Opportunity and risk at the same time: A new method of gene editing could help to correct pathogenic mutations and hereditary diseases in the embryo – and in all of this person’s descendants. Unlike the common CRISPR/Cas gene scissors, base editing, which has now been tested on human embryos for the first time, does not cause chromosomal abnormalities and has fewer undesirable side effects. However, it is debatable whether the progress made represents an opportunity for genetic medicine or only further increases the risk of abusive germline interventions – or both.
The CRISPR/Cas9 genetic scissors have opened up completely new opportunities for doctors to correct genetic defects. With this tool, faulty gene letters or gene parts can be removed from the genome in a more targeted manner than before. Depending on the process, the correct sequence is inserted directly or the cell’s own DNA repair is left to complete the missing DNA bases in the correct order. Theoretically, disease-causing or fatal genetic defects could be corrected in fertilized eggs or embryos – some hereditary diseases could be cured in this way.
The problem, however, is that if the genome of an egg, a sperm or an early embryo is changed, this also affects the germ cells of the resulting human being – and ultimately all of its offspring. Therefore, such interventions in the germline are ethically highly controversial. Although they offer the chance to cure hereditary diseases, they can also permanently change the genetic makeup of our species. “We are working on the operating system of a human being,” warned Eric Topol of the Scripps Research Institute in California a few years ago.
Adverse side effects and ethical concerns
And there’s something else: In germ cells and the early embryo, the use of CRISPR/Cas9 seems to lead to undesirable effects more often than expected. Because DNA repair works differently at this stage, duplication or the loss of parts or entire chromosomes often occurs. “In addition, additional genotoxic changes inside and outside the DNA target region have been reported in mice and humans after CRISPR/Cas-induced double-strand breaks,” explain Stepan Jerabek from Columbia University in New York and his colleagues.
So far, the use of the CRISPR/Cas gene scissors for germline editing is considered too risky and is also banned in many countries. However, that didn’t stop Chinese geneticist He Jiankui from presenting the first children whose genomes had been edited using this method in 2018. After international criticism, the researcher was punished for his unauthorized embryo experiments and had to serve three years in prison. Many geneticists have called for a global abandonment of such germline interventions – at least until the methods are more sophisticated and the long-term consequences can be better assessed.
First test of base editing in the embryo
Now there is a new development: Jerabek and his colleagues have tried out a new method of gene editing in human embryos for the first time – so-called base editing. This does not cut out any pieces of the DNA double strand, but rather, using a modified Cas enzyme, only removes individual DNA bases from one of the two strands and replaces them with another nucleotide base. The researchers investigated how well this works in human embryos by editing one DNA base in three different genes in fertilized egg cells.
Two of the genes edited in the embryos, HBG1 and HBG2, are involved in the production of an embryonic form of the red blood pigment hemoglobin. Replacing the DNA base adenine with guanine creates a point mutation through which this embryonic hemoglobin is still produced in adults, which reduces the symptoms of the hereditary blood diseases sickle cell anemia and thalassemia. The third gene, PCSK9, promotes a pathological excess of harmful LDL cholesterol due to its mutation. This is prevented by replacing an adenine base with guanine.
Fewer unwanted side effects than CRISPR/Cas
The team led by Jerabek and senior author Dieter Egli from Columbia University has now presented the first results of this gene editing in human embryos. Accordingly, 76 percent of the blastocyst stage embryos that grew from the fertilized eggs were homozygous for the genetic change in the PCSK9 gene – the changed DNA base was contained in all cells and both chromosome copies. For the two hemoglobin genes HBG1 and HBG2, the success rate was 52 and 68 percent, as the team reports.
Even more important, however: “Unlike the double-strand breaks in DNA induced by CRISPR/Cas, base editing did not lead to chromosomal abnormalities or major DNA losses,” the researchers write. However, gene editing was only successful if the DNA bases intended for the exchange were introduced into the cells in the form of so-called ribonucleoproteins. However, if Egli and his team used the mRNA that was previously used for base editing, cell growth stopped and the embryos did not develop further.
According to the research team, their experiment demonstrates that germline interventions using base editing cause significantly fewer errors and serious side effects than the classic CRISPR/Cas gene scissors. At least a third of the embryos treated with this method developed to the blastocyst stage. According to initial analyses, the embryonic stem cells generated from these gene-edited embryos also showed no serious abnormalities.
…but unresolved problems remain
However, Egli and his team also admit that the technology is far from being fully developed. “Our study also highlights the ongoing limitations of base editing in embryos,” they write. The new method also revealed undesirable changes in DNA bases outside the target section. In addition, a mosaic effect also occurs with base editing: the gene changes are not present in every cell of the developing embryo. “To avoid mosaic embryos, base editing would have to take place no later than five to twelve hours after fertilization,” explains the team.
According to the research team, their experiment represents progress and the first test of base editing in human embryos – but practical application of this methodology is still a long way away: “Even if this may represent a step towards heritable gene editing, transferring it to the clinical context is still premature at this point in time,” emphasize the researchers. Further studies are needed to solve remaining problems such as mosaicism and unwanted DNA changes outside the target site.
Discussion about risks and benefits
“We assume that the data presented here will contribute to the discussion about the risks and benefits of embryo editing,” write Egli and his team. In fact, their experiment has already sparked international discussions. Some researchers see the results as important advances for the future treatment of pathogenic mutations and hereditary diseases in embryos. In Nature News, reproductive medicine scientist Emre Seli of Yale University described this as a “conceptual shift” with great potential.
Others, however, see the methodology as more of a risk: As with germline interventions in general, there is a risk that this technology will be used prematurely or improperly – for example to produce gene-optimized children, according to concerns. “I’m very concerned: every time another step is taken, it normalizes things,” says developmental biologist Stuart Newman of New York Medical College in Nature News.
Source: Stepan Jerabek (Columbia University, New York) et al., bioRxiv preprint, 2026; doi: 10.64898/2026.05.30.728989; Nature News