Have we opened the Pandora’s box of genetics?

In November 2018, Chinese scientist He Jiankui ignited controversy in the scientific community by revealing he had edited the genomes of twin embryos known as Lulu and Nana to be resistant to human immunodeficiency virus (HIV) (Cohen, 2019). Many researchers were horrified that genetic manipulation was performed on a human being. However, He justified his actions, stating that the girls would be protected from developing the potentially lethal disease (Saey, 2018).

He used the CRISPR/Cas9 system to alter CCR5 (Saey, 2018), a coreceptor that allows the HIV virus to enter human cells, as shown in Figure 1 (Blanpain et al., 2002). Research has shown that a 32 base pair deletion in the coding region (CCR5-delta32) confers HIV resistance to those with homozygous genotypes (Ni, Wang, and Wang, 2018). He tried to mimic this deletion, and states that while one twin still has a wild-type CCR5, the other has two non-functional copies of the gene, which should make her resistant to the virus. (Cohen, 2019). Controversy aside, this may seem like a promising method to combat the HIV public health crisis. However, what He’s team may not have accounted for is that the CCR5-delta32 mutation is thought to increase susceptibility to other diseases (Klein, 2008). 

Recent research suggests that those who carry CCR5-delta32 are more likely to have an increased risk of developing flaviviruses (Klein, 2008). The Flaviviridae family are RNA viruses commonly found in ticks and mosquitoes (Centers for Disease Control and Prevention, 2013). They are responsible for a host of potentially deadly diseases, including West Nile Virus, Zika, Tick-borne encephalitis, and Yellow Fever, among others (Centers for Disease Control and Prevention, 2013). 

A study performed in 2006 proved West Nile Virus to be fatal in a group of mice without healthy CCR5 (Epps, 2006), and these findings have since been extended to analysis on humans. In a meta-analysis of four different American cohorts, there is a significantly higher number of patients with West Nile Virus that are homozygous for the CCR5-delta32 mutation than those with typical wild-type alleles (Lim et al., 2008). It has also been reported that in a study of patients with the virus, around 5% of those with West Nile had the homozygous mutant genotype, compared to 1% of a typical population (Epps, 2006). This may seem like an insignificant number, but it equals the magnitude of protection that mutant genotypes are given against HIV (Epps, 2006). In this way, the editing of the genome truly becomes a tradeoff; it is possible to create resistance to HIV, but this increases susceptibility to West Nile in the same proportions. While the mechanism by which the mutation confers resistance is largely unknown (Klein, 2008), it is a consideration that certainly merits future study.

This case study creates an ethical and evolutionary dilemma. If altering an embryo’s genome becomes commonplace, how do medical professionals decide which diseases to eradicate? It is now possible that the Pandora’s box of genetics has been opened; scientists could hold the key to determining how a population will evolve. If genome alterations become permissible, the challenge will be to balance the risks between protecting against one disease, but increasing susceptibility to another. 

Works Cited:

Blanpain, C., Libert, F., Vassart, G. and Parmentier, M., 2002. CCR5 and HIV infection. Receptors & Channels, 8(1), pp.19–31.

Centers for Disease Control and Prevention, 2013. Flaviviridae | Viral Hemorrhagic Fevers (VHFs) | CDC. [online] Available at: <https://www.cdc.gov/vhf/virus-families/flaviviridae.html> [Accessed 27 Oct. 2019].

Cohen, J., 2019. Did CRISPR help—or harm—the first-ever gene-edited babies? [online] Science | AAAS. Available at: <https://www.sciencemag.org/news/2019/08/did-crispr-help-or-harm-first-ever-gene-edited-babies> [Accessed 27 Oct. 2019].

Epps, H.L.V., 2006. CCR5 thwarts West Nile virus. Journal of Experimental Medicine, 203(1), pp.4a–4a.

Lim, J.K., Louie, C.Y., Glaser, C., Jean, C., Johnson, B., Johnson, H., McDermott, D.H. and Murphy, P.M., 2008. Genetic Deficiency of Chemokine Receptor CCR5 Is a Strong Risk Factor for Symptomatic West Nile Virus Infection: A Meta-Analysis of 4 Cohorts in the US Epidemic. The Journal of Infectious Diseases, 197(2), pp.262–265.

Ni, J., Wang, D. and Wang, S., 2018. The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta-analysis. Open Medicine, 13, pp.467–474.

Klein, R.S., 2008. A Moving Target: The Multiple Roles of CCR5 in Infectious Diseases. The Journal of Infectious Diseases, 197(2), pp.183–186.

Saey, T.H., 2018. Researcher defends creating CRISPR twins, fails to quell controversy. Science News. Available at: <https://www.sciencenews.org/article/researcher-defends-creating-crispr-babies-fails-quell-controversy> [Accessed 27 Oct. 2019].

US Department of Health and Human Services 2019. CD4 Receptor. [image]. Available at: <https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/824/cd4-receptor> [Accessed 27 Oct. 2019].