What Do We Really Think About Human Germline Genome Editing, and What Does It Mean for Medicine?

Genome editing has captured widespread attention because of its potential therapeutic applications. Early studies with human embryos have established the feasibility of human germline genome editing but raise complex social, ethical, and legal questions. In light of the potential impact of genome editing on the practice of cardiovascular medicine, we surveyed ≈300 attendees at a recent American Heart Association conference to elicit their opinions on somatic and germline genome editing. The results were revealing and highlight the need to broadly engage the public and solicit the opinions of various constituencies before proceeding with clinical germline genome editing. Genome editing with clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9 (CRISPR/Cas9) has proven so effective in vitro and in vivo that human therapeutic applications are already under pursuit. Clinical trials for somatic genome-editing therapies, that is, modification of cells, tissues, and organs in living people, have been announced in the United States and China. The first reports of human germline genome editing (GGE), that is, embryo modification, were published in 2015 and 2016, although those studies used nonviable embryos and relatively crude first-generation CRISPR/ Cas9 tools. A more recent report in August 2017 of GGE to correct a disease-causing gene mutation in viable human embryos that, in principle, could have been carried to term and resulted in healthy offspring was widely heralded in the press as a breakthrough and drew considerable attention. What was particularly notable about this study was that the correction of the mutation was efficient and specific—unlike the earlier studies, unintended mutations were not observed elsewhere in the genome (off-target effects) in edited embryos, and mosaicism (mutations present in some cells in the embryo but not in other cells) was largely eliminated. Furthermore, the relevance to cardiovascular medicine was unambiguous because the sperm used for the study originated from a man with severe hypertrophic cardiomyopathy, with the corrected mutation being in the cardiac myosin-binding protein C (MYBPC3) gene. In light of this study, it is clear that human GGE is now feasible and might be achieved for some genes without off-target effects. In addition to remaining safety concerns, the path to clinical use will now have to contend with important social, ethical, and legal issues. The future is on us, whether we like it or not. Recognizing the relevance and potential impact of these issues on the future practice of cardiovascular medicine, the American Heart Association Council on Functional Genomics and Translational Biology cosponsored a plenary session entitled Scientific, Clinical and Ethical Implications of Genome Editing at Arteriosclerosis, Thrombosis and Vascular Biology | Peripheral Vascular Disease Scientific Sessions in Minneapolis, MN, in May 2017. The objective of the session was to provide attendees with sufficient background on CRISPR/Cas9 genome editing so that they could then meaningfully explore and discuss how genome editing might be relevant to clinical practice. We (the authors) gave short presentations that covered the basic concepts of CRISPR/Cas9 genome editing; how CRISPR/Cas9 has transformed the way in which mouse models of human physiology and disease are made, making the process far more rapid and efficient; proof-of-concept studies demonstrating that CRISPR/Cas9 targeting of genes in the mouse liver can beneficially modify lipid traits, heralding possible one-shot, lifelong treatments for dyslipidemia and coronary heart disease; potential dangers of genome editing (eg, unintended mutations) and strategies to reduce those dangers; potential clinical scenarios in which one might contemplate performing GGE, including the preemption of devastating genetic diseases in one’s offspring, the reduction of risk of common disorders such as coronary heart disease and Alzheimer disease, and the addition of desired nonmedical traits (enhancements); the possibility of implementing GGE not in embryos but rather in germ cells such as sperm and oocytes, which might be less morally objectionable to some people; and potential adverse consequences of modifying the human germline, such as spreading susceptibility to certain diseases or exacerbating societal inequities. In particular, it was pointed out that although many commentators have noted that in vitro fertilization paired with preimplantation genetic diagnosis can often avoid any need for GGE, there are situations where all unmodified embryos will yield offspring with disease—2 parents with a recessive disorder such as sickle cell disease or cystic fibrosis, or a parent homozygous or (Circ Cardiovasc Genet. 2017;10:e001910. DOI: 10.1161/CIRCGENETICS.117.001910.) © 2017 American Heart Association, Inc.