Transplant surgeon-researchers and physician-scientists at the University of Alberta have conducted ground-breaking research in transplantation that has improved the quality of life of millions of people and saved countless lives. But their best work may be yet to come.
Changing the future for people with diabetes
James Shapiro is best known as the primary creator of the Edmonton Protocol, a life-saving procedure introduced in 2000 for those with a dangerous subset of type 1 diabetes. But he has never stopped innovating, and his most life-changing work may be underway right now.
In 1998, when he became director of the University of Alberta’s islet transplant program, he implemented a new multi-pronged approach – “making seven or eight changes all at once to try to make something work” – with his colleagues, which led to the Edmonton Protocol.
“I learned from my patients what a terrible disease diabetes really is for many of them,” says Dr. Shapiro. The Edmonton Protocol resulted in the first patient being able to go off insulin altogether, a result that was then replicated in seven more patients. The findings were presented at the American Transplant Congress, setting off an unprecedented response, with media and patient families calling from all over the world.
Successful islet transplantation means better blood sugar control, a higher quality of life and reduced risk of complications. “One of the very early patients has now been free of the need for insulin injections for almost 20 years, with his original transplant. Just over 60 per cent of patients continue to have measurable function,” reports Dr. Shapiro.
But – in addition to the longer-term function failure of transplanted islets – there simply aren’t enough donors. “Last year, there were 31,812 organ donors worldwide – there were 422 million people living with diabetes. If this treatment went mainstream, it would take us 90,000 years to treat everybody,” he explains.
The gap led Dr. Shapiro’s quest to find an alternative solution through stem cell research. “We’ve treated around 20 patients in Edmonton so far, and there’ve been several more treated in different centres across the U.S. in two different trials. What we’ve found is we can get the cells to survive, differentiate and turn into human insulin-inducing cells,” he says, adding that he and his team are also collaborating with scientists across Canada to find a way to enable patients to generate islet cells using their own stem cells.
What will this mean for people with diabetes? In an interview with folio.ca, Kerry Elliott, the first patient to undergo a stem cell transplant as part of the clinical trial in Edmonton, put it this way: “Diabetes is doing its best every day to kill you, and you are doing your best to stop it from doing that. To be free of that, to not have to worry about that – even for a week – I couldn’t even tell you what that would be like. It would be unbelievable.”
We have to find better ways of looking after people than we have right now. To make that happen, we must believe in the process of discovery.— Dr. Philip Halloran Nephrologist and researcher
Twenty-two years later, a patient writes to say ‘Thank you for my life’
Lori West trained as an MD, a pediatrician and a pediatric surgeon before going to Oxford University to train in medical research. “You can’t dabble around if you hope to change the field,” she says, adding that her motivation was compelling. “I worked with children who had lethal heart problems. If something didn’t change, they were going to die.”
She started by taking on one of the most daunting obstacles to her patients’ survival – the accepted notion that organs can only be transplanted between two people of the same blood type. She was convinced this didn’t apply to her infant patient population, but it meant turning an accepted clinical practice “on its head,” she explains. “It took a while to convince people that the science was sound.”
The first child who had one of the cross-blood-type transplants is now 22 years old. “He is healthy. He has a future. He wrote to me a few years ago on Valentine’s Day, the anniversary of his transplant, to say, ‘Thank you for my life,’” she reports.
Yet there are always more problems to tackle. One she’s focused on now is the anti-rejection drugs transplant patients must take for the rest of their lives to prevent their bodies from rejecting their organs. “They can have many side effects; they don’t always work. So, transplant researchers and clinicians are always asking how we can do better.”
As scientific understanding of the body’s immune system advanced over the last decade, Dr. West and her team began investigating the possibility of harnessing regulatory cells called Tregs to suppress rejection with fewer side effects.
Her national work also involves increasing donation rates. “Because we don’t have enough organs, we can’t even try with all the people who could potentially benefit,” she says. “I just met with the family of someone who died many years ago; it was so important to them to have something good come out of that tragedy. They want us to understand that it means the world to them, even all these years later, that someone is still alive because their son’s heart was transplanted.”
Helping donated organs work longer
“I can say categorically, without bias, that (Philip) Halloran is the most influential individual in transplantation over the past 25 years,” said Bruce Kaplan, professor of medicine at the Mayo Clinic in Scottsdale, Ariz.
Dr. Halloran’s work in researching the immune response to organ transplants has contributed to a dramatic drop in the rate of transplantation failures over the past 30 years, from 55 to five per cent.
A nephrologist and researcher, he has investigated the mechanisms of organ transplant rejection and injury and treatments that improve outcomes in transplantation and organ diseases. He developed the world’s leading centre for molecular studies of organ transplants and organ diseases, and recently developed the Molecular Microscope Diagnostic System (MMDx), which reads organ transplant biopsies using microarrays.
