In the nearly five years since the first genetically modified pig heart was transplanted into a living heart failure patient at the University of Maryland Medical Center, the field of xenotransplantation has made significant advances but remains in the research realm. The biggest challenge lies in detecting and reversing immune-driven injuries to the transplanted organ, including rejection and organ failure.
In a new paper published today in the journal Nature, University of Maryland School of Medicine (UMSOM) researchers and their colleagues outlined a roadmap for developing state-of-the-art precision diagnostic tests that could help detect the earliest signs of injury and rejection when it potentially can be reversed.
"Evidence from early clinical cases shows that advanced diagnostic technologies can detect important biological signals that conventional monitoring methods often miss," said study lead author Raphael Meier, MD, PhD , Associate Professor of Surgery at UMSOM and a transplant surgeon at UMMC. "By integrating multiple streams of information, we can identify problems earlier, personalize treatment, and ultimately improve long-term outcomes for patients."
Genetically modified pig organs—hearts, livers, kidneys, and lungs—have been transplanted into patients and deceased research donors (who no longer have brain function) in research settings over the past five years with varying degrees of success. The gene editing, used to knock out porcine molecules that triggered human immune reactions, has demonstrated success at preventing severe hyperacute rejection where the organ fails within hours or even minutes of transplant.
But these clinical procedures, including the first ever successful pig-to-human heart transplant at University of Maryland Medical Center in 2022, revealed the next challenge after hyperacute rejection: subclinical but accumulating immune-mediated injury to the transplanted organ that is difficult to detect using traditional monitoring approaches. While the transplanted organs functioned for weeks or months, the procedures are not yet reliable enough to serve as a clinically viable alternative to organ transplants from human donors.
"Despite major progress in the field, we still don't know the best combination of immunosuppressive drugs for xenotransplant patients. Stronger drugs carry real risks, so we need to protect the transplanted organ without endangering the patient. Treatment tailored to each patient and guided by real-time diagnostic testing may turn out to be essential to making these transplants safe," said study coauthor Muhammad Mohiuddin, MD , Professor of Surgery at UMSOM and Director of the Cardiac Xenotransplantation Program at UMSOM. Dr. Mohiuddin spent more than 30 years researching novel immunosuppressive therapies for xenotransplantation in preclinical studies on animals before co-leading the surgery to transplant the first genetically modified pig heart into a human patient.
In their review paper, the research team — which included Alexandre Loupy, MD, PhD, Director of the Paris Institute for Transplantation and Organ Regeneration (PITOR), and members from the University of Alberta, Edmonton, and NYU Langone Health — examined the recent 20 xenotransplantation cases using advanced multimodal diagnostics, integrating multiple sources of biological information to uncover molecular signatures of early antibody-mediated rejection, persistent innate immune activation and complement-mediated injury to transplanted organs. These injuries, the researchers note, were not detected through conventional laboratory pathology and clinical analyses.
To surmount the new, emergent clinical challenges of xenotransplantation, Dr. Meier and his colleagues proposed a precision medicine framework with four pillars, beginning with enhanced, multimodal tissue diagnostics to better understand early, subclinical injuries to transplanted organs. They also recommend continuous, non-invasive monitoring of xenotransplantation patients for signs of injury and the development of international xenotransplantation data repositories and advanced research platforms — including single-cell sequencing and AI-driven analytics resources — for interrogating that data.
"To move xenotransplantation from extraordinary cases to a reliable standard of care, we need precision diagnostics built into every trial, from shared data repositories and real-time monitoring to advanced tissue and molecular analysis," said Mark T. Gladwin, MD , Dean of the University of Maryland School of Medicine and Vice President for Medical Affairs at the University of Maryland, Baltimore. "That integrated approach will help us understand, with much greater precision, how and why these organs are injured after transplantation."
Ultimately, making xenotransplantation clinically reliable and available outside a few elite medical centers may require tailored immunosuppression treatments for each patient. The diagnostic framework laid out in the paper could serve as an important roadmap for reaching that goal.
"Xenotransplantation holds extraordinary promise to transform the field of transplantation and address one of the most pressing challenges in modern medicine," said Bert W. O'Malley, MD , UMMC President and Executive Vice President for the Academic Health Division of the University of Maryland Medical System. "While significant clinical hurdles remain, they can be overcome through continued innovation and collaboration across disciplines and institutions. We are proud of the extraordinary strides we've made toward a future where fewer lives are lost waiting for an organ, and we look forward to accelerating that progress."
On January 7, 2022, Dr. Mohiuddin and Bartley Griffith, MD , the Thomas E. and Alice Marie Hales Distinguished Professor of Transplant Surgery at UMSOM, made history by implanting a genetically modified pig heart into David Bennett, a 57-year-old patient with terminal heart disease. It was the only currently available option for the patient who did not qualify for a human heart transplant. He lived for two months post-transplant. They performed a second transplant in 2023 on Lawrence Faucette , a 58-year-old patient who lived for nearly six weeks following the surgery. Dr. Mohiuddin serves as the Scientific/Program Director, and Dr. Griffith as the Clinical Director, of UMSOM's Program in Cardiac Xenotransplantation .
Dr. Meier and colleagues' new paper, titled "Multimodal precision diagnostics in clinical xenotransplantation," can be found online at: https://doi.org/10.1038/s41586-026-11096-0
