For the last 10 years, a facility at the National Institutes of Health (NIH) in Bethesda, Maryland, has housed baboons with pig hearts beating in their abdomens. They’re part of an experiment that researchers there hope will help develop pig organs safe for transplant into people, about 22 of whom die each day in the United States alone while waiting for human organs that are in short supply. Today, those NIH researchers and their collaborators report record-setting survival data for five transplanted pig hearts, one of which remained healthy in a baboon for nearly 3 years. The results—in baboons that kept their original hearts and were regularly given hefty doses of immune-suppressing drugs—aren’t enough to justify testing pig organs in humans yet. But they come as an encouraging piece of evidence for the long-struggling field of cross-species organ transplants, known as xenotransplantation.

“People used to think that this was just some wild experiment and it has no implications,” says Muhammad Mohiuddin, a cardiac transplant surgeon at National Heart, Lung, and Blood Institute in Bethesda, who led the study. “I think now we’re all learning that [xenotransplantation in humans] can actually happen.”

Simply moving an organ from one animal species into another provokes a violent and immediate attack from the host’s immune system. In early cross-species transplants, “we measured the survivals in minutes,” says David Sachs, a transplant immunologist at Harvard Medical School in Boston, who has worked on xenotransplantation for several decades. In pigs—the most likely candidate for human replacement tissue, in part because their organs are similar in size—a carbohydrate called α 1,3-galactosyltransferase (gal) on the surface of blood vessel cells would prompt the human body to make antibodies that latch onto it and cause blood clots. Once scientists developed a genetically engineered pig lacking the gal gene in 2001, porcine organs began to survive for months in baboons and other nonhuman primates. But these animals still had to be kept on a drug regimen that protected the foreign organ by suppressing their immune systems, leaving them vulnerable to infections.

Mohiuddin and his colleagues have been experimenting with more targeted drugs that might protect a transplant without dramatically tamping down the whole immune system. Among the most promising, he says, is an antibody that blocks communication between certain immune cells by binding to a receptor on their surface called CD40. In the new experiment, the group used the anti-CD40 antibody, along with the blood-thinning drug heparin, to prevent clotting in five baboons transplanted with hearts from genetically engineered pigs. These pigs lacked the gal gene, and also expressed genes for two human proteins: one that helps regulate blood clotting, and another that blocks the signaling molecules that prompt an antibody response leading to damaging clots.

Instead of swapping out a baboon’s original heart, the researchers hooked up the pig heart to blood vessels in the baboon’s abdomen. That way, they could study immune rejection without doing a more elaborate heart surgery—and without needlessly killing a baboon if their approach was a flop. The engineered hearts combined with immunosuppression soon smashed the existing record for pig-to-baboon heart transplants—179 days. “Every [scientific] meeting, we’d go and say, ‘Oh, we got the first 236-day survival, the first 1-year survival, the first 2-year survival,’” Mohiuddin says. “It was losing its charm.” His audiences started asking whether the baboons had developed tolerance—whether they could now sustain these hearts without high doses of immunosuppression.

So the researchers began to taper the baboons off the anti-CD40 antibody. That turned out to be the end of the experiments—the baboons rejected the hearts once the anti-CD40 antibodies left their systems, the team reports online today in Nature Communications. They found that in two baboons who had been on immunosuppression for a year before tapering off, the hearts could survive with lower doses of the drug. But two baboons tapered off the drugs 100 days postsurgery began to reject their hearts almost immediately. (One baboon died from an antibiotic-resistant infection about 5 months after the transplant.) The tapering experiments suggest that a lower “maintenance dose” might be effective, Mohiuddin says. But it also means this transplant approach would require lifelong immune suppression.

In human patients that would confer an increased risk of infection, says Sachs, whose own lab is working on ways to induce long-term tolerance after organ transplants. “Somebody might feel [that] if you can save a person’s life but you have to leave them on long-term immunosuppression … that’s OK,” says Sachs, “but that’s something that has to be decided.”

Another major caveat, says transplant immunologist and physician Daniel Salomon of Scripps Research Institute in San Diego, California, is that the results don’t prove the hearts would function well in the chest. “Having to actually do the pump work to keep the animals alive … is a big deal,” he says. “Just contracting in the abdomen and doing nothing physiological is much easier.” Mohiuddin and his team are gearing up for true heart replacement surgeries in a new group of baboons.