Columbia Team Uncovers Risks in Editing Human Embryo Genes

Researchers from the Vagelos College of Physicians and Surgeons have found that while gene editing methods can accurately edit human embryos giving scientists a valuable window into normal development, the risks are serious enough to keep them out of clinical use for now.

Editing the genome helps scientists understand how it works, and doing so in embryos reveals the earliest steps of development. Early embryos accrue a surprising amount of DNA damage as they grow, and most embryos made through IVF stop developing within the first few days. “By introducing such damage using editors, we are starting to understand how human embryos handle damage in their genomes. Long term, we hope to learn how to prevent genetic and developmental abnormalities during IVF to create more efficient, safer, and more affordable fertility treatments,” explains Dieter Egli, senior author of the research published in Nature.

The team used base editing, a more precise tool than earlier editors, to change single DNA letters in one-cell embryos, then tracked development for six to seven days, the stage when IVF embryos can be implanted. In some experiments, editing was 100% successful with apparently normal development. But it sometimes caused unpredictable changes elsewhere, making it unsafe for the clinic. “Given our findings, it is currently not possible to do so safely,” Egli says.

A decade earlier, Egli’s lab had tried CRISPR. Egli saw the attempt mostly fail, deleting large chromosome sections. Base editors instead work more gently, swapping a single letter on one strand rather than cutting both. Applied to genes tied to high cholesterol (PCSK9) and blood disorders (HBG1, HBG2), base editing succeeded in 100% of an embryo’s daughter cells when used before the first cell division, but also caused chromosomal deletions, additional edits near the intended site, and mosaicism. “Mosaicism creates a range of possibilities, making it impossible to predict outcomes, and is thus preventing meaningful application for use in the clinic,” Egli says. High levels of base-editor mRNA also caused some embryos to stop developing entirely.

Egli still sees long-term promise in editing embryos to prevent disease before mutations spread through billions of cells, but the flaws blocking clinical use won’t be easy to fix. “By their very nature, in order to edit a gene, you first have to damage DNA,” says Stepan Jerabek, the paper’s lead author. “When other technologies without this risk are available to prevent disease, gene editing is not the method of choice,” Egli adds. His lab now plans to use base editing to study DNA damage in embryos, work that could help reduce genetic abnormalities and embryo loss during IVF.