A study published on Sept. 9 in Nature by researchers at the Columbia University Vagelos College of Physicians and Surgeons has revealed that while cutting-edge base editing techniques can accurately modify genes in human embryos, they also present significant risks that currently preclude their clinical use.
Columbia University Study Uncovers Hidden Risks in Human Embryo Base Editing
The research team, led by Dieter Egli, associate professor of developmental cell biology in the Department of Pediatrics at Columbia University, worked alongside an international team of collaborators to examine how single-cell human embryos handle targeted genetic modifications. Genome editing is considered essential for scientists seeking to understand the earliest steps of normal human development.
By introducing such damage using editors, we are starting to understand how human embryos handle damage in their genomes,
Egli noted, explaining that early human embryos naturally accrue a surprising amount of DNA damage as they grow, with most IVF embryos stopping development within their first few days.
Evaluating Base Editing Versus CRISPR in Early Embryos
Approximately 10 years ago, Egli’s lab first attempted to use CRISPR to edit a gene in early human embryos. CRISPR functions like a pair of scissors, cutting both strands of a cell’s DNA to insert a new sequence and relying on the cell to glue the broken ends back together.
Because human embryos typically bungle the repair of double-stranded DNA breaks, the CRISPR approach largely failed, leading to the deletion of large sections of chromosomes and entire chromosomes as development progressed. To overcome these limitations, the Columbia team utilized base editing, a next-generation approach described as working more like a pencil with an eraser. Instead of cutting both strands, base editors remove one letter from a single strand of DNA and replace it with another.
In the study titled Highly efficient base editing at PCSK9 and normal human embryo development,
the researchers targeted three specific genes linked to significant health conditions:
- PCSK9: Linked to high cholesterol and cardiovascular disease.
- HBG1 and HBG2: Involved in haemoglobin production, where mutations can cause blood disorders such as sickle cell anaemia and beta-thalassemia.
Unpredictable Changes, Mosaicism, and Developmental Arrest
The researchers followed each embryo’s development for 6 to 7 days—the stage when IVF embryos can typically be implanted—to check if edits were made correctly and passed to all cells. In certain experiments, editing was 100% successful with apparently normal development.
However, the techniques also produced unpredictable changes. The base editor introduced modifications at additional sites in the genome as the embryo developed, including areas near the intended target, which resulted in embryos exhibiting a mosaic of genetic alterations. Furthermore, when the mRNA of certain base editors was present at high levels, the embryos suffered developmental arrest between the 1-to-4-cell stage.
I think our study will discourage inappropriate use of these techniques in the clinic, because we clearly demonstrate the risks,
Egli stated. While editing human embryos holds long-term potential to help carriers of disease-causing mutations have healthy children through IVF, the researchers emphasized that safe clinical application is currently not possible.
