The critical shortage of human organs for transplant continues to drive research into xenotransplantation – the process of using animal organs for life-saving procedures.New studies from NYU Langone Health offer a significant step forward in overcoming the hurdles of immune rejection,a major barrier to successful xenotransplantation. Researchers detailed a recent experiment involving a genetically-modified pig kidney and a brain-dead donor,providing unprecedented insights into the human body’s response and potential treatment strategies. These findings, published November 13 in *Nature*, bring the possibility of broader access to organ transplants closer to reality for the more than 90,000 Americans currently on the waiting list [[number]].
Researchers at NYU Langone Health report significant progress toward making transplants from animals – a process called xenotransplantation – a viable option for patients with organ failure. Two new studies offer insights into overcoming the major hurdle of preventing the human body from rejecting animal organs.
The need for alternative organ sources is critical. Currently, the demand for transplants far exceeds the number of available human organs. According to UNOS, the non-profit organization that manages the nation’s organ donation system, more than 90,000 people in the U.S. are on the waiting list for a transplant, and approximately 11 die each day while waiting. This demand is expected to increase as the population ages and rates of conditions like diabetes, hypertension, and obesity rise.
While dialysis can sustain life for individuals with end-stage renal disease, it’s a challenging process for the body and typically only provides a temporary solution, lasting around five years on average. Xenotransplantation offers a potential long-term alternative.
The primary challenge in xenotransplantation has always been the body’s natural immune response. New research, published November 13 in the journal Nature, sheds light on how to minimize organ rejection from pigs, which are considered a promising source due to their anatomical similarities to humans.
Understanding the Rejection Process
The human immune system is designed to protect the body from harmful invaders like bacteria and viruses. However, it can sometimes overreact, attacking anything it perceives as foreign – including a donated organ. When a foreign object is introduced, the immune system launches an attack, sending antibodies to target and potentially damage the transplanted organ, leading to failure.
Even in human-to-human transplants, rejection is a major concern, requiring lifelong use of powerful immunosuppressant medications. When the donor is an animal, like a pig, scientists genetically modify the organ to increase its compatibility with the human body.
The recent studies focused on meticulously examining how the human body reacts to a pig organ. Researchers transplanted a genetically modified pig kidney into Maurice Miller, a 57-year-old man who was declared brain dead in July 2023.
Miller had previously expressed his wish to donate his organs, but his cancer diagnosis made him ineligible. His family then consented to donate his entire body for research purposes.
Maurice Miller (Família Miller)
According to Robert Montgomery, co-author of the study and director of the NYU Langone Transplant Institute, using a brain-dead individual allowed researchers to collect tissue and blood samples in ways that would be too invasive for a living recipient or even a non-human primate.
“This deceased donor may be the most studied human in history,” Montgomery said.
The research team removed Miller’s kidneys and transplanted a genetically engineered kidney from a pig bred by the biotechnology company Revivicor. Miller’s body was maintained on a ventilator in the ICU for two months, during which time doctors regularly collected biopsies of the kidney, monitored his blood, and analyzed other tissue samples.
The team observed two instances where Miller’s body attempted to reject the pig kidney. However, for the first time in xenotransplantation history, Montgomery stated, they were able to successfully manage the rejection with existing anti-rejection medications, and the organ continued to function. The experiment was halted on the 61st day.
This aspect of the research, Montgomery explained, will help doctors determine which immunosuppressant drugs are most effective in patients receiving pig organs. Understanding the optimal drug regimen is crucial for the success of future transplants.
“It also gives us a sense of relief as we move forward with the clinical trials that we’re halfway through now, knowing that when you put a pig kidney in a human, from a physiological standpoint, it just does its job,” Montgomery said. “The kidney is able to do most of the things a human kidney can do, and as for the things it doesn’t do, we either have redundancy and don’t necessarily need it, or there are some medications we need to supplement. But other than that, we’re ready to move forward.”
The new research, he added, “brings us significantly closer to safe pig-to-human organ transplants.”
The genetically modified pig kidney, shown moments after removal following 61 days of observation (Joe Carrotta for NYU Langone Health)
Mapping the Immune Response in Detail
During the periods when Miller’s body began to reject the organ, doctors were able to create a detailed map of how his immune system responded to the pig kidney and identify the pathways the body was using to trigger rejection. They also mapped the genomics associated with these pathways, analyzing 5,100 pig and human genes and identifying all of the body’s immune cells to track immune behavior at a uniquely granular level.
“We were really able to dissect what happened almost on a daily basis,” said Brendan Keating, co-author of the study and a faculty member in the Department of Surgery at NYU Grossman School of Medicine and the NYU Langone Transplant Institute.
Researchers were also able to observe the differences in the immune response to a pig organ compared to what happens with a human organ transplant. This detailed understanding of the immune system’s reaction is a critical step forward.
The researchers believe they have identified biomarkers in the blood that could eventually be used to detect organ rejection much earlier, before damage occurs. Early detection is key to improving transplant outcomes.
While the study represents a significant advancement, Montgomery emphasized that it involved only one individual, and the results need to be replicated in a larger group of people to confirm the consistency of the reactions. The researchers have recently secured funding to test immunosuppression techniques in 20 additional patients.
“We’re Getting Better at This”
Just last year, scientists made substantial progress in understanding how pig kidney transplants function.
The most notable success involved Tim Andrews of New Hampshire, the fourth living person in the U.S. to receive a kidney from a genetically modified pig.
Andrews set a record when his pig kidney continued to function for 271 days. Doctors removed the organ in late October after noticing a decline in function, but prior to that, the transplant had been so successful that Andrews was able to take long walks and even throw the first pitch at a Boston Red Sox game.
Vasishta Tatapudi, physician and transplant nephrologist at NYU Langone Transplant Institute, performs a biopsy of a genetically modified pig kidney on the 61st day of the latest xenotransplantation study at NYU Langone Health (Joe Carrotta for NYU Langone Health)
The type of research found in the new studies is important for the field, said Minnie Sarwal, co-director of the Kidney and Pancreas Transplant Program at the University of California, San Francisco.
“Sixty-one days of stable renal function is a new proof of concept, and I think that reinforces that genetically modified pig kidneys can support physiological function in the human circulation,” said Sarwal, who was not involved in the new research. “As a first step, the proof of concept is clearly very important, because it fills the gap between what we previously worked with in short-duration pre-clinical models and allows us to move toward true clinical viability, even if it’s not long-term. But 61 days is better than, say, hours or maybe a few days.”
Sarwal, who focuses on therapeutic innovations for immunosuppressant drug development, said the new studies also demonstrated that rejection was treatable.
“That part isn’t groundbreaking, but I find it very reassuring that our current treatments work in this model, which is what we expected, but it’s good to see the confirmation,” she said.
Mapping the immune response could provide researchers with additional “molecular checkpoints amenable to pharmacological treatment,” allowing them to develop better immunosuppression options for transplant recipients, Sarwal added.
Montgomery believes his team’s experience also offers hope that xenotransplantation will one day become a more viable option.
“We’re getting better at this, and I think that’s the message I’d like to convey,” Montgomery said. “There will be ups and downs. Nothing worthwhile doing is exempt from some complications.”
But, he added, “everything is solvable.”
