Profiles in surgical research: Shafique Keshavjee, MD, FACS, FRCSC

Editor’s note: The Bulletin is collaborating with the American College of Surgeons (ACS) Surgical Research Committee to present a series titled “Profiles in surgical research.” These interviews are published periodically and highlight prominent surgeon-scientist members of the ACS.

Shafique “Shaf” Keshavjee, MD, FACS, FRCSC, a thoracic surgeon-scientist at the University of Toronto, ON, is recognized internationally for his contributions to the field of lung transplantation. Early in his career, he developed the most widely used lung preservation solution, and more recently, he has pioneered the application of ex vivo lung perfusion (EVLP) to recondition and repair injured human donor lungs before transplantation.

Dr. Keshavjee has served in numerous leadership roles, including director, Latner Thoracic Surgery Research Laboratory, University of Toronto; surgeon-in-chief, University Health Network-Toronto General Hospital; member, board of directors, International Society for Heart and Lung Transplantation; and treasurer, American Association of Thoracic Surgeons (AATS). He has received numerous awards for his contributions to the field, including the George Armstrong-Peters Prize, Canada’s Top 40 Under 40 Award, and the University of Toronto Lister Prize in Surgery.

Dr. Keshavjee completed his medical education, general surgery residency, and cardiothoracic surgery fellowship training at the University of Toronto. He completed additional fellowship training in airway surgery at Harvard University, Boston, MA, and heart-lung transplantation at the University of London, UK.

Dr. Keshavjee was interviewed by Dr. Emamaullee in December 2018.

Were you the first person in your family to become a physician? What inspired you to choose a medical career?

Yes, I was the first person in my immediate family to become a physician. I definitely went into medicine intending to become a surgeon. I am not sure what specifically inspired me. One of the great things about training at the University of Toronto was that many of the clinicians were also lecturers for the medical school curriculum, so we saw a link between what we were learning and what physicians were doing in the clinic. In my third year of medical school, I heard about the first successful lung transplant in the world being done at the Toronto General Hospital. Until then, I had not even realized that a lung transplant was being attempted. During my clinical rotations, I was working with Joel Cooper, MD, FACS, the surgeon who had just done the lung transplant, so it was a case of being in the right place at the right time.

This story highlights the topic you are interested in, “how to make surgeon-scientists.” At that time, lung transplantation had been attempted 40-plus times, and every single time, the patient had died. Dr. Cooper was working in the research lab with the intent of making lung transplantation successful by sorting out the issues systematically. This methodology created a framework for me early on that going to the laboratory was how you were going to change medicine in the future.

How did you get involved in doing research?

It is critical to be in an institution that values scientific investigation and supports it. This emphasis is so important, not only for the trainees, but also for new faculty. When I was training as a medical student, I obviously saw examples of it, including my mentor Dr. Cooper. At the University of Toronto, we had the surgeon-scientist training program, where you take a research sabbatical during residency to obtain an advanced degree, such as a master of science or a doctor of philosophy degree. Your salary is supported while you focus on research and learn how to be a scientist, including preparing grants. The concept of seeing the value of the research and its connection to how you can change the lives of your patients and transform the future of medicine is one of the secrets to success in surgical research.

As surgeons, we wonder, “How can we make this possible? Patients are dying of this today. Can we do it better?” Sometimes we experience failure. We begin to think, “How can we make it safer or easier to do?” This really does make the science a lot more exciting, and I believe it is important to have complementary research and clinical practice. Your efforts will feed off each other and make sense.

There is this aspect of surgery where the good outcomes kind of blur into the background, while the patients we couldn’t help live on in our memory. I believe that doing research to try to find a way to help those patients drives us to the lab. It seems to be a common theme among surgeon-scientists.

You stayed on as faculty after completing your training in Toronto. Did the university give you a startup package and designated lab space? What was your clinical practice and research blend?

University support is an essential component to success in surgical research and is a challenging area for some institutions and investigators. When I came back to the University of Toronto after fellowship, my departmental leadership wanted me to become a successful surgeon-scientist, and thus provided me with lab space, startup funds, and designated mentorship from surgeon-scientist teachers. Of course, I wanted to be a good surgeon, so I also had operating room (OR) time and resources. However, the focus was really about getting enough time in the lab.

I think a real challenge for many academic centers is that they will hire surgeons whom they want to do science and then focus every review on clinical relative value units, case mix, and collections. At our institution, when we evaluate a new surgeon-scientist, “How many operations are you doing?” is usually the last question that we consider. In fact, we might tell them they are doing too much surgery to be focused on the science. To hire surgeons with an expectation to do research and then only focus on how much business they are bringing in creates a difficult situation for many surgeon-scientists.

In my interview with John Alverdy, MD, FACS, he stated that the next generation of surgeons is training in an environment that cultivates certainty. The expectation is that you will have the computed tomography scan before going to the OR, and if you have a negative laparotomy, it will result in a case presentation at the morbidity and mortality conference. Demanding such a high level of certainty may weed out the people who can tolerate uncertainty—which is the underlying necessity for scientists. Have you observed this transition in your career?

