The British love to regulate. We have a long history of developing novel regulations governing numerous areas of society, from finance and food to technology and transport. Health care in particular has kept statutory draftsmen busy for many decades, and the United Kingdom has not shrunk from regulating novel (and sometimes controversial) therapies and technologies. It was one of the first jurisdictions in the world to develop a comprehensive framework for the regulation of in vitro fertilization (IVF) and embryo research, and U.K. law addresses human cloning, preimplantation genetics, stem cell research, and gene therapy—among many other areas.
Of course, the United Kingdom’s passion for regulation pales into insignificance next to the regulatory fervor of the European Union (EU). The EU has also been particularly keen to protect the health of its citizens, and so a large body of EU law has evolved which seeks to ensure that therapies (including tissue – and cell-based therapies) are safe and efficacious.1
In this context of enthusiastic regulation, it is perhaps unsurprising that gene editing fits relatively comfortably within the existing U.K. regulatory landscape for research and therapy (whether as a result of national or EU law). Notably, however, very different regulations apply depending on whether the technology is applied to somatic or embryonic cells. This article briefly considers both regulatory frameworks, though it focuses on the regulation of gene editing in human embryos due to its more complex and controversial legal questions.
Somatic Cell Gene Editing
The medical possibilities, whether real or imagined, using somatic cell gene editing are seemingly endless—from resolving the human organ shortage to curing cancer, and the repair or removing of mutations that could cause disease. Gene editing is not a new discovery; however, the recent development of techniques such as CRISPR/Cas9 enable the genome to be edited cost-effectively at precise locations in specific ways.
In the United Kingdom, the use of somatic cell gene editing in humans is regulated under the advanced therapy medicinal products (ATMP) legal framework, which has its foundations in EU law. The EU’s ATMP Regulation2 amended the existing EU Medicinal Products Directive3 by introducing a new category of medicinal product, the ATMP, with a view to harmonizing the regulation of advanced therapies within Europe. An ATMP is any of the following intended for human use:
- A gene therapy medicinal product (GTMP);
- A somatic cell therapy medicinal product (sCTMP); or
- A tissue-engineered product (TEP).4
Each of these could contain gene-edited cells.
ATMPs that are placed on the market in the EU must have a marketing authorization, and the ATMP Regulation established a tailored regime for the evaluation and granting of marketing authorizations for ATMPs, managed by the European Medicines Agency (EMA). The manufacture of ATMPs in the United Kingdom also needs to be authorized by the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA), and manufacturers must show that they comply with the applicable principles of good manufacturing practice (GMP). There are also a range of specific requirements relating to distribution, clinical trials, and pharmacovigilance.5
There are, however, two ways in which ATMPs may be made available in the United Kingdom without a marketing authorization: the “hospital” exemption (which is specific to ATMPs) and the “specials” exemption (which may apply to any medicinal product). Among other requirements, the hospital exemption may be relied upon for an ATMP that is custom-made to meet an individual medical prescription for a patient; similarly, the specials exemption may apply where the ATMP has been created for an individual patient. By their very nature, gene-edited cells are created for an individual, and therefore it is likely that these exemptions will be relied upon to allow the therapeutic use of gene-edited somatic cells without the need for further regulation (though hospitals require a license from the MHRA to rely on either the hospital or specials exemption).
Gene Editing in Human Embryos
The creation, storage, and use of human embryos outside the human body is tightly regulated in the United Kingdom under a legislative framework designed in the 1980s and implemented through the Human Fertilisation and Embryology Act 1990 (1990 Act). The same 1990 Act also regulates all research involving human embryos. The use of embryos in treatment and research must be conducted under a license granted by a statutory regulator, the Human Fertilisation and Embryology Authority (HFEA), and unlicensed research or treatment (or activity outside the terms of a license) is a criminal offense.
The HFEA grants separate research and treatment licenses, briefly considered in the context of germline gene editing below.
Gene Editing: Research
With some very limited exceptions, the 1990 Act does not regulate the use of specific techniques in research: there is no statutory provision regarding gene editing in human embryos for research, nor is there any prohibition of such research. Instead, the regulations focus on the purpose of proposed research projects. Applications for an HFEA research license must demonstrate that the proposed project is “necessary or desirable” for one of a number of statutory purposes, which include:
- Increasing knowledge about or developing treatments for serious diseases or serious medical conditions;
- Increasing knowledge about the causes of any congenital disease or congenital medical condition;
- Increasing knowledge about causes of miscarriages;
- Developing methods for detecting presence of gene, chromosome, or mitochondrion abnormalities in embryos before implantation;
- Increasing knowledge about the development of embryos; or
- Promoting advances in the treatment of infertility.6
In addition, the license application must explain why it is necessary (not merely desirable) to use human embryos, as opposed to another source of material. The applicant must also show evidence of ethics approval from a recognized research ethics committee.
