A New Era in Organ Transplantation

By Sarah C. P. Williams, Illustration by Davide Bonazzi

Nicholas, a sanitation worker in Staten Island, was in his late 20s when he was diagnosed with kidney failure— likely due in part to genetic factors— and told that he needed a new kidney. His mother had undergone a kidney transplant when Nicholas was a teenager, so he already had some idea of what to expect after an organ transplant: lifelong immune-suppressing drugs. The medications, he knew, would prevent his body from rejecting the new kidney. They would also make him more prone to infections and long-term complications.

Nicholas’ father agreed to donate a kidney to him, and their medical team at NewYork-Presbyterian/ Columbia began planning the transplantation surgery. That’s when Nicholas first heard about the PANORAMA clinical trial. Nicholas could couple the kidney transplant with a bone marrow transplant, also from his father. If it worked, the experimental dual transplant would convince his body’s immune system to accept the new organ. He might be able to forgo lifelong immunosuppression and avoid the severe side effects and illnesses that can accompany such drugs.

“Not having to be on immunosuppressants for the rest of my life was very appealing,” says Nicholas. “I had seen the long-term effects on my mom and knew that it wasn’t ideal.” In April 2023, Nicholas received one of his father’s kidneys, as well as an infusion of his bone marrow. By April 2024, he had been fully weaned off all immune drugs. He was the second patient in the trial to achieve this status.

“It’s very gratifying to see how well he is doing,” says Joshua Weiner, MD, the transplant surgeon leading PANORAMA. “It feels kind of like magic.”

Of course, the breakthrough results are far from magic: They follow decades of deep research into exactly why the human immune system rejects organ transplants and how to avoid this potentially fatal reaction. Columbia researchers have been at the forefront of studies on how to make the body tolerate transplants without shutting down the immune system. Their results have implications for improving humanto- human transplants and advancing xenotransplantation, which involves using animal organs in humans.

The challenges of making one person’s immune system tolerate an organ from another person without any immunosuppressant drugs, it turns out, overlap with the challenges of making a person tolerate an organ from another species. Achieving the first is a kind of stepping stone to the second.

“The potential implications of this line of research are just mind-boggling,” says Megan Sykes, MD, director of the Columbia Center for Translational Immunology (CCTI). “There are over 100,000 people waiting for organs right now, and thousands die every year. With xenotransplants, we could be transplanting all of them.”

At NewYork-Presbyterian/Columbia, surgeons have not yet transplanted an animal organ into a human, but Dr. Sykes and her colleagues say they are making plans to do so.

“Now is a very auspicious time in the field,” says Columbia professor of surgery David Sachs, MD, an investigator at the CCTI and a longtime leader in xenotransplantation. “We’re right at the cusp of taking this from many years of basic research to the clinic.”

Teaching Transplant Tolerance

In 1973, researchers in London studying mice born without a thymus—a small organ near the heart that trains T cells produced in the bone marrow to recognize foreign antigens versus self-antigens—discovered that the animals could tolerate tissue grafts from other species. When they transplanted rabbit skin onto the backs of the mice, the mice grew a patch of rabbit hair. By contrast, mice with an intact thymus rejected such transplants; their rabbit skin grafts blackened and shriveled. Intrigued, the scientists expanded their tests.

“These researchers even described putting chicken skin on the mice, and the [thymus-free] animals started to grow feathers,” says Dr. Sachs. “For those of us interested in transplants, this was a huge sign that it might eventually be possible to transplant organs from other animals into humans.”

The London experiments were some of the first suggesting that the body could be coaxed to tolerate a transplant without an immune response. They also hinted that the thymus and its immune cells were the key to this tolerance.

At the time, Dr. Sachs was the chief of transplantation biology at the National Cancer Institute and was interested in how to overcome the major challenges with organ transplantation. There were not—and still are not—enough human organs for those who needed them; today, about 5,000 Americans a year die while on a transplant waiting list. In addition, anyone who receives a donor organ must remain on immunosuppressant drugs to keep their immune system from attacking the new organ.

“These patients live with a chronic illness,” Dr. Sachs says. “They have to take many, many pills a day and deal with all the side effects and complications, which include things like diabetes, high blood pressure, osteoporosis, and an increased infection and cancer risk.”

Even with immunosuppressants, transplanted solid organs often fail after five or 10 years, depending on the organs—mostly because the immune system eventually attacks them. This imperative to re-transplant patients with a second donor organ further burdens the growing lists of those waiting for new organs.

