CRISPR-Cas9 is a gene editing tool that has been the subject of considerable ethical debate since researchers at Sun Yat-sen University in Guangzhou used it in 2015 for germline editing in non-viable human embryos. Their research specifically involved modifying genes implicated in the development of β-thalassemia, a blood disorder that limits hemoglobin production [1]. Following the publication of this study, many bioethicists and other stakeholders called for a voluntary moratorium on human germline gene editing. One of the concerns associated with therapeutic applications of germline editing is the potential to affect multiple generations. This concern is not associated with somatic gene editing, as those genetic changes cannot be passed onto offspring. When obtaining informed consent to treat patients with somatic cell gene editing techniques, associated risks and benefits will only affect the patient in question. However, with germline editing, risks and benefits can potentially affect multiple generations. There is currently no consensus on how information about a potentially multigenerational impact could be presented to a parent consenting for germline editing of their children [2].
It is also not clear that any current methods for germline editing present any therapeutic benefits over somatic cell line editing. In the 2015 study involving CRISPR-Cas9, all of the embryos involved exhibited mosaicism, and off target gene cleavages were also observed. The authors of this study indicated that further improvements of CRISPR-Cas9 would be needed for effective clinical application [1]. Concerns regarding possible multi-generational effects of a tool with imperfect fidelity and specificity provides a clear and generally accepted ethical case for holding off on therapeutic applications of CRISPR-Cas9 until improvements are made and more research is done [2].
Despite these concerns, in November of 2018, He Jiankui, a researcher at the Southern University of Science and Technology in Shenzhen, announced he had used CRISPR Cas-9 for germline editing in viable human embryos — specifically a pair of twins conceived via in vitro fertilization. The parents of the twins reportedly consented to the use of the gene editing tool, and in exchange, were given free fertility treatments. Given the lack of consensus of how to obtain informed consent for germline editing, it is unsurprising that He’s announcement of his work was met with a great deal of concern from bioethicists worldwide. Further causes for concern include the fact that He failed to register with a Chinese clinical trial registry until well after he claimed to have started his research, and the glaring potential for coercion associated with the offer of free fertility treatment [3].
Furthermore, He’s experiment involved altering the CCR5 gene in a way that would theoretically protect against HIV infection. While the father of the twins was HIV positive, given the variety of existing strategies to minimize the risk of HIV transmission, many question why He choose this gene to edit. Furthermore, while alteration of the CCR5 gene can reduce risk of HIV infection, it increases risks associated with other viruses, including the West Nile and influenza viruses. Because CRISPR-Cas9 has been shown to produce mosaic embryos in previous research, it is also questionable how effectively altering the CCR5 gene with this tool would prevent HIV contraction in the relatively unlikely case the twins were exposed to the virus. Altogether, electing for germline editing of the CCR5 gene seems a rather bizarre choice, which further compounds concerns that the informed consent process for the parents involved in this experiment was subpar at best [3].
As He’s research has not yet been published in a peer-reviewed journal, it is unclear whether there is any validity to his claims about his use of CRISPR-Cas9. Some would certainly prefer a scenario where germline editing of viable human embryos has not yet been attempted, especially in such a cavalier manner. Nonetheless, his announcement has sparked new discussion of the many ethical concerns associated with germline editing — as well as the effectiveness of a voluntary moratorium on germline editing.
- Liang P, Xu Y, Zhang X, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363-372. doi:10.1007/s13238-015-0153-5
- Lanphier E, Urnov F, Ehlen Haecker S, Werner M & Smolenski J. Don’t edit the human germ line. Nature. 2015;519(7544):410-411. doi:10.1038/519410a
- Marchione M. Chinese Scientist Says He Made Gene-Edited Twins Using CRISPR Technology. The Associated Press. November 26, 2018.
Michelle Arnold is member of the The University of Arizona College of Medicine – Phoenix, Class of 2022. She received her Bachelor’s degrees in Biochemistry and Spanish from Arizona State University in 2015 and a Master’s degree in Applied Ethics and the Professions (Biomedical and Health Ethics) also from Arizona State University in 2017. She has interests in medical humanities, patient-provider relationships, and improving healthcare for underserved communities.