Navigating the Genomic Frontier: Balancing Promise and Prudence in Regulating Human Gene Editing in the United States

Gene editing has been a topic of debate for decades, with layers of controversy surrounding it. Despite the potential benefits gene editing can have in completely eliminating birth defects and curing diseases such as cancer, some claim that the possible complications could be even more detrimental (Gyngell et al., 2016). With the improvement of gene editing technology, the question regarding the extent of its regulation in humans in the US becomes even more relevant. In order to come to a conclusion, the science and safety of the different types of gene editing in humans must be evaluated.

According to Rasmus O. Bak and associates, researchers from Cellpress Reviews, gene editing has been around since the late 20th century, through the discovery of ZFNs and TALENs. These methods revolved around the principle that homologous recombination (HR) could improve resistance to disease, which can also be improved on by DSBs (double strand breaks). ZFNs and TALENs are created when zinc fingers and TAL effectors respectively “are fused to the endonucleolytic DNA cleavage domain of the Fok1 endonuclease” (Bak et al., 2018). The above methods of editing nucleotides paved the way for faster, more efficient methods, specifically the CRISPR/Cas9 system.

Jeremy Sugarman, a professor of bioethics and medicine at the Johns Hopkins Berman Institute of Bioethics, discussed the CRISPR/Cas9 system’s improvement on the gene editing process. The CRISPR/Cas9 system is an “efficient, inexpensive, and precise method to edit genes at the level of individual nucleotides” (Sugarman, 2015). It does so by using a 100-nucleotide sgRNA (single guide RNA) to direct the Cas9 endonuclease to a specific site, where it proceeds to cleave the chromosomal target (Bak et al., 2018). The creation of this system has led to the growth of genetic editing over the past few decades, which formed the foundation of today’s genome editing advances.

Gene Editing in Plants

Currently, the CRISPR/Cas9 system is becoming increasingly common in the agricultural industry, as seen by the increasing production of GMOs. In order to genetically modify plants, the CRISPR/Cas9 system uses different pathways to modify genes at specific loci (Mao et al., 2019). This resulted in the alteration of specific genes and preservation of others. Gene editing has mostly been applied to transformable plants, where a few transformed cells have the ability to regenerate the rest of the plant. To date, gene editing has proven to be mostly complication-free, and safe for plant health and human consumption.

Despite all of the upsides, there have been some complications regarding the CRISPR/Cas9 system in plants, specifically off-target mutations. On certain occasions, the Cas9/sgRNA complex can cut the wrong DNA sequences, which could alter parts of the genetic code of an organism. However, these occurrences in plant cells are extremely rare, as evidenced by “results from off-target mutations [of whole genome sequencing] in Arabidopsis, rice and tomato, [where] very limited off-target effects were identified” (Maoet al., 2019). Additionally, these types of errors can mostly be avoided through the use of guide RNA with more specific tools such as CRISPR-P and CRISPR-GE. (Mao et al., 2019; Yin et al., 2017). If these more specific methods are implemented in humans, they could also yield safer results.

Gene Editing in Humans

Gene editing extends beyond plants, with a plethora of potential applications in the human body, some of which are currently being tested. Gene editing has multiple branches, each of which have slightly different purposes. Janet Rossant, a biologist from the University of Toronto, elaborates on the 3 main uses of gene editing in a peer-reviewed scientific journal. She postulates that it can be used for research in human cells in order to “help understand normal development, model human disease and develop new treatments” (Rossant, 2018). Additionally, somatic cell editing targets specific cells, making sure that disease from mutations, such as cancer, won’t occur. Lastly, germline gene editing, the branch with most controversy, edits the DNA of embryos in order to prevent birth defects of the embryo and future generations (Rossant, 2018). Each of these types of gene editing have different purposes, but the process involved is very similar.

Huimin Zhang and his associates, researchers for the Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, state that one significant use of somatic gene editing is to edit the genome of cancer cells. Due to cancer being “caused by genomic changes in tumor cells, CRISPR/Cas9 can be used in the field of cancer research to edit genomes for exploration of the mechanisms of tumorigenesis and development” (Zhang et al., 2021). The authors proceed to discuss the two major factors in cancer being formed: tumor suppressors and oncogenes. The inactivation of tumor suppressors and the activation of oncogenes lead to tumor growth and cancer. The CRISPR/Cas9 system successfully changes oncogene and tumor suppressor activity, leading to the inhibition of tumor growth, and the ability to potentially cure cancer in a patient. (Zhang et al., 2021)

Germline gene editing can be used to virtually eliminate the presence of birth defects and other diseases in an embryo. Julian Savalescu (a bioethicist and professor for the University of Oxford) and his associates discussed how widespread these benefits could be on future generations. According to his findings, about 6% of babies have severe birth defects as a result of genetics, and “advanced and precise gene editing techniques could eradicate genetic birth defects, thereby benefiting nearly 8 million children every year,” which could be potentially transformational in the medical field (Savalescu et al., 2015).