True transplant tolerance—a healthy, fully functioning immune system that tolerates a new organ indefinitely— could solve all of these problems. Without the hazard of organ rejection, patients could receive a donor organ and forgo lifelong immunosuppressants. Those organs could even come from other species, offering a potentially limitless source of new organs.

Building on the findings about thymus-free mice, Dr. Sachs—along with Dr. Sykes, who had trained in his lab before starting her own transplant research program— began studying how to achieve transplant tolerance in animals with intact immune systems. Simply removing their thymus was not enough, as the immune cells the organ had produced throughout the animals’ lives would already be circulating in the blood. Instead, more creative approaches would be required.

The Science of Self

White blood cells are made in your bone marrow, and then travel to the thymus gland to mature. In the thymus, these critical immune cells (T cells, short for thymus cells) learn what molecules are “self,” or are part of your own body, and should be ignored. Everything else, including not only pathogens, but also tissues from other people or animals, can provoke an immune reaction.

In the 1990s, Drs. Sachs and Sykes started testing how to co-opt this process and teach a healthy mouse’s immune system to recognize a new organ as “self.” They discovered that there were two ways to do this: Transplant bone marrow from an organ donor at the same time as a new organ, or transplant a matching thymus. Either approach on its own could coax the recipient’s newly developing T cells into recognizing the donor’s cells as “self.”

Using these methods, Dr. Sykes successfully transplanted pig skin onto mice. Again, the animals tolerated the skin—the same outcome as the thymus-free mice. But this time, the mice had fully functioning immune systems, capable of fighting off germs and keeping them healthy.

“I still clearly remember being at this meeting and calling back into my lab to see how everything was going,” says Dr. Sykes. “My postdoc told me that, for the first time, we had achieved tolerance in a mouse with an intact thymus. It was incredibly exciting.”

But humans aren’t mice, and over the last decade, Dr. Sykes has dug into the particulars of how a human immune system could be coaxed to tolerate a xenotransplant from a pig. The species has a body anatomy compatible with a human’s, and scientists have already proven adept at breeding and genetically modifying them.

Dr. Sykes developed mice with humanized immune systems to investigate how human cells—rather than those from the mice themselves—reacted to pig transplants. She found that a perfect balance was needed between pig immune cells and the original human cells so they could coexist. Achieving this balance, first in mice, and then in large animal models, was a struggle, requiring new drugs to adequately suppress the recipient’s immune system.

“The true human self is already taught as self, and then our goal is to teach the body that the donor is another self,” says Dr. Sykes. “It turns out to be quite complicated to do that.”

Extending Organ Lifespans

Over the last three decades, Drs. Sachs and Sykes have charted a methodical, painstaking course in their quest for xenogenic tolerance as they scaled up to transplanting whole pig organs into non-human primates.

Initially, the transplants were plagued by hyperacute rejection. As the scientists learned more, however, survival times stretched to hours, days, and even months.

Much of that extension was because of a new understanding of the immune system, tweaks to the scientists’ protocols with thymuses and bone marrow, genetic modification of the pig, and new drugs to control the organ recipient’s immune response.

Over the last few decades, Dr. Sachs has bred a line of pigs designed to provide organs to people. The pigs are smaller than traditional swine—only growing to 100 to 200 pounds rather than to more than 1,000 pounds, which makes them capable of yielding human-sized organs. The herd is genetically identical and engineered not to express alpha-gal, a sugar known to trigger some of the most severe immune reactions in humans.

The new pig organs, coupled with the group’s findings on how to induce tolerance, have brought human xenotransplantation one step closer to reality. Building on this work, transplant surgeon Greg Nowak, MD, PhD, adopted the xenotransplantation model of transplanting pig thymuses and kidneys, so-called thymokidney grafts, into baboons.

“The main barrier to improving long-term xenokidney survival is early post-transplant proteinuria,” explains Dr. Nowak. “In our studies testing different kidney xenotransplantation models, we observed that baboons receiving thymokidneys did not develop proteinuria.”

While the mechanism behind this resistance to protein leakage is still under investigation, findings from Dr. Nowak’s lab have already laid the groundwork for an FDA-approved clinical trial.

Pigs and People

Pediatric heart surgeon Andrew Goldstone, MD, PhD, says one of the hardest parts of his job is waiting for organs. His patients are often newborns or infants born with severe heart defects. The only way to treat them is to provide them with a new heart.

