People seeking a kidney transplant often have to wait years for a donor organ to become available—and many die before ever receiving one. Xenotransplantation, in which organs from one species are transplanted into another, could alleviate the organ shortage. But bridging millions of years of evolutionary divergence between two species is a tall order, so for decades organ xenotransplantation was largely impractical.

A new study that was published on Wednesday in Nature demonstrates a key metric of xenotransplantation: the long-term survival of organ recipients. The study authors transplanted the kidneys of genetically engineered Yucatán pigs into cynomolgus monkeys, and the recipients survived for a median of six months, with at least two out of 15 monkeys bearing the desired edits living for more than two years. Prior to the study, xenografts usually survived in nonhuman primates for around three months or less. The new data could help convince regulators that xenotransplantation is ready for clinical trials in humans.

According to eGenesis, the company that led the study, the U.S. Food and Drug Administration requires data showing at least one-year survival of xenografts in nonhuman primates before it will approve clinical studies. “Not only can we get up to a year, we can reach up to two years in the monkey,” says CEO Michael Curtis. “It sets the foundation to go to the clinic with confidence.”

The eGenesis researchers aren’t the first to show a xenotransplant survival rate of more than a year in nonhuman primates. But previous studies relied on aggressive immunosuppressants to tame the body’s immune responses, and their successes were often positive outliers rather than consistent outcomes. In the new study, a third of the monkeys survived for a year or longer while on standard immunosuppressants.

“It’s the consistency that impressed me in this paper,” says Muhammad M. Mohiuddin, a professor of surgery at the University of Maryland School of Medicine, who wasn’t directly involved in the research but reviewed the study and wrote an accompanying commentary.

Xenotransplants have been carried out in humans in the past. In late September Mohiuddin and his colleagues successfully transplanted a heart from a genetically modified pig into a 58-year-old man, who is currently being monitored in the hospital. The same team performed a similar surgery in January 2022, and the recipient lived for two months before passing away. But these surgeries were exceptions—they only received the FDA’s go-ahead because the participants were terminally ill people who didn’t have any other option. And it’s harder to argue for this expanded access, or “compassionate use,” of kidney xenotransplants when dialysis exists as a stopgap measure. Dialysis is a traumatic and arduous experience, however.

Genetically engineered pig kidneys and hearts have also been tested in people who have suffered brain death when their family has consented to the experiment. Such investigations allow scientists to assess the procedures’ safety and performance in a setting closer to the human body, says Jayme Locke, a surgeon at the University of Alabama at Birmingham, who has carried out some of these experiments. But these so-called decedent models come with their own challenges: they usually involve just one person and usually only last for days to weeks. Although these studies provide valuable information, the FDA does not consider them a substitute for clinical trials, for which it requires preclinical data in nonhuman primates.

The strategy eGenesis has employed for making xenografts last longer is to genetically engineer the pig donor to be more biologically compatible. In the new study, the researchers reported making a total of 69 genetic edits. By contrast, previous attempts by other companies introduced 10 tweaks or fewer to pigs’ genome.

Many of eGenesis’s edits serve to coax the host’s immune system to accept the foreign organ instead of attacking it. Pig tissues contain three types of sugar molecules that can trigger the primate immune system to reject the transplanted tissues, so three of eGenesis’s 69 genetic tweaks prevented the donor animal from making these molecules. Another seven of the changes were human gene additions to essentially “make the pig cells behave a little bit more like human cells,” says study co-author Wenning Qin, eGenesis’s senior vice president of innovation. It’s the equivalent of disguising the foreign substrates as the host’s own.

The biggest hurdle—which the remaining 59 edits aimed to overcome—was the risk of transmitting a zoonotic disease from the pigs to the monkeys. The porcine genome contains 40 to 70 copies of DNA from porcine endogenous retroviruses (PERV) that are harmless to modern pigs but could be reactivated in humans. In the late 1990s concern over these viruses infecting transplant recipients prompted calls for a moratorium on xenotransplantation, but ultimately the FDA allowed research to resume.

These viral genes were challenging to address because there are so many of them—beyond what traditional gene-editing techniques could disable on a practical timeline. But in the 2000s the scientific field gained a new ally: the Nobel Prize–winning gene-editing toolkit CRISPR-Cas9. Now scientists could make more edits to the genome in one go and do so more accurately to boot. Qin estimates that relying on pre-CRISPR techniques to disable all the viral fragments in the Yucatán pig genome would take her more than 50 years to complete, as opposed to the mere months that were needed with CRISPR.

These data will be used by eGenesis to apply for regulatory approval to run phase I clinical trials, which the company hopes to start in 2025. “I really look forward to seeing it go all the way to humans and make a positive impact on human health care,” Qin says. “I have been in the field for a long, long time. I think it would be a good way to conclude my professional career if I had a product [going] to the clinic.”

It remains to be seen which cluster of gene edits makes for the best xenograft—or even which ones are necessary. For example, the company Revivicor, which is owned by United Therapeutics and provided the pigs used in the University of Maryland transplants, leaves the porcine viral genes intact. Instead Revivicor has opted for a different pig breed that carries fewer viral sequences in the first place. In Mohiuddin and his team’s experience conducting xenotransplants so far, they haven’t observed zoonotic activation in humans, he says. (The pig heart his team transplanted into a human in 2022 contained traces of a different pig virus, but the physicians saw no evidence of a viral infection while the recipient was alive.) In addition, removing all the PERV genes may have unintended side effects. Mohiuddin says he’s concerned that overtampering with the pig genome could lead to unhealthier pigs and lower-performing donor kidneys.

Other factors besides gene edits can also influence xenotransplantation outcomes. A regimen of immunosuppressants can help stave off organ rejection for some time. A goal of xenotransplantation is to one day genetically engineer away the need for such medication, however. Monkey models are an imperfect proxy for people, in part because monkeys aren’t cooperative patients and are challenging to take care of postsurgery. Additionally, monkeys are thought to be immune to endogenous pig viruses. The success of xenografted kidneys in a monkey isn’t necessarily indicative of how they would eventually function in a human.

“Understanding pig kidney physiology in a human is going to become a whole new field,” Locke says. Survival is only one part of the picture; the kidney’s long-term function, from its blood filtration rate to its hormonal regulation, is another important measure that scientists have barely explored. For now, it’s still too early to tell which research group has the best approach to xenotransplantation, she says. “That’s part of why we need to be able to study all of them,” Locke adds.