Policy ForumGenetic Technology Regulation

Editing policy to fit the genome?

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Science  22 Jan 2016:
Vol. 351, Issue 6271, pp. 337-339
DOI: 10.1126/science.aad6778

Balancing therapeutic prospects brought by scientific advances with regulation to address highly contested socioethical issues is the ultimate challenge in dealing with disruptive science. Human genome editing is a powerful tool that offers great scientific and therapeutic potential (1, 2). Yet, it rejuvenates socioethical and policy questions surrounding the acceptability of germline modification.

The first national research application for licensing genome editing in human embryos is about to be filed in the United Kingdom (3). This is a country offering robust oversight, while also adopting a bold approach toward innovative science. At the same time, a revised pan-European regulation on clinical trials will come into effect in May of 2016 that would continue a prohibition on carrying out gene therapy clinical trials that “result in modifications to the subject's germ line genetic identity” (4). “Genetic identity,” however, has yet to be defined, and we need to look for an approach to genome editing that can lead toward compromise or consensus.

Defining the contours and diversity of national policy frameworks governing the human germ line is difficult. The permissibility of conducting research on clinical applications of genome editing on early human development is often considered part of the regulatory approaches to assisted human reproductive technologies, stem cells, or genomic research. Similarities and differences between approaches also need to be considered. Internationally, policies extend across a continuum that distinguishes between degrees of permissiveness, that is, between legally binding legislation and regulatory and/or professional guidance or research versus clinical applications. We drew on a representative sample of 16 countries to provide a global ”snapshot” of the spectrum of policy and legislative approaches (restrictive to permissive) regarding human germline editing, human embryonic stem cell research, human reproductive cloning, human research cloning, human somatic gene therapy, and pre-implantation genetic diagnosis (see the figure). Our sample also represents countries in which innovative research in the fields of genomics and stem cells is being carried out and/or that are hot spots for stem cell and reproductive tourism. For each technology, we showed whether it is being governed by laws (legislation) or by normative documents and policies (regulatory).

Where legislation has been adopted either prohibiting or restricting germline interventions, it is mostly accompanied by criminal sanctions ranging from hefty imprisonment terms to fines (e.g., Australia, Belgium, Brazil, Canada, France, Germany, Israel, Netherlands, and United Kingdom). However, such restrictive legislation frequently requires that there be intentionality on the part of the individual (mens rea). For example, legislation adopted in Australia targets the intentional alteration of “the genome of a human cell in such a way that the alteration is heritable by descendants or the human whose cell was altered” (5, 6). It further criminalizes intentionally placing “an embryo in the body of a woman knowing that, or reckless as to whether, the embryo is a prohibited embryo.” Under Australian law, an embryo with an altered germ line or an embryo created solely for research purposes is considered a “prohibited embryo” (5, 6). The intentionality provision has created a degree of policy uncertainty, particularly in terms of downstream restrictions on certain applications, such as clinical uses.

Restrictive policy approaches also usually include upstream limitations, which outlaw a technology or an application regardless of its purpose by means of tight regulations, blanket prohibitions, or moratoria. These types of restrictions are exemplified in broad, bottom-up bans on human embryo and/or germline manipulations, embryo genetic testing, and somatic cell nuclear transfer technologies. Germany and Canada have adopted upstream criminal bans on germline interventions and also restrict embryo research.

Nonetheless, some enacted prohibitions can be rendered ineffective or inadequate in practice, such as when the scope of laws focuses on a particular technology that is later outpaced by scientific developments. Similarly, prohibitions will be limited if exceptions are allowed. This is the case for provisions that, although aiming to adopt a restrictive approach toward embryo research, allow for interventions deemed therapeutically beneficial to the embryo or necessary for the preservation of its life, or are required in order to achieve a pregnancy (e.g., Belgium, Germany, and France). The vague language of such provisions means they would become obsolete once the particular intervention is considered standard clinical practice (7, 8). Legal uncertainty comes into play when dealing with medical innovation.

Finally, restrictive policies signal a critical attitude toward science because of fears of commodification of potential human life, and they advocate for strong government intervention in the regulation of research.

