Since its advent, CRISPR-Cas9 has revolutionised scientific research allowing scientists to precisely modify specific genomic regions in different species and in a variety of biological systems. In the last few months, two articles published in Nature took this technology a step further and reported its first ever application to viable human embryos.
Professor Shoukhrat Mitalipov and colleagues at Oregon Health & Science University successfully corrected a heritable mutation in the MYBPC3 gene that causes a life-threatening condition known as hypertrophic cardiomyopathy. The authors fertilised donated healthy human oocytes with sperm from an affected male and observed that embryos could repair the paternal DNA using the maternal copy of the gene as a template through a mechanism called homology-directed repair. While the efficiency was surprisingly high with a low incidence of unwanted mutations elsewhere in the genome, also known as off-target effects, safety matters concerning the possible application of CRISPR-Cas9 to treat human genetic pathologies still remain to be addressed.
Image: Human Blastocyst. Credit: Dr. M. Shahbazi & Prof. M. Zernicka-Goetz >
More recently, an international team led by Dr. Kathy Niakan from the Francis Crick Institute in London used the same technology to study the function of the POU5F1 gene encoding the pluripotency transcription factor OCT4. While the importance of this gene was well documented in mouse embryos and in human embryonic stem cells, it had never been possible to investigate its role in human development. By performing gene knock-out in donated human zygotes, the authors demonstrated that most POU5F1-null embryos failed to reach the blastocyst stage and that a functional OCT4 protein is required for proper lineage segregation in human pre-implantation development. Furthermore, unlike in mice, they observed that in such embryos the expression of other important genes such as CDX2 and NANOG was also affected, thus revealing human-specific features of the transcriptional regulation governing the first few days of our lives.
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These studies followed a previous proof of concept work by a Chinese group that had showed for the first time that CRISPR-Cas9 could be efficiently used for modifying the genome in aneuploid human zygotes. However, the enormous potential of this techniques raises ethical concerns and warrants clear world-wide legislations to regulate its use in human embryos for both clinical and research purposes.