In Pursuit of Transformational Research: Pushing the Boundaries of Transplant Possibilities

A Research-Enabled Success Story

At his one-year anniversary party since receiving a life-saving liver transplant, Mark Hofeling invited his former surgeon Dr. Graziano Oldani to cut the cake. “That’s how much I trusted him,” jokes Mark. Less than two years prior, Mark had no suspicion that his liver had reached stage 3 cirrhosis—the result, primarily, of a genetic deficiency of the Alpha-1 antitrypsin protein in his liver, also exacerbated by a decades-long drinking habit.

Essentially, Mark quips, “The roof was leaking, the foundation was cracked, the drinking set the house on fire.” Dr. Oldani performed Mark’s liver transplant at Vancouver General Hospital in August 2024. Surrounded by his team of medical staff, Mark vividly remembers standing in the surgical room, his feet on the cool floor. He recollects, “The fact that I could stand there without fear, on the edge of the grave, and the only people who could get me out of that pickle [were] in that room. I laid down, everybody came and said hi, touched my shoulder, affirmed that the liver was a great match. I felt good about it. So I said, ‘I’m good. Let’s go.’”

Nine days later, Mark walked out of the hospital into a bright sunny day and into the rest of his life. Daily he is cognizant that he came too close to death, and only thanks to his donor, and the wealth of research that goes into successful organ donation and transplant, could he walk away with a second chance. Because his donor match was strong, Mark only requires a small regimen of immunosuppressants.

Why ‘Good Enough’ Isn’t Enough

But many other transplant recipients aren’t so fortunate. While transplantation remains one of the most successful treatments in modern medicine, significant challenges remain. Current immunosuppression medications carry real long-term side effects and compromise the body’s natural defence mechanisms. These drugs do not specifically target the new organ but rather the immune system as a whole, which leads to a precarious balancing act between preventing rejection and managing toxicity. This can result in kidney damage, cancer, and infections. Additionally, the number of patients needing a life-saving organ are more than the available donors—in British Columbia, people still die on the waiting list.

The team at Vancouver General Hospital, along with BC Transplant, has done a great deal to expand the donor pool. They have established a successful living donor liver transplant program and implemented normothermic machine perfusion (NRP)—a technique that restores blood flow and oxygen to organs after death—to expand the use of marginal organs that would otherwise be discarded. But scientists have an obligation to look further into the future and be brave in exploring unconventional ideas—pursuing research that could one day address both problems at once.

Dr. Graziano Oldani’s research does exactly that. His work aims to have one species grow a complete organ for another, which is a process known as interspecific blastocyst complementation. In this approach, a hosting species is genetically modified to lack the specific developmental niche that creates the liver. Cells from another species are then introduced at the embryonic stage, when the immune system is not yet mature and these foreign cells are accepted. These donor cells repopulate the missing organ, growing it entirely within the host. The hope is that in the future, large animals could grow the organs we need using the patient’s own cells—eliminating both the donor shortage and the need for immunosuppression.

Transforming the Future of Transplantation

Within the lab, Dr. Oldani and his team have demonstrated proof of concept in creating chimeras, which is a living creature made from a mix of different biological sources. Using black-coated mice cells, they inject cells from light-furred rats. Successful chimeras are those mice born with traits indicating they have accepted the rat cells –  for instance, mice born with patches of light fur. This also means their livers are composed of cells from both species, and despite being a mouse-sized liver it is repopulated with rat cells and can be successfully transplanted back into young rats—matched for size—with no rejection concerns and no need for immunosuppression.

Dr. Oldani’s hope is that eventually pigs will be able to grow autologous (patient-derived) human livers that can be transplanted into recipients with 100% success, potentially eliminating the need for immunosuppression entirely.

In the lab, Dr. Oldani and his team have produced several chimeras—proof that this potential is real, and they endeavour to eventually translate the research into large animal chimeras, which brings this concept one step closer from the lab into practice.

This research is similar to but different than xenotransplantation—genetically engineered animal organs transplanted into humans. While researchers in xenotransplantation have had some limited success, there are unique barriers facing liver transplantation. Dr. Oldani views research around the liver as distinct because of “all the thousands of proteins that the liver fabricates, they wouldn’t interact the same way in a human,” he says. While pure xenotransplantation will likely offer a viable solution for kidney transplantation, for the liver it will more likely serve only as a bridge—buying time for a patient in acute liver failure. Dr. Oldani’s research helps address this fundamental limitation.

Making Dreams Real: Research is the Foundation

At a recent event, Mark had the opportunity to speak with Dr. Oldani, where he expressed both his deep gratitude and a personal need to participate in advancing life-saving transplant research any way he could. He says, “I’m the guy who got hit by lightning and walked away. I know what it feels like to walk up to the edge of the grave and vault over it in the most spectacular way. I feel like I have an obligation to advance the cause in any way I can.”

Through his friendship with Mark, Dr. Oldani gained unique insight into the experiences of  recipients, both in body and mind. “Knowing him,” says Dr. Oldani, “I discovered a whole new perspective on the implications of what we do. I do not recall anybody before him being so insightful about what happened to them. His being very good at putting into words what his experience was helped me approach patients undergoing liver transplant better, and in a more compassionate way.” The profound connection Mark and Dr. Oldani share speaks to the importance of both the exchange of knowledge and connections shared between the people whose lives are saved through transplant, the medical researchers and professionals in the field, and even a donor’s family.

Written by Amy Russell-Coutts

At ODTRF, we are privileged to have Dr. Graziano Oldani serve on our Scientific Advisory Board, where he brings valuable expertise, vision, and passion to help guide the future direction of the research we fund and the work we do.