor type-5 ( CCR5 ) genes in the host cells. For instance, an in vitro trial conducted in China reported that genome editing of CCR5 by CRISPR/Cas-9 showed no evidence of toxicity (infection) on cells and they concluded that edited cells could effectively be protected from HIV infection than unmodified cells. 48

Role in Agriculture

As the world population continues to grow, the risk of shortage in agricultural resources is real. Hence, there is a need for new technologies for increasing and improving natural food production. CRISPR/Cas-9 is an existing addition to the field since it has been used to genetically modify foods to improve their nutritional value, increase their shelf life, make them drought-tolerant, and enhance disease resistance. 18 There are generally three ways that CRISPR is solving the world’s food crisis. It can restore food supplies, help plants to survive in hostile conditions, and could improve the overall health of the plants. 49

Role in Gene Activation and Silencing

Beyond genome editing activity, CRISPR/Cas-9 can be used to artificially regulate (activate or repress) a certain target of a gene through advanced modification of Cas-9 protein. 15 Researchers had performed an advanced modified Cas-9 endonuclease called dCas-9 nuclease by inactivating its HNH and RuvC domains. The dCas-9 nuclease lacks DNA cleavage activity, but its DNA binding activity is not affected. Then, transcriptional activators or inhibitors can be fused with dCas-9 to form the CRISPR/dCas-9 complex. Therefore, catalytically inactive dCas-9 can be used to activate (CRISPRa) or silence (CRISPRi) the expression of a specific gene of interest. 50 Moreover, the CRISPR/dCas-9 can be also used to visualize and pinpoint where specifically the gene of interest is located inside the cell (subcellular localization) by fusing a marker such as Green Fluorescent Proteins (GFP) with dCas-9 enzyme. This enables site-specific labeling and imaging of endogenous loci in living cells for further utilization. 51

Challenges for CRISPR/Cas-9 Application

Despite its great promise as a genome-editing system CRISPR/Cas-9 technology had hampered by several challenges that should be addressed during the process of application. Immunogenicity, lack of a safe and efficient delivery system to the target, off-target effect, and ethical issues have been the major barriers to extend the technology in clinical applications. 52 Since the components of the CRISPR/Cas-9 system are derived from bacteria, host immunity can elicit an immune response against these components. Researchers also found that there were both pre-existing humoral (anti-Cas-9 antibody) and cellular (anti-Cas-9 T cells) immune responses to Cas-9 protein in healthy humans. Therefore, how to detect and reduce the immunogenicity of Cas-9 protein is still one of the most important challenges in the clinical trial of the system. 53

Safe and effective delivery of the components into the cell is essential in CRISPR/Cas-9 gene editing. Currently, there are three methods of delivering the CRISPR/Cas-9 complex into cells, physical, chemical, and viral vectors. Non-viral (physical and chemical) methods are more suitable for ex vivo CRISPR/Cas-9-based gene editing therapy. 54 The physical methods of delivering CRISPR/Cas-9 can include electroporation, microinjection, hydrodynamic injection, and so on. Electroporation applies a strong electric field to the cell membrane to temporarily increase the permeability of the membrane, allowing the CRISPR/Cas-9 complex to enter the cytoplasm of the target cell. However, the main limitation of this method is that it causes significant cell death. 55 Microinjection involves injecting the CRISPR/Cas-9 complex directly into cells at the microscopic level for rapid gene editing of a single cell. Nevertheless, this method also has several disadvantages such as cell damage, which is technically challenging and is only suitable for a limited number of cells. 56 The hydrodynamic injection is the rapid injection of a large amount of high-pressure liquid into the bloodstream of animals, usually using the tail vein of mice. Although this method is simple, fast, efficient, and versatile, it has not yet been used in clinical applications due to possible complications. 57 The chemical methods of CRISPR/Cas-9 delivery involves lipid and polymer-based nanoparticles. 58 Lipid nanoparticles/liposomes are spherical structures composed of lipid bilayers membrane and are synthesized in aqueous solutions using Lipofectamine-based reagents. The positively charged liposomes encapsulated with negatively charged nucleic acids thereby facilitate the fusion of the complex across the cell membrane into cells. 59 Polymeric nanoparticles, such as polyethyleneimine and poly-L-lysine, are the most widely used carriers of CRISPR/Cas-9 components. Like lipid nanoparticles, polymer-based nanoparticles can also transverse the complex in the membrane through endocytosis. 60

Viral vectors are the natural experts for in vivo CRISPR/Cas-9 delivery. 61 Vectors, such as adenoviral vectors (AVs), adeno-associated viruses (AAVs), and lentivirus vectors (LVs) are currently being widely used as delivery methods due to their higher delivery efficiency relative to physical and chemical methods. Among them, AAVs are the most commonly used vectors due to their low immunogenicity and non-integration into the host cell genome compared to other viral vectors. 62 However, the limited virus cloning capacity and the large size of the Cas-9 protein remain a major problem. One strategy to tackle this hurdle is to package sgRNA and Cas-9 into separate AAVs and then co-transfect them into cells. Recent methods employ a smaller strain of Cas-9 from Staphylococcus aureus (SaCas-9) instead of the more commonly used SpCas-9 to allow packaging of sgRNA and Cas-9 in the same AAVs. 54 , 61 Lately, the development of extracellular vesicles (EVs), for the in vivo delivery of CRISPR/Cas-9 to avoid some of the limitations of viral and non-viral methods has shown a great potential. 63