If these requirements are fulfilled, the HFEA may grant a license permitting research involving human embryos. The HFEA has recently followed this statutory process in granting a research license to the Francis Crick Institute in London permitting the use of CRISPR/Cas9 in human embryos for the purposes of developing treatments for serious disease, increasing knowledge about the development of embryos, and promoting advances in the treatment of infertility.7
It is a condition of all HFEA research licenses that embryos used or created under the license cannot be used in treatment. It follows that, if a gene editing technique is applied to an embryo pursuant to an HFEA license, that embryo could not lawfully be implanted—indeed, to do so would constitute a criminal offense.
It is also an offense to keep or use an embryo after 14 days from creation or from the appearance of the primitive streak (if that appearance is earlier than the 14-day period). There is therefore a statutory limit on the duration of research, though there have been recent calls for this 14-day limit to be extended.8
Gene Editing: Treatment
The 1990 Act has withstood the test of time remarkably well in a fast-paced area of scientific and clinical development. In 2008, however, it was amended to bring the legislation up to date. At the same time, Parliament introduced a new approach to the regulation of IVF treatment that relies upon the concept of “permitted” gametes and embryos.9 An embryo is a permitted embryo if “no nuclear or mitochondrial DNA of any cell of the embryo has been altered.”10 Under section 3 of the 1990 Act (as amended), only a permitted embryo may be transferred to a woman. It therefore follows that if the DNA of an embryo has been altered through the application of a gene editing technology, the embryo is not a permitted embryo and could not be lawfully used in treatment. There is a further restriction in schedule 2 of the 1990 Act which states that an HFEA treatment license “cannot authorise altering the nuclear or mitochondrial DNA of a cell while it forms part of an embryo.” Through this somewhat circuitous route, U.K. law prohibits the use of germline gene editing as a reproductive technology.
There is a noteworthy postscript to this explanation. As a result of the progress that had been made in research into the use of mitochondrial donation technologies to prevent the transmission of mitochondrial disease, Parliament was persuaded to include a power in the 2008 amendments to enable the Secretary of State for Health to allow an embryo that had been subject to a process “designed to prevent the transmission of serious mitochondrial disease” to be a permitted embryo.11 That power was utilized in 2015, permitting the HFEA to grant licenses for the use of mitochondrial donation in treatment.12 No such power was included to allow for the use of gene editing technologies (nor for any process that would alter the nuclear DNA of an embryo). The lawful use of gene editing in treatment would therefore require a change to the primary legislation, requiring further parliamentary debate.
The European Context and Eugenics
As the above extracts illustrate, U.K. legislation is generally drafted in objective and unemotional terms. While there may be underlying principles and ideals, these are seldom articulated in the legislation itself. This is largely true of the 1990 Act in its approach to the regulation of embryo research and reproductive technologies, including reproductive genetics.13 By contrast, other European countries have adopted legislation that seeks to prohibit germline interventions and “eugenic” practices. For example, Belgian law includes a prohibition on “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,” and French law prohibits “carrying out a eugenic practice aimed at organising the selection of persons.”14 Such terminology is capable of a wide variety of interpretations, creating uncertainty around the application of such principles to new technologies such as gene editing.
Certain EU legislation features similar terminology. The EU Clinical Trials Directive, for example, prohibits trials that “result in modifications to the subject’s germ line genetic identity,” and it has been suggested that this might prevent clinical trials in the EU involving the application of gene editing technologies to human embryos.15 The Directive, however, concerns clinical trials “on medicinal products for human use,” whereas gene editing in an embryo involves the application of a process or technique. Furthermore, editing the DNA of an embryo does not create a “product,” let alone a “medicinal product.”
Similarly, the Charter of Fundamental Rights of the EU (Charter) includes the right to the “integrity of the person,” which includes a prohibition of “eugenic practices, in particular those aiming at the selection of persons.”16 During the passage of the Mitochondrial Donation Regulations through the U.K. Parliament, it was argued by those opposed to the draft legislation that this prohibition extended to mitochondrial donation techniques, and it is predictable that the same argument may be made in relation to gene editing technologies. As with the Clinical Trials Directive, however, the concern is—in my view—misplaced. This prohibition was included in the Charter on the recommendation of the European Group on Ethics in Science and New Technologies to address two concerns:
• Practices which involve for instance forced sterilisation, forced pregnancies or abortions, ethnically enforced marriages, etc, all acts which are expressly regarded as international crimes by the Statute signed in Rome on July, 18, 2000 to create the permanent International Criminal Court.
