Heritable Genome Editing
This page assembles the sections of the Guidelines that specifically address research involving heritable genome editing. Other sections of the Guidelines may be relevant to such research (e.g., Section 2.1 Review Process, Section 2.3 Procurement and Informed Consent of Human Biological Materials, and Chapter 3. Clinical Translation of Stem Cell-based Interventions).
2.2.2 Category 2
2.2.2 Category 2. Forms of research with embryos, certain chimeras, and stem cell-based embryo models that are permissible only after review and approval through a specialized scientific and ethics review process. A comprehensive review should be coordinated with other relevant oversight, such as that provided by human subjects review committees, in vitro fertilization (IVF) clinic oversight bodies, and animal research review processes (see 2.2.1), and the research should comply with local law and policy. All such research should have a compelling scientific rationale and necessitate the use of these materials rather than employ alternative models. The research should use the minimum number of embryos necessary to achieve the scientific objective. Forms of research requiring comprehensive review by a specialized review process encompass the following activities:
- Research involving the genetic alteration of human embryos or gametes used to make embryos in vitro.
2.2.3 Category 3
2.2.3A Category 3A. Research activities currently not permitted. Research under this category should not be pursued at this time because the approaches are currently unsafe or raise unresolved ethical issues. There may be valid reasons for undertaking the research in the future, but this should not proceed until the safety and ethical issues are resolved. Such research includes:
- Research in which human embryos that have undergone modification to their nuclear genome are transferred into or gestated in a human uterus. Genome-modified human embryos include human embryos with engineered alterations to their nuclear DNA and embryos generated from a human gamete that has had its nuclear DNA modified, when such modifications could be inherited through the germline. While there are valid reasons for pursuing this line of research, which may include situations where correcting a deleterious gene variant is the only way that prospective parents may have a genetically-related child (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020), conduct of such research will be dependent on appropriate policies, regulations, and oversight.
2.2.3B Category 3B: Prohibited research activities. Research under this category should not be pursued because of broad international consensus that such experiments lack a compelling scientific rationale or are widely considered to be unethical. Such research includes:
- Research in which human embryos produced by reprogramming of nuclei are implanted into a human or animal uterus (often referred to as human reproductive cloning).
Emerging Categories of Embryo Research That Merit Close Review: Heritable Genome Editing
Recommendation 22.214.171.124: Until there is further scientific clarity regarding how to achieve desired genetic alterations, additional evidence for safety, and wider discussion and consensus on ethics (i.e., whether it should be done and, if so, under which circumstances), any attempt to edit the mitochondrial genome or modify the nuclear genome of human embryos for the purpose of human reproduction is premature and should not be permitted at this time (see Section 2.2.3A, Category 3A, a).
Preclinical research that entails modifying the nuclear genomes of gametes, zygotes, and human embryos may be permissible under a rigorous specialized oversight process (Category 2). Such research promises to enhance fundamental knowledge and is essential to inform deliberations about the potential safety and use of nuclear or mitochondrial DNA genome editing in strategies aimed at preventing the transmission of serious genetic disorders.
Scientists currently lack an adequate understanding of the fidelity and precision of techniques for genome editing of human embryos, as well as a full appreciation of the safety, ethics, and potential long-term risks and benefits to individuals born following such a process. This is described in more detail in the recent report, Heritable Human Genome Editing, from the International Commission on the Clinical Use of Human Genome Editing (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020), which suggests a responsible translational pathway in certain circumstances, albeit one that cannot currently be met. Of note, the focus of this report was on developing a responsible translational pathway; it did not include a broad look at the societal and ethical issues, as these were outside its task. Such issues have been considered elsewhere (e.g. by the Nuffield Council on Bioethics). The forthcoming report from the WHO Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing will bear in mind societal views and ethical principles, but this will focus on mechanisms of governance.