The most frequent approach is intermediate. Hereunder, the application of genomic technologies in embryos and germ cells is allowed but closely monitored by governments (8) with the goal of providing efficient and safe mechanisms for conducting research. In the context of genome editing, a particular technology or an intervention is not banned per se. Rather, specific downstream applications are forbidden, such as attempting to initiate a human pregnancy with an embryo or a reproductive cell whose germ line has been intentionally altered (e.g., France, Israel, Japan, and Netherlands). In sum, reproductive purposes are typically outlawed, whereas scientific research activities, such as investigating basic biology or aspects of the methodology itself are generally permitted.

A few countries have permissive approaches that aim to promote scientific progress with the belief that it is beneficial for humanity. Here, a wide range of activities are permitted, provided that governance is observed, mostly by means of de facto or case-by-case approval by a licensing authority. Illustrative examples of this approach are found in policies adopted in the United Kingdom and China, where conducting research for reproductive purposes is permitted and potential clinical applications are not explicitly outlawed. Given that governance depends on different approvals or licensing agencies deciding on a case-by-case basis, there is a risk of arbitrary applications or inconsistencies. In addition, when governed by guidelines or professional codes alone, without effective enforcement mechanisms, the risk is to end up (or to be perceived) as self-serving and as following a consumer model (e.g., Mexico, or state-level regulations found in the United States) (7).

Representative country policies toward genome-related technologies.

The sources for all the information shown are listed in the supplementary materials.


OVERARCHING ISSUES. One problem that can be seen in all of the approaches described is vagueness in distinctions between clinical and research applications, as well as in basic definitions. There is considerable uncertainty over whether already existing bans on genome editing in embryos and germ cells for clinical purposes (e.g. to induce a pregnancy) also encompass a prohibition to conduct research, including reproductive research (such uncertainties can be found in the laws of China, France, Israel, Netherlands, South Korea, and United Kingdom). Israeli legislation forbids “using reproductive cells that have undergone a permanent intentional genetic modification (germline gene therapy) in order to cause the creation of a person” (9) although a license may still be obtained “for certain types of genetic intervention” provided that “human dignity will not be prejudiced” (9). In the United Kingdom “altering the genetic structure of any cells while it forms part of an embryo” (10) is banned unless licensed.

In the majority of cases, we have analyzed, vague or narrow terminology has inadvertently created barriers or ambiguities that may allow for interpretations or practices to circumvent or hinder the intent of the policy, without violating its literal interpretation. For example, legislation adopted in Belgium prohibits carrying out “research or treatments of eugenic nature that is to say, focused on the selection or amplification of non-pathological genetic characteristics of the human species” (11). In turn, French law creates a new category of criminal offense, typified as “crimes against the human species” (12, 13). To that end, it states that “no person may undermine the integrity of the human species” and bars “carrying out a eugenic practice aimed at organizing the selection of persons” (12, 13). However, no further guidance is provided as to what constitutes a eugenic practice or what should be the spectrum of permissibility (if any) with regards to the selection of human traits.

Terminological debates on what constitutes a “human embryo” or a “reproductive cell” are ongoing in many countries (8). As a result, in some jurisdictions a human embryo is an entity determined by a particular point in time (e.g., Australia, Canada, Singapore) or, established by its capacity to develop into an individual or a human being (e.g., Belgium, Japan, Germany, Netherlands). Similar scenarios are present with respect to what constitutes a germ line. We believe that scientific understanding and precision in legal definitions of what constitutes a human embryo and/or its germ line are essential to developing coherent policies.

SETTING THRESHOLDS. The recent spate of policy activity by professional organizations, funding and regulatory agencies appears to be converging on an intention to “advance cautiously.” What this entails has yet to be clearly articulated. For some, caution means maintaining a vigilant attitude while evidence mounts for the benefits and risks of the technology together with their social implications. For others, caution entails adopting tiered approaches, for example, by temporary, self-regulatory moratoria or funding restrictions (1416). What remains elusive is the determination of thresholds for acceptability (17, 18).

Preimplantation genetic diagnosis (PGD) was first regarded as highly controversial (19) and now is mainly governed within the general biomedical research context. Many countries allow genetic testing in preimplantation embryos subject to governance and according to substantive, medically determined requirements [see figure and (19)]. The development and evolution of PGD policies, together with their medical and social uptake, may provide a suitable model for defining research and, eventually, clinical reproductive applications of genome editing.

