Base editing clarifies risks of genome editing in human embryos

Base editing can efficiently alter the DNA of human embryos, but it can also result in unintended genomic changes.

Researchers from Columbia University, New York, and collaborating institutions, showed that some embryos developed to the blastocyst stage after a protein-delivered base editor was used to make single-letter changes to their DNA. However, inadvertent alterations to the genome were also found, highlighting important safety considerations which need to be addressed before progression to clinical applications.  

'By introducing such damage using editors, we are starting to understand how human embryos handle damage in their genomes,' said Dr Dieter Egli, the study's leader and associate professor in the Department of Paediatrics, Columbia University. 

The research, published in Nature, aimed to use base editing to explore mechanisms of DNA damage repair during early development, rather than the role of specific genes (see BioNews 1345, 964 and 920). Targeting the PCSK9, HBG1 and HBG2 genes, DNA nicks and mismatches associated with adenine base editing were introduced into single-cell embryos.

While editing of the intended genes was successful, with some embryos developing to blastocyst stage, there were unintended effects including mosaic DNA changes, rare chromosome breakage and chromosomal abnormalities.

'Although base editing represents a significant improvement over CRISPR/Cas9 in terms of DNA repair precision, our findings also show that many important questions regarding safety must be answered before these methods can be considered for clinical use in human embryos,' said Dr Štěpán Jeřábek, the first author of the study and a research scientist in Dr Egli's laboratory.

Previous work by Dr Egli used CRISPR/Cas9-based genome editing in human embryos. However, significant aberrations such as large chromosome deletions were common with this approach, attributable to the double-strand DNA breaks introduced (see BioNews 1103). In the new study, base editing was used to investigate how embryos responded to the DNA lesions associated with single-strand breaks and mismatches. Although base editing caused fewer large deletions and chromosomal abnormalities than observed when Cas9 cuts DNA, unintended effects were still apparent.

Genome editing can provide information about genomic instability and DNA repair mechanisms during early development. This sort of research using base editing could be useful for understanding normal human development, and the reasons why many human embryos created via IVF do not progress past the first few days.

Base editing has also been proposed as a method to edit disease-causing genes in embryos. However, as the researchers in this instance acknowledge, further work is required to understand and reduce the risks associated with unintended genomic changes before the technique could be used in the clinic.

'The purpose of basic research is to expand the boundaries of knowledge while helping us better understand the possibilities and limitations of current technologies. That is precisely why this work represents an important contribution to both scientific and public debate,' added Professor Jan Konvalinka, director of the Institute of Organic Chemistry and Biochemistry Prague, Czechia, who was not directly involved in the work.