The designed sgRNA will mismatch to the non-target DNA and can result in nonspecific, unexpected genetic modification, which is called the off-target effect. 57 The CRISPR/Cas-9 target efficiency is determined by the 20-nucleotide sequences of sgRNA and the PAM sequences adjacent to the target genome. It has been shown that more than three mismatches between the target sequence and the 20-nucleotide sgRNA can result in off-target effects. 64 The off-target effect can possibly cause harmful events such as sequence mutation, deletion, rearrangement, immune response, and oncogene activation, which limits the application of the CRISPR/Cas-9 editing system for therapeutic purposes. 65 To mitigate the possibility of CRISPR/Cas-9 off-target effect, several strategies have been developed, such as optimization of sgRNA, modification of Cas-9 nuclease, utilization of other Cas-variants, and the use of anti-CRISPR proteins. 66 Selecting and designing an appropriate sgRNA for the targeted DNA sequence is an important first step to reduce the off-target effect. 67 When designing sgRNA, strategies such as GC content, sgRNA length, and chemical modifications of sgRNA must be considered. Generally speaking, studies revealed that GC content of between 40% and 60%, truncated (short length of sgRNA), and incorporation of 2ʹ-O-methyl-3ʹ-phosphonoacetate in the sgRNA ribose-phosphate backbone are the preferred methods to increase genome editing efficiency of CRISPR/Cas-9. 67 , 68 Modifying the Cas-9 protein to optimize its nuclease specificity is another way to reduce off-target effects. For instance, mutating either one of the catalytic residues of Cas-9 nuclease (HNH and RuvC) will convert the Cas-9 into nickase that could only generate a single-stranded break instead of a blunt cleavage. 69 It has been reported that the use of the inactivated RuvC domain of Cas-9 with sgRNA can reduce the off-target effect by 100 to 1500 times. 70 Moreover, the nuclease Cas-12a (previously known as Cpf1) is a type V CRISPR/Cas system that provides high genome editing efficiency. 71 Unlike the CRISPR/Cas-9 system, CRISPR/Cas-12a can process pre-crRNA into mature crRNA without tracrRNA, thereby reducing the size of plasmid constructs. The Cas-12a protein recognizes a T-rich (5ʹ-TTTN) PAM sequence instead of 5ʹ-NGG and provides high accuracy at the target gene loci than Cas-9. 69 Recently, the use of multicomponent Class I CRISPR proteins, such as CRISPR/Cas-3 and CRISPR/Cas-10 provides better genome editing efficiency than Cas-9. 72 The Cas-3 is an ATP-dependent nuclease/helicase that can delete a large part of DNA from the target site without prominent off-target effect. For instance, the DMD gene were repaired by Cas-3-mediated system in induced pluripotent stem cell. 73 The Cas-10 protein does not require the PAM sequence and can identify sequences even in the presence of point mutation. 72 Anti-CRISPR (Acr) proteins are phage derived small proteins that inhibit the activity of CRISPR/Cas system. They are a recently discovered method to reduce off-target effects of CRISPR/Cas-9. 74 From Acr proteins, AcrIIA4 specifically targets Cas-9 nuclease. AcrIIA4 mimics DNA and binds to the Cas-9 site, making impossible to perform further cleavage in area outside the target region. 75 Furthermore, CRISPR/Cas-9 gene editing has been challenged by ethics and safety all over the world. Since the technology is still in its infancy and knowledge about the genome is limited, many scientists restrain that it still needs a lot of work to increase its accuracy and make sure that changes made in one part of the genome do not have unforeseen consequences, especially in the application towards human trials. 52

Conclusions

CRISPR/Cas-9 system in nature is used to protect prokaryotes from invading viruses by recognizing and degrading exogenous genetic elements. CRISPR/Cas-9 gene editing is adopted from acquired immunity in prokaryotes and consists of two elements: guide RNA used to locate (bind) the target DNA to be edited and Cas-9, a protein that essentially cuts the DNA at the location identified by guide RNA. The fundamental part of the CRISPR/Cas-9 gene-editing process is the identification of the target gene that determines the phenotype of interest and designing the guide RNA. Now it becomes a new era in molecular biology and has countless roles ranging from basic molecular researches to clinical applications. Although tremendous efforts have been made, there are still some challenges to rub in the practical applications and various improvements are needed to overcome obstacles in order to assure its maximum benefit while minimizing the risk.

Funding Statement

No funding was received.

Abbreviations

AAVs, adeno-associated viral vectors; ABE, adenine base editor; Acr, anti-CRSPR; AVs, adeno-viral vectors; ATP, adenosine tri-phosphate; BCL11A, B-cell lymphoma 11 A; CAS-9, CRISPR-associated protein-9; CBE, cytidine base editor; CCR5, chemokine receptor type 5; CFTR, cystic fibrosis conductance transmembrane receptor; CRISPR, clustered regularly interspaced short palindromic repeat; CrRNA, CRISPR ribonucleic acid; DMD, Duchenne muscular dystrophy; DNA, deoxyribonucleic acid; DSBs, double-stranded breaks; HDR, homology-directed repair; LVs, lentivirus vectors; NHEJ, non-homologous end Jjining; PAM, protospacer adjacent motif; PD-1, programmed cell death-1; RNA, ribonucleic acid; TALENs, transcriptionactivator like effector nucleases; TRAC, T-cell receptor alpha; TRBC, T-cell receptor beta; TracrRNA, trans-activating CRISPR ribonucleic acid; ZFNs, zinc finger nucleases.

Ethics Approval and Consent to Participate

Not applicable.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors declare that they have no conflicts of interest for this work.