The current goal is “Healthy babies not designer babies”(Rossant, 2018), hence the focus is around preventing diseases through both somatic and germline editing. This would involve the prevention of hereditary diseases in embryos and the treatment of mutation-related diseases through somatic cell editing. Focusing on life saving applications may ensure less controversy among the scientific and ethical scholarly communities on the use of this emerging technology.

Possible Complications

Although gene editing in humans seems like a promising idea, some complications may arise. As seen in plants, there is always going to be a threat of off-target mutations, which have numerous side effects. Off-target mutations can lead to loss of gene function, cancer, undesirable phenotypes, and mosaicism. Maryam Mehravar and other researchers for the Avicenna Research Institute, state that mosaicism is “the presence of more than one genotype in one individual,” an abnormality that occurs both in nature and due to genetic editing (Mehravar et al., 2019). The rate of mosaicism varies based on several factors factors, such as mosaicism’s frequency in genetically edited organisms, especially human embryos. While mosaicism may appear to be a negative outcome, this may not always be the case. Mutant strains derived from CRISPR/Cas9 induced mosaicism may be beneficial in understanding gene function (Mehravar et al., 2019). Nevertheless, mosaicism is a significant reason for scientific and government concern; hence research should be directed to more specific technologies to better address these concerns.

Conclusion

Despite gene editing’s minimal side effects in plants, it is acknowledged that human genome editing is significantly more complex. Therefore, to develop a sustainable platform that supports mainstream human genome editing , thoughtful and specific federal regulations on somatic and germline editing would have to be developed. As stated by Robin Alta Charo, Professor of Law and Bioethics at the University of Wisconsin–Madison, “countries that choose to permit germline editing will need a pathway to responsible governance” as well as “a road map for preclinical in vitro and animal research that will enable regulators to evaluate proposed human clinical trials,” (Charo, 2019). Furthermore, professional certification and guidelines may be considered, as well as establishment of best practices. Such regulatory and ethical infrastructure provides oversight and monitoring and will enhance transparency and build public confidence on genome editing, thereby building public support for responsible development of human genome editing for the prevention of disease by utilizing specific technology, ensuring the least harmful outcome possible.

Sources

Bak, R. O., Gomez-Ospina, N., & Porteus, M. H. (2018). Gene Editing on Center Stage. Trends in genetics : TIG, 34(8), 600–611. https://doi.org/10.1016/j.tig.2018.05.004

Charo, R. A. (2019). Rogues and Regulation of Germline Editing. New England Journal of Medicine, 380(10), 976–980. https://doi.org/10.1056/nejmms1817528

Gyngell, C., Douglas, T., & Savulescu, J. (2016). The Ethics of Germline Gene Editing. Journal of Applied Philosophy, 34(4), 498–513. https://doi.org/10.1111/japp.12249

Mao, Y., Botella, J. R., Liu, Y., & Zhu, J. (2019). Gene editing in plants: progress and challenges. National Science Review, 6(3), 421–437. https://doi.org/10.1093/nsr/nwz005

Mehravar, M., Shirazi, A., Nazari, M., & Banan, M. (2019). Mosaicism in CRISPR/Cas9-mediated genome editing. Developmental Biology, 445(2), 156–162. https://doi.org/10.1016/j.ydbio.2018.10.008

Savulescu, J. (2015, June 26). The moral imperative to continue gene editing research on human embryos. SpringerLink. https://link.springer.com/article/10.1007/s13238-015-0184-y?error=cookies_not_supported&code=7c6955e1-f804-4e1a-8282-e6acf51d5a5e

Yin, K. (2017, July 31). Progress and prospects in plant genome editing. Nature. https://www.nature.com/articles/nplants2017107?error=cookies_not_supported&code=38f1c265-b7d9-478e-9119-eefef6790a3d