DNA Repair in Early Human Embryos Sheds Light on Gene-Editing Safety

A new study comparing how early human embryos repair different kinds of DNA damage could inform the safety of future gene-editing therapies aimed at preventing inherited diseases. The research, published in the journal Nature, was led by first author Štěpán Jeřábek, who is affiliated with both Columbia University and the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague), with IOCB Prague scientists Iva Pichová and Michal Doležal also involved.

Although DNA repair is essential for normal embryonic development, little has been known about how it works at the earliest stages. The study is the first detailed comparison of how human embryos respond to two different types of DNA damage: the researchers used CRISPR-Cas9, a gene-editing tool, to introduce double-strand breaks into embryonic DNA, and a technique called base editing to produce single-strand nicks, then analyzed how the embryos' repair mechanisms responded to each.

"The study shows that early human embryos are able to effectively repair single-strand DNA damage, whereas the repair of double-strand breaks is significantly less reliable at this stage of development," said Jeřábek. Doležal and Pichová contributed to purifying the protein-based editors used to introduce the single-strand DNA changes; the team found that delivering these editors directly into embryonic cells as proteins, rather than as messenger RNA, was compatible with normal embryonic development.

The researchers also successfully isolated stem cells from the edited six-day-old embryos, providing enough genetic material for detailed analysis of the effects of gene editing and its consequences in later generations of cells. Jeřábek said the goal was not to develop a method for genetically modifying human embryos, but to understand through basic research how DNA repair works in early human development — and that base editing, while a significant improvement over CRISPR-Cas9 in repair precision, still leaves important safety questions unanswered before such methods could be considered for clinical use in human embryos.

The research was conducted in Dieter Egli's laboratory under the oversight of Columbia University's ethics committee.