Are we ready for designer babies?

In 2005, Jiankui He shook the world with his announcement of the birth of twin girls; twin girls whom he, along with his team of researchers, had altered their embryonic DNA using CRISPR technology. The reason this was so troubling for scientists across the world to hear is the side-effects of gene-editing through CRISPR hasn’t yet been studied sufficiently to ensure safe practice on humans. Jiankui He however understood the naturally occurring CCR5 gene mutation results in significant HIV resistance and believed if he could successfully insert such mutation into the DNA of an embryo, then this could have significant implications for HIV treatment in the future. The rest of the scientific community however thought what Jiankui He did was extremely dangerous and made him look more like a “mad scientist” than a groundbreaking physician. Now because CRISPR technology does have the potential for revolutionizing medicine in the future, scientists have continued working to better understand how to effectively manipulate genes while limiting off-target effects to a minimum. The study I looked at in particular was interested in using CRISPR/Cas9-mediated gene editing to  effectively cleave the endogenous β-globin gene (HBB) in human pre-implantation embryos. The human β-globin (HBB) gene encodes a subunit of the adult hemoglobin and is mutated in β-thalassemia (Hill et al., 1962). β-thalassemia is a blood disorder that reduces the production of hemoglobin, thus leading to a lack of oxygen in parts of the body. Now while β-thalassemia can take on a mild form, β-thalassemia major can have significant complications beyond some weakness and fatigue. Researchers in this study sought for a mechanism of eliminating the β-thalassemia gene mutation from human DNA before actually using the CRISPR technology on human subjects. Studies have shown that polyspermic zygotes such as tripronuclear (3PN) zygotes, discarded in clinics, may serve as an alternative for studies of normal human zygotes (Balakier, 1993). Polyspermic zygotes, which occur in ~2%–5% of zygotes during in vitro fertilization (IVF) clinical trials, may generate blastocysts in vitro but consistenly fail to develop normally in vivo (Munne and Cohen, 1998), providing an ideal model system to examine the targeting efficiency and off-target effects of CRISPR/Cas9 during early human embryonic development (Bredenoord et al., 2008; Sathananthan et al., 1999). This study showed the CRISPR/Cas9 system could cleave the endogenous gene efficiently in human tripronuclear zygotes with the double strand breaks created through cleavage were repaired by either non-homologous end joining or homologous recombination directed repair. The study also showed however, mosaicism and mutations at non-target sites were apparent in the edited embryos, thus demonstrating that CRISPR/Cas9 has notable off-target effects in human 3PN embryos. I believe this study was very significant in presenting the possibility for successful gene editing using CRISPR, but once again it emphasized the need for further research being conducted prior to any advancement into human trials.

Study of Interest: https://link.springer.com/article/10.1007/s13238-015-0153-5?ref

Works Cited:

Balakier H (1993) Tripronuclear human zygotes: the first cell cycle and subsequent development. Hum Reprod 8:1892–1897

Bredenoord AL, Pennings G, de Wert G (2008) Ooplasmic and nuclear transfer to prevent mitochondrial DNA disorders: conceptual and normative issues. Hum Reprod Update 14:669–678

Hill RJ, Konigsberg W, Guidotti G, Craig LC (1962) The structure of human hemoglobin. I. The separation of the alpha and beta chains and their amino acid composition. J Biol Chem 237:1549–1554

Liang, P., Xu, Y., Zhang, X. et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6, 363–372 (2015). https://doi.org/10.1007/s13238-015-0153-5

Munne S, Cohen J (1998) Chromosome abnormalities in human embryos. Hum Reprod Update 4:842–855

Sathananthan AH, Tarin JJ, Gianaroli L, Ng SC, Dharmawardena V, Magli MC, Fernando R, Trounson AO (1999) Development of the human dispermic embryo. Hum Reprod Update 5:553–560