A preprint describing genetically edited human embryos is raising concerns among scientists that the U.S. is becoming more accepting of using gene editing to enhance embryos.

“The cat’s out of the bag,” says Alexis Komor, deputy director of the Sanford Stem Cell Innovation Center at the University of California, San Diego, who was not involved in the new finding.

A team of researchers, led by senior author and Columbia University cell biology researcher Dieter Egli, used base editing—a form of gene editing that involves small cuts to a single strand of DNA—to edit two genomic sites in human zygotes, or embryos at the single-cell stage, that correspond to PCSK9, a gene that regulates cholesterol, and HBG1 and HBG2, two genes that are responsible for the fetal form of the oxygen-carrying protein hemoglobin. The genes were chosen because they were well-studied, not for potential therapeutic purposes, the investigators wrote in the preprint. The experiment was first reported by the New York Times.

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The authors acknowledged that their data will likely “contribute to the conversations surrounding the risks and benefits of embryo editing.” They cautioned that although their work “may be a step towards heritable editing, translation to a clinical context remains premature.” The study has not yet been peer-reviewed.

Any use of human embryos in research should be toward a therapeutic end that will ultimately benefit patients, says Krishanu Saha, a biomedical engineer at the University of Wisconsin–Madison who works with human stem cells and was not involved in the study. It’s not clear the Columbia work fits that goal, he says, in part because the embryos did not carry a pathogenic mutation the editing aimed to fix.

“I would not call it a breakthrough, and it does not establish genome-wide safety or clinical readiness,” Saha says. “I find it hard to think about a scenario where this is medicine.”

The work has served basic research purposes, though, Egli says. “The first goal is knowledge,” he says. “That often leads to new ways to help people.”

The discovery of a gene-editing tool based on CRISPR—perhaps the most well-known method for modifying genes—in 2012 broke open the possibility of editing genomes to treat disease, potentially as early as in the womb or before an embryo is implanted. That raised questions about whether the same technology could be used to make edits purely for parental preference rather than medical necessity.

In 2020 an international commission addressed these concerns by outlining the conditions under which society should deem human germ line editing acceptable.

In the meantime, scientists have continued to refine the technology with improvements to CRISPR and next-generation editing tools. But there was an informal moratorium against using them to edit human embryos.

In 2018 Chinese researcher He Jiankui shocked the world by announcing the birth of two girls whose genes he claimed to have edited by using CRISPR to knock down a gene at the embryonic stage (a court later revealed that a third genetically edited baby was born). Jiankui spent three years in prison and was fined three million yuan (about $430,000 at the time) for violating medical regulations.

That research had at least one major ethical difference from Egli’s, Saha says: in Jiankui’s experiment, the embryos were carried to term and resulted in children.

Despite the outcry, some saw Jiankui’s claims as a demonstration that embryo editing is safe, Saha says, because the two girls were born, and no issues have been reported. Through that lens, some may see Egli’s work as additional proof of safety, he says.

The embryos Egli’s team edited had no chromosomal abnormalities or large deletions and few small changes, according to the preprint. But the embryos survived only when the researchers delivered the editing machinery in the form of a protein. When they used an RNA molecule instead, the embryos stopped developing.

Most of the edited embryos also showed mosaicism, in which genomes vary from cell to cell. Base editing would need to occur sooner, at five to 12 hours after fertilization, to prevent that, according to the preprint.

Researchers in China have been using base editing in embryos since 2017; in at least one case, this work involved a collaborator in the U.S. The embryos were not used for pregnancies. Base editing is itself a step toward safer editing—under a strict definition of safety that prioritizes minimizing “off-target effects,” Saha says. While CRISPR cuts both strands of DNA and relies on the genome to repair itself, base editing cuts just one and uses a guide RNA to make a specific base swap.

But there are far greater ethical concerns to consider, Saha says. “The real safety involves the birth and long-term follow-up of the child.”

Any research involving humans or human materials that uses federal funding must go through an ethical approval known as an institutional review board (IRB) review. In the early 2000s, when researchers first began using embryonic stem cells, many institutions added a second review step involving what’s known as a stem cell research oversight (SCRO) committee.

Though Congress has, for the past three decades, barred the use of federal funds for research in which human embryos are created or destroyed—with a few narrow exceptions—universities generally pass such research through IRB and SCRO anyway, says Megan Allyse, a visiting bioethicist at Case Western Reserve University, who studies reproductive ethics and was not involved in the study. But there is no legal requirement that they do so.

The work described in the preprint was funded by the Institute of Organic Chemistry and Biochemistry in Prague, the New York Stem Cell Foundation, the company Genomic Prediction and the Korean Fund for Regenerative Medicine, according to the preprint.

“There are lots of guardrails on here, and it’s not clear how this particular research study threaded its way through those guardrails,” Allyse says.

An independent ethicist assessed the ethical review process, Egli says. It involved consent with the donors and IRB and embryonic SCRO (ESCRO) reviews. The work has been submitted to a journal for review, and more details will be included in the final publication, he adds. Journals typically evaluate ethical review before publishing a study, Allyse says.

In the absence of strict oversight, a kind of “gentleman’s agreement” has limited embryo editing in U.S. academic labs, Komor says. The Columbia team may have broken that agreement, she adds, especially if the scientific community accepts it—unlike what happened to Jiankui. “It kind of opens the floodgates” she says of the work, calling it “a gateway to embryo editing to do enhancements.”

Egli disagrees, pointing out that the approach demonstrated toxicity, “which is not justified when you don’t address a medical need.”