Medical determinations for PGD have most commonly depended on the “gravity” of the genetic condition (i.e., “serious” or “severe”) or whether the condition is “untreatable.” This gravity threshold was adopted in Mexican legislation in the context of criminalizing genetic manipulation. Under the Penal Code of the Federal District of Mexico, human genetic manipulation is prohibited when its purpose is other than “the elimination or reduction of serious diseases or defects” (20). Similarly, the Singaporean Bioethics Advisory Committee in 2015 reiterated “that the clinical practice of germline modification be prohibited, pending scientific evidence that techniques to prevent or eliminate serious genetic disorders have been proven effective” (21).

Some countries (e.g., United Kingdom, Canada, Australia, Israel, Netherlands, and Japan) (19, 22) have added a “substantial risk” of occurence qualifier to the determination of gravity for PGD, which imposes another filter affecting acceptability. The degree or probability of risk has not been further defined in any jurisdiction. Even more controversial is the requirement of allowing PGD only to prevent the risk of transmission of “untreatable” and “incurable” diseases to descendants. These concepts remain vaguely articulated in both professional guidelines and in national legislation.

The Hinxton Group has proposed a self-regulatory approach that indirectly applies this PGD model to genome editing. The group, without endorsing any particular intervention, or particular policy model, maintains that a plausible spectrum of permissibility might range from correction of serious, early-onset or late-onset disease-causing mutations (e.g., Tay-Sachs, cystic fibrosis, or Huntington's disease), through the introduction of known disease-preventing changes (e.g., against HIV infection), to nonmedical enhancements (e.g., increased muscle mass) (23).

In a recent statement, the International Summit on Gene Editing noted a proposed array of applications for germline editing in clinical research and therapy. They ranged from the avoidance of severe inherited diseases to “enhancement” of human capabilities. The statement concluded that it would “be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved…and (ii) there is broad societal consensus about the appropriateness of the proposed application.” Ongoing appraisal of scientific advances and societal views was also recommended (16).

We maintain that the thresholds the PGD model delineates for medical determinations and substantial risk of occurrence (albeit still relatively flawed and contentious) represent a robust approach to regulation. However, precision in language and understanding will also be necessary in order to move forward in this context.

Many questions still remain to be addressed. Are there defensible uses for genome editing so as to select, or deselect, certain human traits? Will conferring immunity against disease or the reparation of a deleterious gene be considered enhancement? Are there any thresholds for nonmedical interventions?

Public acceptance may change as the benefits of genome editing emerge for disease prevention. Eventually, as we move from research to the clinic, the collective sum of individual decisions could constitute a de facto policy. However, we believe that the task of adopting policy guidance for the acceptability (if at all) of germline interventions is more than just editing policy to fit individual genomes or circumstances.

References and Notes

  1. Regulation No. 536/2014 of the European Parliament and the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC…. (2014).
  2. Australia, Prohibition of Human Cloning for Reproduction and the Regulation of Human Embryo Research Amendment Act, Act no. 172 (2006).
  3. Australia, Prohibition of Human Cloning for Reproduction Act 2002 (last amended by Act no. 144), (2008).
  4. Israel, Prohibition of Genetic Intervention (Human Cloning and Genetic Manipulation of Reproductive Cells) Law (1999) (last renewed), (2009).
  5. United Kingdom, Human Fertilisation Act (1990) (last amended), (2008).
  6. Belgium, Act on Research on Embryos in Vitro-Loi du 11 Mai Relative a la Recherché sur les Embryons in Vitro (2003).
  7. France, Bioethics Law/Loi No. 2004-800 du 6 août 2004 relative à la bioéthique (last amended), (2009).
  8. France, Code Civil (1804) re the Bioethics Law (last amended), (2015).
  9. Organizing Committee for the International Summit on Human Gene Editing, International Summit Statement, 1 to 3 December 2015, Washington, DC (National Academies, Washington, DC, 2015) http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a.
  10. Penal Code of the Federal District of Mexico (Mexico DF) (2002) (last amended), (2014).
  11. Bioethics Advisory Committee of Singapore, Ethics Guidelines for Human Biomedical Research (Singapore, 2015).
  12. The Hinxton Group, Statement on Genome Editing Technologies and Human Germline Modification (2015); www.hinxtongroup.org/hinxton2015_statement.pdf.
  13. Acknowledgments: Partially supported by the EUCelLEX EU-FP7 Program, Grant Agreement No. 601806 and the Canada Research Chair in Law and Medicine, McGill University. We thank S. L. Zuchner for comments and suggestions. The opinions expressed above are those of the authors alone.
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