Should CRISPR be used to edit human embryos?

CRISPR-Cas9 as the revolutionizing gene editing technology has been widely applied in many fields, from basic research, drug discovery, gene and cell therapy, disease diagnostics, to engineering various species for bioproduction1. The 2020 Nobel Prize in Chemistry has been awarded to two scientists Emmanuelle Charpentier and Jennifer A. Doudna for their contribution to the development of CRISPR gene editing technology. 

For some parents with serious genetic disorders, gene editing technology could help them have a healthy and biologically related child without passing down any genetic diseases. However, the debate over if CRISPR could be used to edit human embryos to prevent genetic disease has been ongoing for years, surrounding both biological safety concerns and ethical issues.

In June 2020, three independent teams published their findings on preprint server bioRxiv that use CRISPR–Cas9 to remove genetic defects in human embryos can make large, unwanted changes to the genome at or near the target site2. The three preprints have not been published in peer-reviewed journals, yet already heighten safety concerns on human embryo editing. 

The first preprint was posted online on 5 June by Kathy Niakan’s team from the Francis Crick Institute at UK. In their study, CRISPR/Cas9 was used to mutate the POU5F1 gene, which is important for embryonic development. They also developed a comprehensive computational approach to assess on-target mutations. Among 18 edited embryos, edits beyond on-target locus and chromosome segmental loss and gain were observed in 22% of the embryos3

The second team led by stem-cell biologist Dieter Egli from Columbia University tried to use CRISPR-Cas9 to correct a mutation in EYS gene, which can lead to blindness. Out of 17 embryos, 15 (88%) embryos were modified via CRISPR induced end joining cell repair process. However, only 2 of them were mosaic, whereas the majority were nonmosaic zygotes that only had single modification. Further analysis found that unrepaired double stranded DNA breaks created by CRISPR/Cas9 could persist through mitosis stage and contributing to frequent chromosome loss4. (This study has been published on Cell on October 29, 2020. https://www.cell.com/cell/pdf/S0092-8674(20)31389-1.pdf )

The third team led by Shoukhrat Mitalipov from Oregon Health & Science University studied the efficacy of using CRISPR/Cas9 and a repair template for repairing a mutation that causes a kind of heart disease. Despite showing 40% repair of the target locus, extensive loss of heterozygosity is also observed5.

All the three studies uses CRISPR–Cas9 for the experiments, and taken together underscored the necessity of further studying how CRISPR-Cas9 induced DNA breaks are repaired by various DNA repair mechanisms during different development stage in preimplantation human embryos1.

Can other genome editing approach which do not generate double strand break have better performance in human embryo editing? 

Base editing, a new class of CRISPR-based tools, can introduce a precise nucleotide change in specific gene loci without causing a double-strand break, have been successfully applied for base correction in mouse and human embryos. It is thought to result in fewer off-target effects and higher clinical safety. However, its efficiency in human embryos is generally low, limiting its utility in functional genetic studies. In 2018, a research team from China reported the successful use of base editing in human embryos to correct a Marfan syndrome pathogenic mutation at the efficiency of about 89%, which is very remarkable6Substantial off-target editing of base editors in both genomic DNA and RNA were also reported in papers7. In the paper published in January, Hye Kyung Lee et al revealed that Cytosine base editor 4 generates off-target mutations in mouse embryos8

In September, a commission convened by the National Academy of Sciences (NAS) and the UK Royal Society, released a much-anticipated 200-page report on Heritable Human Genome Editing (HHGE). The report charts a course for limited use of HHGE to help couples have a healthy, biologically related child, once several important criteria have been met9Dame Kay Davies , HHGE commission co-chair, summarized the main conclusions of the report in a webinar: First, “no clinical use should be considered until we can make precise genomic changes without undesired changes.” Second, “before any country decides to approve HHGE, there should be international mechanisms to ensure preclinical mechanisms have been met.” And third, “any clinical use should proceed cautiously” with uses restricted to a particular set of circumstances. 

“Commission charts narrow path for editing human embryos”, as Science reported10. We hope to see more studies that are exploring solutions to overcome the safety concerns of using CRISPR-based gene editing for heritable genome editing in a research setting, as well as any potential ethical issues in the near future to shed light on this topic. 

When will the moratorium on clinical use of CRISPR for heritable genome editing be lifted? The question remains.

Related articles

References

1. https://www.genscript.com/crispr-news/three-recent-independent-studies-show-unwanted-chromosomal-changes.html 

2. Heidi Ledford. CRISPR gene editing in human embryos wreaks chromosomal mayhem, Nature (2020). DOI: 10.1038/d41586-020-01906-4

3. Gregorio Alanis-Lobato et al. Frequent loss-of-heterozygosity in CRISPR-Cas9-edited early human embryos, (2020). DOI: 10.1101/2020.06.05.135913

4. Michael V. Zuccaro et al. Reading frame restoration at the EYS locus, and allele-specific chromosome removal after Cas9 cleavage in human embryos, (2020). DOI: 10.1101/2020.06.17.149237

5. Dan Liang et al. FREQUENT GENE CONVERSION IN HUMAN EMBRYOS INDUCED BY DOUBLE STRAND BREAKS, (2020). DOI: 10.1101/2020.06.19.162214 

6. Zeng, Yanting, et al. "Correction of the Marfan syndrome pathogenic FBN1 mutation by base editing in human cells and heterozygous embryos." Molecular therapy 26.11 (2018): 2631-2637.

7. Park S, Beal PA. Off-Target Editing by CRISPR-Guided DNA Base Editors. Biochemistry. 2019;58(36):3727-3734. doi:10.1021/acs.biochem.9b00573

8. Lee, H.K., Smith, H.E., Liu, C. et al. Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos. Commun Biol 3, 19 (2020). https://doi.org/10.1038/s42003-019-0745-3 

9. https://www.genengnews.com/insights/new-report-charts-a-course-for-heritable-human-genome-editing/

10. https://www.sciencemag.org/news/2020/09/commission-charts-narrow-path-editing-human-embryos 


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