“Thankfully, we don’t see many deaths among the healthy pediatric population,” he says. “But that means there are very few donors for our kids who need new hearts.”

Some of the children he sees must wait six months or more—hooked up to a mechanical heart device in the hospital—before they receive a heart. Others die while waiting. These patients need a new source of child-sized hearts, which is precisely what Dr. Sachs’ miniature swine can provide. That is why Dr. Goldstone started collaborating with the CCTI to study the potential of transplanting pig hearts.

“In the early days, it might be that a pig heart can act as a bridge while someone waits for a human heart,” he says. “And if it provides a child with a new, working heart—even temporarily—it could completely change that child’s life.”

Before that can happen, though, Dr. Goldstone and his colleagues must be sure that the pig heart will be accepted by the child’s immune system. Early experiments have shown that far higher levels of immunosuppressants are needed to allow humans to accept pig organs than to accept human organs. A handful of patients around the world have now received pig kidneys, and most have lived only a few months due to a variety of complications.

“People are starting to see that these levels of immunosuppression are probably unsustainable,” says Dr. Sykes. “So I feel that our work on tolerance all these years is now being vindicated.”

The earliest pig organ transplants, like those that have already happened at other institutions, will likely rely on high levels of immunosuppression, Drs. Sykes and Goldstone say. With the Nowak lab at Columbia, Dr. Goldstone has successfully transplanted pig hearts into small baboons. Now, he’s investigating what happens as those baboons and pig hearts continue to grow.

Drs. Sachs and Sykes and their colleagues are continuing to make genetic alterations in their swine to decrease the differences from humans that cause rejection. Transplanting pig organs into people with long-term success will likely require more than just genetic changes and better immunosuppression. Bone marrow or thymus transplants—or some other method of inducing immune tolerance, and therefore requiring fewer immunosuppressant drugs— are suspected to be the eventual path forward.

“This is the Holy Grail of transplant medicine and research,” says Dr. Goldstone. “If you can do a transplant without immunosuppression and without the risk of rejection, you’ve suddenly made transplantation a permanent cure.”

Reaching Patients

In April 2024, surgeons at New York University (NYU) transplanted a genetically engineered pig kidney, as well as the animal’s thymus, into a patient with both heart failure and kidney failure. Although the organs had come from a commercial biotech company, Columbia’s team paid close attention to the surgery, and gave advice to the NYU team planning it. The method was based on what Columbia had already achieved in baboons.

The organ was removed 47 days later, and the patient remained on immunosuppressant drugs. Even though the patient died months after the transplant, the medical team considered many parts of the procedure valuable. Dr. Sykes’ group examined T cells from the patient to help gauge how well the transplanted pig thymus worked, and how the patient’s immune system was responding to the new organ.

“We think that this patient’s newly transplanted pig thymus was functioning, which is very promising,” says Dr. Sykes.

The Columbia xenotransplant team is now waiting for another approval from the FDA for the compassionate use of a thymokidney in patients.

But in the meantime, these efforts have provided a pathway to tolerance for those receiving donor human organs, like Nicholas, the kidney transplant recipient who has already been weaned off immunosuppressants. The PANORAMA trial is the second in which Drs. Sykes and Sachs and colleagues have used concomitant human bone marrow and kidney transplants. In the first, seven of 10 participants were fully taken off immunosuppressants. Initial results of that study were published in 2008 in the New England Journal of Medicine. The trial halted when a key drug used in the regimen became unavailable. It took a decade before a new company began to make it again.

Now, the research has resumed as PANORAMA. So far, three of four patients receiving kidney transplants at Columbia were weaned off immunosuppressant drugs for part of their course. One remains completely off immunosuppression, and the other two are being maintained on low-level immunosuppression. There have been a few tweaks to exactly how the bone marrow transplant is carried out, compared to the studies that were performed a decade ago. With these changes, none of the patients have experienced a significant episode of the early kidney inflammation that was common in the first trial, but there has been an increased incidence of low-level antibody formation, the significance of which needs to be evaluated. Thus, the results are very encouraging, but there is still further work to be done before the new protocol will be widely available.

For Drs. Sykes and Sachs and their colleagues who have been working to improve transplants for more than 30 years, the results are extremely gratifying.

“This is a field in which you have to be willing to accept delayed gratification,” says Dr. Sachs. “You can go for weeks or months without things working, and the high you get when it finally works has to make up for all those times.”