Basic and preclinical research is needed to minimize the potential harms resulting from intended and unintended edits, which could be passed to future generations, as well as direct or indirect effects of the editing process that could affect embryo viability or developmental potential.
3.4.8 Clinical Research that Involves Heritable Changes to the Human Genome
Heritable Genome Editing
Recommendation 126.96.36.199.1: Substantial preclinical research is needed to minimize the potential harm associated with clinical applications involving heritable genome editing; therefore, any attempt to modify the nuclear genome of human embryos for the purpose of reproduction is premature and should not be permitted at this time (see Section 188.8.131.52, Category 3A, a).
Any decision to proceed with heritable genome editing, where modified human embryos are transferred into a uterus or otherwise allowed to develop in utero, must be preceded with adequate preclinical research to minimize the potential harms from intended and unintended edits (see Recommendation 2.1.4). The first-in-human clinical uses should only be considered for the most favorable balance of potential harms and benefits and this will be most clearly defined for diseases and patients for which there are no viable alternatives. This may include prospective parents for whom there are no or very limited available alternatives for preventing transmission of diseases and conditions for which mortality is high and morbidity is severe. Other options for having a healthy child, including adoption, gamete or embryo donation, and preimplantation genetic testing, should be considered with appropriate counselling prior to any decision to proceed.
Recommendation 184.108.40.206.2: If the technical and safety challenges associated with human heritable editing are resolved (see Recommendations 2.1.4 and 220.127.116.11.1), any applications for the initial clinical use of human heritable genome editing should be evaluated on a case-by-case basis. This evaluation needs to consider not just the scientific methods, but also the societal and ethical issues associated with the proposed use.
The decision to proceed with first-in-human clinical uses needs to be taken openly with robust consideration of informed public opinion generated through meaningful public engagement. In addition, and critically, any experimental use of heritable human genome editing should only proceed in jurisdictions with appropriate and robust regulations and oversight.
A key consideration of potential uses of heritable genome editing is whether the prospective parents have feasible options for conceiving a genetically related child who does not inherit a serious genetic disease, such as preimplantation genetic testing and selection of embryos. The initial uses should be confined to prospective parents who lack reasonable alternatives.
It is important that the biological consequences of the intended genome edit are well understood, both for the immediate offspring and for future generations who might inherit it, in order to minimize the potential for an intended edit to have unintended deleterious consequences (on its own, via genetic interactions with other loci, or via environmental interactions). At present, the best way to achieve this goal is to use editing to change a known pathogenic genetic variant to one that is present in unaffected family members, common in the relevant population, or known not to be disease-causing.
Recommendation 18.104.22.168.3: A comprehensive regulatory and ethical framework for overseeing heritable genome editing must be established before any first-in-human clinical applications are considered. This framework should build on the existing regulatory frameworks for new biotechnologies, the practice of medicine, and the principles outlined in these guidelines (see Section 3.3 and 3.4).
The regulatory framework for heritable genome editing must ensure that there is robust multi-generational follow-up to identify adverse reactions that may occur due to inherited genome alterations. However, this needs to be done in such a way as to protect the confidentiality of the prospective parents and any children born. The framework must ensure that there is a robust informed consent process that builds on the informed consent process discussed in these guidelines (see recommendations 22.214.171.124 and 126.96.36.199) and includes a discussion of potential alternative treatments (if any) and the multigenerational risks and benefits of pregnancies involving the implantation of germline genome edited embryos, including those derived from genetically modified gametes.
Recommendation 188.8.131.52.4: Regulators, research funders, and academic and medical societies should seek to prevent the premature or unethical clinical uses of heritable genome editing unless and until the safety, ethical, and societal issues associated with the clinical use of heritable genome editing are resolved.
It is incumbent upon the entire biomedical research community to monitor for potential unethical and premature clinical uses of human heritable genome editing technologies. Researchers are strongly encouraged to report potential unethical uses to regulators, funders, licensing bodies, and academic societies to evaluate potential unethical uses of this technology.