Kidneys from pigs that had been genetically modified to have human-like immune systems worked successfully when transplanted into two patients who had recently died, the team that performed the experiments has reported1. Although the organs seemed to function, some researchers question the value of the experiments and argue that clinical trials in living people are the only way to find out whether transplants from pigs can help to alleviate the shortage of human organs available to people who need them.
Researchers have transplanted pig organs into non-human primates with great success: one baboon lived for more than two years with a genetically modified pig heart2. But baboons’ immune and metabolic systems are different from humans’, and certain immunosuppressive drugs routinely used in human organ transplants don’t work in non-human primates, says Robert Montgomery, a transplant surgeon at New York University (NYU) in New York City who led the experiments. People who have recently died, he says, are “the closest thing we’re going to get to a living human without the risk of harm”.
In their transplant tests, which they performed in September and November 2021, Montgomery and his colleagues used pigs that had been genetically engineered to lack a gene called alpha-1,3-galactosyltransferase (αGal). The pig version of αGal triggers the human immune system to reject xenotransplants (organs transferred from a different species). With each kidney that the researchers transplanted, they also transplanted a pig thymus, an organ that produces immune cells that don’t react to foreign organs.
They tested these “thymokidneys” in two people who had been declared legally dead one to two days earlier because they did not have brain function. The researchers did not remove the patients’ own kidneys, but grafted the pig kidneys onto the veins and arteries that carried blood to and from the recipients’ legs. They then monitored the kidneys’ function and the patients’ immune responses for 54 hours — a limit imposed by NYU’s ethics board and based on the amount of time typically required to harvest a person’s organs for transplantation.
In a paper published on 19 May in The New England Journal of Medicine, the researchers said that the patients showed no immediate immune reaction to the organs1. Montgomery calls this “very reassuring”, although he says that a later immune reaction might have arisen if the patients had been kept on life support for months. The amount of urine increased after the transplant and creatinine — a bodily waste product — decreased, suggesting that the pig kidneys were working as intended.
Other researchers, however, are sceptical of the results. For one thing, the pigs used in the study were missing only one gene despite research showing that modifying three or more genes helps the human immune system to better accept the organ3. “It’s a pig that’s not relevant to what we need to know,” says David Cooper, a transplant surgeon at Massachusetts General Hospital in Boston. Montgomery says that some of the immune response could be controlled using drugs.
Moreover, it’s difficult to tell whether the pig kidneys were functioning or whether the urine and creatinine were actually coming from the patients’ own kidneys. “You can’t interpret the results,” says Paige Porrett, a transplant surgeon at the University of Alabama at Birmingham. In January, she and her team published results from their own study4 in which they removed both kidneys from a person who had been brain dead for five days. After testing whether the patient’s antibodies would attack the pig organ, they transplanted two kidneys from a pig with 10 genetic modifications and monitored the deceased patient for 74 hours.
Like Montgomery’s team, Porrett’s team saw little immune reaction against the organs. But although the pig kidneys produced some urine, they did not process creatinine, suggesting that they weren’t functioning properly. Porrett suspects the reason for this was that the patient’s metabolic systems were shutting down because he had been dead for five days. She says that her group has transplanted pig kidneys into several more people who had been declared brain dead and is planning to publish the results soon.
Cooper is not surprised by either group’s findings: research in baboons and human serum had already shown5 that primate immune systems won’t immediately reject a pig organ that lacks αGal. The unanswered questions, he says, are whether the human immune system will attack the organ months later and whether the organ will continue to function. “I personally don’t think we’ll get definitive data from doing studies in brain-dead patients,” he says.
Montgomery and Porrett say that it might be medically possible to extend the experiment, because some patients can survive for months after being declared brain dead. For instance, physicians have occasionally kept pregnant women on life support to allow the fetus to finish developing.
But doing this for research purposes creates ethical problems, says Rebecca Pentz, a bioethicist at Emory University in Atlanta, because patients’ bodies should be released to their families as soon as possible. According to a set of guidelines6 that she authored in 2005, researchers should maintain people who have irreversible loss of brain function on life support for only one day, unless there are valid scientific reasons to extend the period.
Still, Pentz says that the NYU study followed the regulations set by the researchers’ ethics board. “It’s a smart use of the newly dead,” she says. “I do think xenotransplantation — if we can work out the science — is going to be an ethical advance because we can save more human lives.”
Partly because of such limitations, Cooper and others argue that it’s time to start transplanting animal organs into living people — something that has only been partially successful. In January, researchers at the University of Maryland got special permission from the US Food and Drug Administration (FDA) to perform the first emergency transplant of a genetically modified pig heart into a man who was certain to die otherwise.
The man died two months later. In a 20 April webinar hosted by the American Society of Transplantation, the researchers behind the study said that they thought he had died from porcine cytomegalovirus — an animal virus that is harmless to humans but that caused the immune system to reject the organ.
Porrett points out that the infection hadn’t been detected in the living pig, and that it remains unknown whether other latent animal viruses might start affecting humans long after a transplant has taken place. “We will not be able to answer that until we have patients we can follow for months or years,” she says.
Porrett and Cooper’s groups are applying to the FDA to start small clinical trials that would transplant genetically modified pig kidneys into human patients. The kidney is the ideal organ to start with, Cooper says, because, unlike a heart, it can be removed if problems arise and the patient can be placed on dialysis. “It should be done cautiously,” he says.