In a milestone for the newly resurgent field of xenotransplantation, a 39-year-old brain-dead person in China has become the first human to receive a lung from a pig. With consent from the person’s family, researchers took the organ from a CRISPR’d pig, trimmed it, and stitched it into their chest, where it remained for nine days.
The procedure was intended to test whether pigs that have been gene-edited to make their organs less recognizable to the human immune system — and thus less prone to rejection — could one day be used to supply hospitals for transplants. In the past few years, surgeons in the U.S. have transplanted pig hearts and kidneys into both living patients and people who had been declared clinically dead because they lacked brain function. Last year, doctors in China became the first to attempt a similar procedure with a liver from a pig. This is the first time anyone has tried it with a lung.
The clinical need for donor lungs is enormous. According to the Global Observatory on Donation and Transplantation, 8,236 lung transplants were performed worldwide in 2024, an increase of 6% over the previous year, but tens of thousands more patients remain on waitlists. The results of the experiment, which were published Monday in Nature Medicine, are exciting, experts told STAT, because they suggest that lung xenotransplantation could, one day in the future, become an option for patients. But they also point to how much more work has to be done before that day can arrive.
“It’s not ready for prime time,” said Shaf Keshavjee, a professor of thoracic surgery at the University of Toronto and director of the Toronto Lung Transplant Program who was not involved in the research. “Importantly, they’ve shown us we’re not there yet; don’t go trying this on a patient because it ain’t going to work.”
On May 15, 2024, a team of researchers at the First Affiliated Hospital of Guangzhou Medical University took the left lung of a CRISPR’d pig and transplanted it into a 39-year-old person who had been declared brain-dead by four clinical assessments. The recipient received a daily regimen of immunosuppressive drugs and their right lung was left in place.
The first minutes to hours post-transplant are the most dangerous — that’s when human antibodies swarm over the new organ, glomming onto any “foreign” sugars and cell-surface proteins, summoning clot-forming platelets and triggering inflammation to fight off molecules the immune system perceives as a threat. The Guangzhou subject didn’t see these signs of hyperacute rejection.
But by the 24-hour-mark, the patient’s body had begun producing pro-inflammatory molecules and white blood cells began infiltrating the pig lung. On chest scans researchers watched the new organ fill up with fluid — a sign of tissue damage. By day 3, they also saw signs of antibody-mediated rejection of the lung. On day 9, the experiment was terminated at the request of the recipient’s family.
“For our team, this accomplishment is a meaningful beginning,” study co-author Jiang Shi, told STAT over email. “Lung xenotransplantation presents unique biological and technical challenges compared to other organs. Our aim is to create a rigorous scientific pathway toward a safe, durable lung xenograft, not to claim clinical readiness today.”
Because the lung’s primary function is to rid the blood of carbon dioxide and bring in fresh oxygen, it’s continually exposed to the outside air, including any bacteria, viruses, pollen, or environmental toxins that happen to be floating around in it. To deal with these airborne threats, the lungs have several overlapping layers of immune defense that can be called quickly into action. At the same time, the biological structures that facilitate the gas exchange make the organ very fragile compared to the muscular heart or the stem-cell laden liver, which can regenerate after damage.
Striking the delicate balance of turning down the lungs’ immune response while not injuring the organ or opening up patients to respiratory infections proved so challenging that surgeons didn’t achieve consistent long-term success with transplants of lungs from deceased human donors until the 1980s, decades after the first successful kidney, liver, and heart transplants. Making the leap to a lung from another species adds additional complexity.
The lung in this study came from a Bama miniature pig created by the company Clonorgan Biotechnology in Chengdu, China, and raised in a specialized pathogen-free facility. It contained six CRISPR gene edits — silencing three genes that code for immune system-tripping sugars found on the surface of pig cells, and adding three genes for human proteins that regulate inflammation and other aspects of the immune response.
U.S.-based xenotransplant companies eGenesis and Revivicor have been developing pigs with additional genetic modifications, including eliminating DNA harboring a number of pig viruses that have shown the potential to jump into human cells. Luhan Yang, a cofounder of eGenesis who developed the ability to create such PERV-free piglets as a Harvard graduate student in George Church’s lab and is now leading Qihan Biotech in Hangzhou, China, told STAT that the new report highlights the need to explore further modifications to make the pig lung more human-friendly.
“Despite the knockout of xenogeneic antigens and the introduction of complement inhibitors such as CD46 and CD55, profound humoral immune responses persist against the xenogenic lungs,” she said in an email. In addition to more CRISPR editing, she said other treatments that temporarily neutralize pig-recognizing antibodies to create a window of opportunity for immune tolerance would also be worth investigating. “This is an insightful study,” Yang said, that “offers significant contributions to understanding immune responses toward xenograft lungs and provides a valuable reference for future advancements in this field.”
One limitation of the study was that by leaving behind the right lung of the patient, the group in Guangzhou was not able to assess whether the pig lung was life-supporting. Although they measured changes in carbon dioxide and oxygen in the arteries and veins of the pig lung, experts told STAT it was impossible to tell if tissues were being properly oxygenated by it or the human lung.
“Their conclusion that they have a functioning pig lung is a little optimistic,” said Richard Pierson, a professor of surgery at Harvard Medical School and Massachusetts General Hospital who works on xenotransplantation. In studies with baboons, his team has shown it’s possible to block blood flow to the native lung and then measure the pig lung’s performance, including its ability to keep the recipient’s heart pumping. “They could have done that here and that would have added a whole lot of information,” Pierson said.
Shi, the study leader, told STAT that his team designed the study primarily to determine whether hyperacute rejection would occur and to characterize infection dynamics, and that retaining one native lung best served these aims while providing a safety reserve. The team is planning to perform more transplants into brain-dead patients, Shi said, and those future experiments will explore testing bilateral lung transplantation, evaluating pig lungs with more gene edits, and refining the immunosuppressive regimen.
In this first patient, the Guangzhou team used a heavy mix of more than a half-dozen treatments to tamp down the patient’s immune defenses. “It was the whole kitchen sink,” said Keshavjee. Such an intensive cocktail given to a living patient would most likely lead to a life-threatening infection within days to weeks. “I think the big flaw there is that the level of immunosuppression was unreal,” the Toronto surgeon said.
Despite these limitations, Keshavjee, who is working on a competing type of technology using CRISPR to edit human lungs to expand the pool of potential donors, still sees the work as an important step for the field of xenotransplantation. More than anything, he said, it shows that brain-dead patients are turning out to be a very useful tool for evaluating when genetically modified organs (whether from humans or other species) are ready for clinical trials: “We’re learning that the decedent model is very valuable in solving this problem of how do you bring these fantastic things forward.”