Yes, it has changed noticeably over the course of my career. When I was a resident, lung transplantation had become successful, but in reality, patients only had a 50/50 chance of making it out of the hospital. Now they have a 97 percent chance of making it out, at least in our institution. The expectations for these near-perfect results extend beyond our trainees. Sometimes our patients expect a miracle, and when something goes wrong, they seem totally surprised. I believe that excellent outcomes should be expected, but like you said about the negative laparotomy, we used to say, “If you haven’t seen a bunch of normal appendices, you probably were not operating enough and missing a bunch of acute appendicitis.”

I often reflect on my area of liver transplant—about Thomas Starzl, MD, PhD, FACS, and my mentors, who were facing a seemingly insurmountable task of taking on an operation that then had a 100 percent failure rate. It certainly required a certain kind of wherewithal that almost doesn’t exist anymore. When surgeons try to do heroic things in today’s climate, they seem to encounter many barriers, many naysayers, and are under the microscope.

It takes a certain amount of courage and strength to say, “OK, if others haven’t done it, that doesn’t mean I won’t be able to do it.” Surgery has evolved so that certain aspects of what you are trying to do have improved, which will enable what you are going to do. The really important consideration is how we facilitate surgeons doing unique things that have failed 40 times in a row. Once they have a successful outcome, they need the support to try again. Doing that safely and, frankly, in today’s legal environment, while also managing patient expectations, is different than it was 50 years ago.

For this reason, I have established an innovation committee at the University of Toronto, which I chair and that is composed of other innovative surgeons from multiple specialties, as well as a bioethicist, a patient, and a layperson. Any time surgeons want to do something unique and different, they present to the committee. There are different levels of presentation: one is just introducing a new device that’s already received Food and Drug Administration or Health Canada approval; then there are procedures that are new to our hospital but have been done before elsewhere with data to support successful implementation. Then there is the category of “never been done before.” We have several examples where we have successfully and safely introduced a new technology or procedure and had it become standard of care.

Obviously, lung transplantation is one example. The first three lung transplants in Toronto failed. Dr. Cooper did years of research in the lab and came back to our research ethics board and presented the animal studies from his lab and some data regarding the advent of cyclosporine for immunosuppression. The board gave him permission to do three more cases, and then they rewrote history in lung transplant. More recently, we have successfully established new procedures, particularly with EVLP. You need to create the path for innovation, which is the translation of your research into clinical care.

Can you take us back to the very beginning of your own career and developing EVLP?

When I first entered the lab as a resident, my research project was to develop lung preservation. The lung preservation they were doing at the time was very crude, an adaptation from kidney. The results had been very unpredictable, so the first paper I wrote was the method for stable 12-hour lung preservation. Dr. Cooper had given me the task of developing a reliable and reproducible method for lung preservation. Ultimately, we developed a low-potassium dextran (LPD), which is now the world standard lung preservation solution called Perfadex. That was my master’s thesis work. I started out in the lung preservation arena, but then realized that we had a unique opportunity and model to study ischemia-reperfusion injury. It is different from other injuries that can happen out of the blue; you can know exactly when ischemia-reperfusion injury will occur. We hypothesized that we could prepare the organ for that event. I started on the quest of gene therapy to repair lungs via genetic modification.

We spent 15 years working on adenoviral vector cells to help regulate interleukin-10 (IL-10)—a key regulatory cytokine both in the innate immune response and the acquired immune response in transplantation. It takes six to nine hours to get expression, and it works well in the proof of concept studies. Practically speaking, it would be highly impractical to be flying all over North America, squirting the vector in the lung prior to procurement, and then expecting all the organ recovery teams to wait for 12 hours while the lungs get better. The natural progression was to find a way to do this with the organ out of the body. The problem with cold preservation is that when you flush the organ and cool it down, you cool down all metabolic processes, so the repair or gene upregulation is slowed down. We had to find a way to do this with normothermia, except the lung dies in less than 20 minutes in normothermia.

Using a similar approach as my mentor Dr. Cooper did with me, I tasked my research fellow Marcelo Cypel, MD, with figuring out how to keep the lungs alive during normothermia. We knew that we needed to create a support system for the lungs so we could work on repairing them. Ninety percent of donor lungs were not being used around the world, and I knew many might be usable if we could improve their functional tests. So, we sought to create a support system for the lung. Marcelo showed that we could keep a porcine lung at normothermia for 12 hours outside the body and subsequently transplant it with excellent function and no deterioration. It was truly unbelievable—unbelievable to me, unbelievable to the entire field. After several subsequent porcine studies, we showed that we could take damaged human lungs that had been turned down, put them on the circuit, treat with the adenoviral vector, and bring these discarded lungs up to transplantable quality.

EVLP is not just about pumping an organ; it involves supporting the organ in a way that you can modify. It falls into the realm of personalized medicine. It is about diagnosing and treating the problems within the donor lungs. We have the drugs on the shelf already, but now we are using the system to treat infections with antibiotics, clear hepatitis C, and so on.

Over the course of developing these amazing breakthroughs, was anything particularly challenging or did you encounter a setback or incident that nearly brought everything to a screeching halt?

