Ongoing reassessment and public participation should precede any clinical trials of heritable germline editing (7.2) Incorporate public participation into the human genome editing policy process about “enhancement” (7.3) When funding genome editing research, consider including research on strategies to improve public engagement (7.4) and for long-term assessment of ethical, legal and social implications of human genome editing (7.5) Copyright © National Academy of Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance PREPUBLICATION COPY—SUBJECT TO FURTHER EDITORIAL REVISION 11 1 Introduction Genome editing6 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 editing somatic cells to restore normal function in diseased organs to editing the human germline to prevent genetic diseases in future children and their descendants. As with other medical advances, each application comes with its own set of benefits, risks, regulatory questions, ethical issues, and societal implications. Important questions raised with respect to genome editing include how to balance potential benefits against the risk of unintended 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 (NAS) and the National Academy of Medicine (NAM)7 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 for use in agriculture and nonhuman animals,8 this committee’s task (see Box 1-1) was focused on 6 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. 7 The NAS and the NAM are referred to throughout this report simply as the National Academies, or the U.S. National Academies when discussed in relation to the academies of other nations. Until 2016, the NAM was known as the Institute of Medicine (IOM). 8 In January 2017, the FDA issued revised draft guidances addressing the regulatory pathway for intentionally altered genomic DNA in plants and non-human animals. This would include DNA intentionally altered through genomic editing. The guidances do not affect the regulatory pathway for human applications that are regulated as human Copyright © National Academy of Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance 12 HUMAN GENOME EDITING PREPUBLICATION COPY—SUBJECT TO FURTHER EDITORIAL REVISION human applications.9 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. BOX 1-1 Statement of Task The study will examine the scientific underpinnings as well as the clinical, ethical, legal, and social implications of the use of human genome editing technologies in biomedical research and medicine. It will address the following issues related to human gene editing, including editing of the human germline: 1. What is the current state of the science of human gene editing, as well as possible future directions and challenges to further advances in this research? 2. What are the potential clinical applications that may hold promise for the treatment of human diseases? What alternative approaches exist? 3. What is known about the efficacy and risks of gene editing in humans, and what research might increase the specificity and efficacy of human gene editing while reducing risks? Will further advances in gene editing introduce additional potential clinical applications while reducing concerns about patient safety? 4. Can or should explicit scientific standards be established for quantifying off-target genome alterations and, if so, how should such standards be applied for use in the