Ex-Vivo lung transplantation: A model for medical innovation
By: Brittany Campbell
Photograph courtesy of Matthew Wu
Interviewee: Shaf Keshavjee, MD, MSc, FRCSC, FACS
Division of Experimental Therapeutics – Respiratory & Critical Care
Toronto General Research Institute (TGRI)
Clinical Studies Resource Centre Member
Ontario Cancer Institute
When Dr. Shaf Keshavjee completed his Master’s degree with the Institute of Medical Science (IMS) in 1989, he began weaving one of the most seamless blends of medicine, research, and innovation that the University Health Network (UHN) has seen yet. Lung transplantation, at the time, was only six years old. It was costly, dangerous, and often ineffective. The donated lungs themselves were often in poorer shape than the clinical eye could recognize, with no better way to assess them. Today, we can treat damaged lungs before they reach their recipient. The advances that have come from the UHN’s transplant research is now leading the world not only in science, but also in innovation and business prospects.
After publishing his first of over 300 publications on how to preserve lungs from the standard six to twelve hours, Dr. Keshavjee embarked on an endeavor to increase the proportion of suitable lungs available to patients. Completing the Surgeon Scientist Training Program at the University of Toronto allowed him to experience real clinical problems that accompanied the average lung transplantation and address them in the laboratory. “The first steps in turning around a difficult, seemingly impossible clinical problem is to do whatever you can to make a new treatment possible,” he explains. A major problem was that many of the already limited donor lungs were physiologically unsuitable for transplant. Donated lungs can be infected with pneumonia, harbour blood clots, or demonstrate poor function. The standard method of cold static lung preservation slows the rate of the lung’s metabolism to 5%, slowing the dying process, but it does not allow surgeons to address lung quality before the lung is sewn into the recipient. The introduction of normothermic ex-vivo lung perfusion (EVLP) on human lungs in 20081 by Dr. Keshavjee and colleagues would change the way clinicians around the world contend with these issues.
EVLP is a technique that involves taking the chilled donor lung and connecting it to a perfusion circuit that allows the lung to function outside the body. The lung is kept at a physiological temperature inside a specially designed, dome-shaped plastic chamber. There are various tubings and filters surrounding the chamber, designed to assess some aspect of lung function or to deliver medications that combat infection. “The lung is at 37°C, living, breathing, metabolizing…” he tells me enthusiastically. A carefully mixed solution called the ‘perfusate’ is adjusted for the correct pH, bicarbonate and glucose concentrations, akin to what our own bodies do with our blood, before entering through the tube connected to the pulmonary artery.2 No one has ever been able to watch a lung in action outside of the body before, much less have a team of doctors tend to the organ itself, preparing it for transplantation.
A successful lung perfusion can last for up to 12 hours. In this time, common issues like the deflation of alveoli or the presence of toxic waste products, are addressed. Transplant surgeons have realized that they can now operate with more confidence regarding their outcomes, and EVLP is spreading across the United States and Europe. Dr. Keshavjee credits the cutting-edge facilities at the Toronto General Hospital at UHN to allow his team to be the first in the world to successfully transfer EVLP from pig and rat models to routine human use. The impeccable standards of both clinical care and research upheld by the institution creates an environment that facilitates this level of originality and resourcefulness. “My colleagues at places like Harvard and Stanford are often really surprised to see what we have here. Our facilities are among the best in the world.”
The UHN has a history of changing medical practices. Dr. Keshavjee credits the “research machine” for turning heparin, insulin, and pacemakers into world firsts. “Our first goal is to make things possible. We fundraise and apply for many grants in order to see our ideas first come to fruition.” New techniques are, indeed, cost-intensive, which is why the research has to be goal-directed and show potential for ‘deliverables.’ “Money in, money out” he explains. As surgeon-in-chief, he looks to recruit the best talent; people who can design research questions to both help patients and be competitive on the market, so that the research discoveries can then turn around and fund themselves. “Once we’ve made a discovery, we protect our intellectual property (IP),” he explains. When that is done, medical discoveries can be turned into business opportunities that will generate the income for further investigations. EVLP, in this respect, is a success story.
You cannot miss the sparkle in his eye, as Dr. Keshavjee pulls out his iPhone and shows me photos of a half-constructed building. “We started Perfusix in Canada at UHN a year ago, now this is Perfusix USA Inc., the first ‘lung hospital’ in the world,” he divulges, “I am watching it being built in real time.” The building is a rehabilitation centre—not for people, but for donated lungs. In the near future, lungs that are removed from donors will be shipped to Perfusix to undergo EVLP before being shipped to the hospital of the chosen recipient. This soon-to-be three storey facility in Silver Spring, Maryland is the world’s first commercial provider of rehabilitated lungs using EVLP, with the intention of expanding to other organs once the techniques are in place. The culmination of years of research and collaboration that has earned Dr. Keshavjee the Order of Ontario and two Queen’s Jubilee medals has officially crossed over from research bench to the clinic and then to the business world. It is truly the cause of a paradigm shift in the field. It begs the question, with this technique available, how can a surgeon justify transplanting a lung that has not been through EVLP? It almost sounds too risky.
As both Chief Scientific Officer of Perfusix and a prominent clinician, Dr. Keshavjee is enthusiastic about what this means for the future of his patients. Perfusix’s website states its vision: “No patient should die waiting for a new organ.” The technique upon which Perfusix is centred around has already demonstrated its capacity to improve outcomes on a case-by-case basis, and now it is poised to affect the lives of thousands. “I am doing things now that did not even exist when I was student, or even during my training,” he tells me. “That’s where research brings the excitement into my life.”
Cypel M, Yeung JC, Hirayama S,et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008;27(12):1319-25.
Raemdonck DV, Neyrinck A, Cypel M, et al. Ex-vivo lung perfusion. Transplant Int. 2014; doi:10.1111/tri.12317