• Eugenics . . . may also involve genetic manipulations on human beings such as the modification of the germ line in view of enhancement, without any therapeutic aim.17
This touches on an important distinction which is lacking from many legislative and policy instruments that seek to regulate in this field, namely the distinction between the therapeutic and nontherapeutic application of a technology. In the United Kingdom, the use of genetic technologies (such as preimplantation genetic diagnosis and mitochondrial donation) may only be licensed for use in a therapeutic context where there is a significant risk that a child will otherwise inherit a serious genetic disorder. In the event that the editing of embryonic DNA is made lawful in the United Kingdom in the future, it is very likely that similar restrictions will be imposed.
The U.K. regulatory landscape for gene editing requires careful navigation. While sometimes complex, however, it provides a mature, comprehensive, and facilitative environment for research and therapy. The U.K. framework operates to protect patients from unregulated, untested treatments and ensures that both researchers and clinics are licensed and regularly inspected, thus reassuring the public, media, and parliamentarians that the field is properly monitored.
Such a robust framework is particularly valuable when it comes to the application of gene editing technologies to human embryos. In circumstances where U.K. law is comprehensive and clear in its application to gene editing, there is no need to implement a moratorium on the use of this technology in embryos, as has been advocated in certain quarters.18 The strength of this framework is reflected in the successful history of the regulation of preimplantation genetics and mitochondrial transfer in the United Kingdom. This success, however, was built upon a vital foundation of open and accessible dialogue between researchers, clinicians, policymakers, and the public, and it is to be hoped that a similar transparency will be maintained around gene editing research as it continues to develop.
1. At the time of writing, the United Kingdom’s membership in the EU appears to be doomed (though a notable body of U.K. constitutional lawyers are of the view that Brexit cannot in fact be so readily implemented without further steps). Given the uncertainty surrounding both the practical consequences and the time frame for Brexit, this article focuses on the position as it stands with regard to applicable EU legislation.
2. Council Regulation 1394/2007, 2007 O.J. (L 324) 121 (EC) [hereinafter ATMP Regulation].
3. Council Directive 2001/83/EC, 2001 O.J. (L 311) 67 [hereinafter Medicinal Products Directive].
4. ATMP Regulation, supra note 2, at art. 2(1)(a).
5. A third regulator, the U.K. Human Tissue Authority, also licenses the procurement, testing, processing, storage, distribution, and import/export of tissues and cells intended for human application (subject to a range of qualifications and exceptions).
6. Human Fertilisation and Embryology Act, 2008, c. 22, sch. 2 (U.K.).
7. The minutes of the HFEA Licence Committee are available at http://guide.hfea.gov.uk/guide/ShowPDF.aspx?ID=5966.
8. Ian Sample, Researchers Break Record for Keeping Lab-Grown Human Embryos Alive, Guardian, May 5, 2016, https://www.theguardian.com/science/2016/may/04/scientists-break-record-for-keeping-lab-grown-human-embryos-alive.
9. Human Fertilisation and Embryology Act, supra note 6, § 3ZA.
12. Human Fertilisation and Embryology (Mitochondrial Donation) Regulations, 2015, S.I. 2105/572 (U.K.).
13. One exception is the “welfare of the child” requirement enshrined in section 13 of the 1990 Act.
14. See Loi relative à la recherche sur les embryons in vitro [Act on Research on Embryos in Vitro] of May 11, 2003, Moniteur Belge [M.B.] [Official Gazette of Belgium], May 28, 2003, 29287; Loi 2004-800 du 6 août 2004 relative à la bioéthique [Law 2004-800 of August 6, 2004 on Bioethics], Journal Officiel de la République Française [J.O.] [Official Gazette of France], Aug. 7, 2004, p. 14040. For an in-depth analysis of global policies relating to the regulation of gene editing technologies, see R. Isasi et al., Editing Policy to Fit the Genome?, 351 Sci. 337 (2016).
15. Council Directive 2001/20/EC, art. 9(6), 2001 O.J. (L 121) 34 [hereinafter Clinical Trials Directive].
16. Charter of Fundamental Rights of the European Union, art. 3(2), 2000 O.J. (C 364) 1, 9.
17. Draft Charter of Fundamental Rights of the European Union, Charte 4370/00, Contrib 233, p. 21 (emphasis added).
18. See, e.g., Edward Lanphier et al., Don’t Edit the Human Germ Line, 519 Nature 410 (2015).