Challenging the Effectiveness of CRISPR-Cas9 in Repairing Human Embryo Gene Mutations

 

CRISPR-Cas9 gene editing methods are used increasingly more often for the purpose of correcting gene mutations that can impair healthy gene function and physiological development. Recently, however, embryology and genetics experts have questioned last month’s report that allegedly showed the efficiency of CRISPR gene editing techniques in removing a harmful genetic mutation in human embryos.

A Promising Effort

Initially published on August the 2nd in Nature, the study led by Shoukhrat Mitalipov, a leading scientist from Oregon Health & Science University, seemed to show the complete removal of a mutation causing the heart condition known as hypertrophic cardiomyopathy.

An MYBPC3 gene mutation was initially introduced through the DNA of a sperm donor. The sperm, together with the CRISPR-Cas9 components, were directly injected into healthy eggs, and the mutation seemed to be eliminated. The researchers believed that the maternal gene was used as the main template to rebuild a healthy version of the affected genetic material.

On August 28, Maria Jasin, from the Memorial Sloan Kettering Cancer Center at Columbia University, along with four other scientists, have directly challenged the claims made by Mitalipov, and launched their own investigation to highlight the seemingly flawed detection of the suggested repair mechanism and the incorrect assumption regarding the maternal DNA’s ability to conduct a complete repair in the paternal gene.

Lack of Conclusive Evidence in CRISPR-Cas9 Repair Study

The main issues that were raised involved the lack of conclusive evidence to support the initial claims. Jasin and her fellow scientists consider that the maternal and paternal DNA are at too great a distance from each other for the maternal gene to effectively repair the cuts caused by the CRISPR-Cas9 technique. Instead, they suggested that the flawed repair mechanism has led to the addition or removal of enough nucleotides to make the cut area difficult to detect.

Although still currently under review, the new paper raises valid concerns and could bring proof of flawed conclusions made by the initial study as a result of the inherent inability to detect anything but the healthy maternal copy of the gene. Developmental biologist Tony Perry, from the University of Bath, concurs and considers the points raised to be valid. He also points out that maternal and paternal genomes are usually separated by a distance of tens of micrometers immediately following the fertilization process, which renders their interaction for active DNA repair purposes to be largely improbable.

While the scientists who have conducted the initial study stand by their claims, even going so far as to prepare a point-by-point response to the concerns raised by Jasin’s team, Perry further points out that determining precisely which repair process occurred will require significant effort from the bioinformatics specialists.

Photo credit: OHSU

http://cen.acs.org/articles/95/i37/Doubts-raised-over-validity-CRISPR.html

http://www.nature.com/nature/journal/v548/n7668/full/nature23305.html