“When you first start seeing patients and think some of their problems can be solved, you think, ‘Who is going to solve them? Well, maybe I can help,’” says Halloran. “When I was in medical school, I met a kid on the ward who was my age, 22 or 23, and dying of kidney failure. It stays on your mind – you go through your career thinking that you could have saved his life, about how you can help develop solutions for people who are suffering.”
While his profession applauds his accomplishments, Dr. Halloran’s focus is fully on the future. “The goal for us is using the revolution in genetics to help make people better, to change care. We have to find better ways of looking after people than we have right now. To make that happen, we must believe in the process of discovery.”
I worked with children who had lethal heart problems. If something didn’t change, they were going to die.— Lori West Medical researcher
Caring for organs outside of the body
The University of Alberta has been a cardiac surgery leader and innovator since Canada’s first open-heart operation was carried out in Edmonton in the 1950s. Its latest global breakthrough is ex-vivo organ support system (EVOSS) technology, capable of solving two of the greatest challenges in health care: the few healthy donor organs available and the brief window of time now available for transport.
Developed by surgeon-scientists Darren Freed and Jayan Nagendran, the first EVOSS is a portable device that replicates the way breathing moves the chest cavity, ensuring a constant supply of blood and oxygen to the donor organ in transport. A vast improvement on the ice chests that have been used for the past 30 years, EVOSS prevents transport damage and even gives surgeons the opportunity to fix damaged organs before transplanting them.
Dr. Nagendran grew up “down the street” from the University of Alberta, where he trained as a doctor and surgeon. After studying at Stanford University, he returned to Edmonton with the aim of establishing a translational cardiac surgery lab. Five years ago, he was joined by Cambridge-trained Dr. Freed. “As a heart surgeon, you see it so directly – we need to do better, and we can do better. One in three of our patients waiting for lung transplants die before they get an organ,” says Dr. Nagendran.
EVOSS was first used in 2014; in October, Dr. Nagendran completed the first lung transplantation using lungs that would have otherwise been considered non-viable.
The team is now at work on a heart device, and the perfusion techniques they’ve developed are being used with livers, kidneys and, most recently, limbs. They are now commercializing the technology in order to make it available to patients worldwide.
The transplant program at the University of Alberta serves over six-million square kilometres, making it the world’s most geographically isolated transplant program. But the vision of its research team is larger still.
“An organ that becomes available here may be a perfect match for somebody in the Netherlands, and vice versa – but it won’t happen unless we’re able to keep these organs safe for longer periods of time,” says Dr. Nagendran.
UNIVERSITY OF ALBERTA’S TRANSPLANT FIRSTS
1962: Lionel McLeod develops the first chronic hemodialysis program in Canada.
1967: William Lakey performs the first cadaveric kidney transplant.
1982: The Islet Transplantation Group is founded, with Ray Rajotte as director.
1985: Dennis Modry does the first heart transplant in Western Canada and the first heart-lung transplant in the region (in 1986).
1989: The first liver transplant is performed by Norman Kneteman.
1989: The diabetes research team reports its first successful combination islet cell and kidney transplantation in patients with end-stage diabetic kidney disease.
1990: A six-year-old patient received the first pediatric liver transplant; the first infant liver transplant follows in 1994.
1998: James Shapiro and Kneteman perform the first emergency living-related donor liver transplant in Canada on two-year-old Bradley whose life is saved when he receives part of his dad’s liver.
1999: Shapiro performs the first whole pancreas transplant in Alberta.
2000: The first “domino” transplant in Alberta is performed; a type of surgery done when a donor liver causes damage to the other organs of the recipient; the liver is then transplanted to a more stable patient.
2000: Edmonton Protocol in islet transplantation is published in the New England Journal of Medicine. The publication showed that the Edmonton Protocol increased islet transplant success rates from eight to 100 per cent at the one-year mark. In 2001, clinical trials begin around the world.
2001: The American Journal of Transplantation is launched in Edmonton. Founded and edited by Philip Halloran, it has become the most successful and highly cited journal in the field.
2001: The first living donor lung transplant in Western Canada (the third in Canada) takes place.
2003: Dave Bigam performs the first intestinal transplants in Western Canada.
2004: The first infant heart transplant immediately after birth is performed.
2008: The 1,000th liver transplant at the University of Alberta Hospital is performed.
2011: Pediatric cardiologist and clinician-scientist Lori West is instrumental in the creation of the Alberta Transplant Institute (ATI).
2013: The Canadian National Transplant Research Program, a unique national collaboration, is formed and housed in the ATI. Lori West becomes its founding director.
2015: Surgeons perfuse a donated liver out of the body, which keeps the liver preserved as if it is still in the body before transplantation.
2016: Philip Halloran wins the 2016 Prix Galien research award for his work in reducing transplant failure rates from 55 to five per cent.
Produced by Randall Anthony Communications. The Globe’s editorial department was not involved in its creation.