First Precise Base Editing of Human Embryos Achieved, But Mosaicism and Safety Concerns Persist
Key Insights
Researchers at Columbia University have used base editing to make precise single-letter DNA changes in healthy human embryos for the first time, targeting genes linked to cholesterol and blood disorders.
The study demonstrated successful editing in up to three-quarters of cells with no unwanted changes in one case, but mosaicism — where not all cells carry the edit — remains a critical barrier to clinical use.
Scientists emphasize the technology is not ready for the clinic, citing risks including embryo damage from excessive mRNA doses and the inability to confirm non-mosaic embryos through single-cell testing.
A research team led by Dieter Egli at Columbia University has reported the first use of base editing — a precise second-generation CRISPR technique — to alter the genome of healthy human embryos. The findings, posted on the bioRxiv preprint server on 1 June and not yet peer-reviewed, have ignited both enthusiasm for the technology's therapeutic potential and alarm over its ethical implications.
The study marks what some scientists describe as a conceptual shift in the field. "This will go down in history in a positive way — less reckless, more careful and ethical than previous attempts," said Greg Neely, a genomics researcher at the University of Sydney. Emre Seli, an obstetrician and gynaecologist at Yale University, called the work "a conceptual shift ... that really has the potential to move the field forward."
A More Precise Tool, But Not Without Risk
Base editing represents a significant technical advance over the original CRISPR-Cas9 approach, which cuts both strands of DNA and carries a higher risk of unwanted genetic changes, including chromosomal loss. Previous studies had suggested that standard gene editing in embryos could cause the loss of edited chromosomes, rendering the technology unusable in embryos.
By contrast, base editors change a single DNA letter to another and cut only one strand of DNA during the process. Egli and his team used this approach in early-stage human embryos to make single-letter changes — an A to G substitution — in three genes: PCSK9, which helps regulate "bad" cholesterol levels in the blood, and HBG1 (search) and HBG2 (search), which are involved in fetal haemoglobin production and are being studied as potential targets for treating sickle cell disease (search) and thalassemia (search).
For PCSK9, the edit switched the gene off, mimicking naturally occurring protective variants that reduce coronary heart disease (search) risk. In HBG1 (search) and HBG2 (search), the change replicated a natural mutation that produces a protective type of haemoglobin capable of reducing symptoms of sickle cell disease (search) and thalassemia (search).
The Mosaicism Barrier
A critical limitation emerged: the edits did not occur uniformly across all cells. Some cells carried the new genetic letters while others retained the original sequence — a phenomenon known as mosaicism. In one case, the desired change was successfully made in approximately three-quarters of cells with no unwanted changes. The other edit worked in only around half of the cells and frequently caused unintended changes.
The researchers attribute the variable success to differences in guide RNA design, suggesting that better design and testing could reduce off-target effects. Egli noted that since the experiments described in the manuscript concluded, his team has improved their procedures to reduce mosaicism.
However, mosaicism poses a fundamental challenge for clinical application. If a mosaic embryo develops into a child, only some cells in their body would carry the intended change, meaning the individual could still develop the disease the editing was meant to prevent. Currently, there is no reliable way to confirm a gene-edited embryo is not mosaic, because testing a single cell — as is standard practice in IVF genetic screening — is insufficient when cells within the same embryo differ genetically.
Not Ready for the Clinic
Egli was unequivocal about the technology's current limitations. At excessive doses, the snippet of mRNA used to introduce the DNA editor to cells caused the cells to stop dividing. "These base editors — they can have damaging effects on the embryo. So why would you use it if you don't fully understand that?" he said. "In its current form, you can't use it. It's as clear as day and night."
The shadow of the 2018 CRISPR-baby scandal, in which Chinese scientist He Jiankui used first-generation CRISPR-Cas9 to edit embryos that were subsequently implanted and resulted in live births, continues to loom over the field. He's actions were almost universally condemned, and he ultimately served three years in prison for illegal medical practice in China.
Ethical Concerns and "A Solution in Search of a Problem"
Several researchers questioned the clinical necessity of embryo editing altogether. Fyodor Urnov, who studies molecular therapeutics at the University of California, Berkeley, noted that in vitro fertilization and genetic screening are already used to prevent couples from passing on genetic conditions to their offspring. He described editing embryos to treat disease as "a solution in search of a problem," adding that "in practical terms, therefore, this preprint will solely impact the rapidly growing movement of embryo editors for purposes of 'baby improvement.'"
Hank Greely, a biomedical ethicist at Stanford University, expressed concern that affluent individuals might be inspired by the study. "You could set up an IVF lab and a genetic testing lab for probably a handful of millions of dollars and start doing this. ... And one result might be really sick kids," Greely warned.
Egli responded that the data in his preprint demonstrate such an effort would be premature given the risks of applying base editing to embryos.
One potential path around the mosaicism problem would be to edit sperm or eggs before fertilization, ensuring the genetic change is present in every cell from the outset. While this has not been accomplished in humans, recent claims by a start-up of generating sperm in the lab from sperm stem cells have raised the possibility that such stem cells could be gene-edited — though whether this approach should be pursued remains a separate and deeply contested question.