Of course, that happened many times over. Sometimes, when my fellows are discouraged, I tell them these stories. Back when I was doing my master’s thesis work, we had developed LPD and achieved 12-hour preservation of lungs. We then moved forward with a blinded trial in dogs. During the experiment, every dog started dying. We did the transplant, and everything was perfect, and then severe reperfusion injury set in. I was a junior surgeon. I questioned my own technique and the protocol and still could not understand what was happening. Dr. Cooper came to the lab and told me that he trusted my technique. He suggested we look at things systematically to figure it out.

My wife was a surgical resident in the general surgery lab next to me, and she asked me what was in the preservation solution. She noticed that the pharmacy had been making it for us. She suggested that we make it ourselves. I told her that honestly, I didn’t know how to make a solution. So she made the solution herself, according to the composition, and guess what? It worked. We set out to repeat the experiments with the solution we made ourselves, and they were successful. It saved my master’s thesis and has since become a $20 million a year product used globally. Perfadex is the standard of care for preservation of human lungs. We later realized that our pharmacy had changed their sterile water supplier, from one that had used glass bottles to one that was using plastic bags. I took the solution that was killing all the animals, as well as the solution that was working, to our chemical engineering lab. They did mass spectrometry on it and found 500 kilodalton particles in the bad solution. Ultimately, we discovered that these particles were clumps of dextran, which only formed when the solution was exposed to plastic. After solving that problem, every experiment worked, I completed my thesis work and publications, and its eventual commercialization changed the practice of lung transplantation.

Does your wife, Donna McRitchie, MD, FRCSC, take credit for your success after that?

She takes credit for all of my success, and she’s the one who deserves the credit.

How did you get through your first grant application as a young investigator?

I had a lot of mentorship. My master’s thesis committee included Dr. Cooper; Alec Patterson, MD, a critical care pulmonologist; and Art Slutsky, MD, a lung injury specialist. One other traumatic setback I experienced was when Dr. Cooper announced that he was moving to St. Louis, MO, one year into my thesis. Dr. Patterson graciously offered to take over as my supervisor, with Dr. Slutsky’s help. I don’t think I was a hard student to supervise, but I did need supervision. When I was writing my first Canadian Institutes of Health Research grant, Dr. Slutsky advised me to first go after some of the low-hanging fruit, including early investigator grants from the ACS and the AATS. He said these awards would improve my credibility and help me generate preliminary data so that my larger grant would be successful.

I think I’ve been very successful with grants and with papers partly because I’ve succeeded in picking projects that are going somewhere. I like to work on something that I believe is going to make a difference. By design, these are projects that carry more risk. You think to yourself, “If we could achieve that, it would really change this whole game, wouldn’t it?”

When you planned to move forward with clinical trials of EVLP, what barriers did you face at your hospital?

Honestly, I got very little pushback. Partly, it was because I was at the University of Toronto, standing on the shoulders of giants. When our lung transplant team came forward, presented our preclinical data, and offered a well-conceived clinical trial, they took us seriously. Thus far, we have delivered without damaging the hospital’s reputation, and we have done things that have resulted in positive international impact for our field. I think that is something I learned from Dr. Cooper, who told me the story of the first lung transplants and even gave me copies of the original institutional review board (IRB) application. When he made the case to do another lung transplant, the IRB requested three cases, because it was such a high-risk endeavor. They emphasized that if one case failed, it did not imply that it’s not a worthwhile procedure to pursue.

The other important consideration is the patients. I went to them and showed them the preclinical data. I explained that the first thing this study would do is increase the number of lungs that we can use and make better lungs in the future. I told them we would be coming to them at weekly lung transplant patient support meetings and giving some educational talks about the process of lung transplant, including our ongoing research efforts. I explained that we anticipated that we would get approval for this, and then when we were ready, we would ask them to consider being involved. At the end of one meeting, I was swarmed by patients who wanted to be the first one.

What is the status of lung utilization in Ontario? What proportion of lungs can you transplant?

It’s a moving target, but I would say we’re around 40 to 50 percent transplanted. We have been able to double the number of lung transplants we do. We’ve done 180 this year.

More recently, you have developed a business aspect to your research. Can you describe how that happened and what that experience has been like?

So, I told you that my master’s thesis project resulted in Perfadex. I have never received a penny from that, and neither has my institution. At the time, nobody understood the big impact it would have because we were the busiest lung transplant program in the world, doing four to five cases per year. Companies were not interested because of the low numbers. So that was sort of a failure that I didn’t care about at the time because my primary focus was making lung transplant safer and making more transplants possible. A company in Sweden picked it up. It started manufacturing it, we started buying it because I was tired of making it myself, and the rest is history. When you fast-forward to the new innovations that we’ve done in terms of EVLP, I realized that the only way to get this technology to patients and to scale it was to produce a product that can be approved, go through the regulatory process, and then be available to be sold to hospitals.

Initially, every center wanted to do EVLP on its own like we do in Toronto, but in practice, it requires a lot of manpower. In the beginning, my fellow and I did most of the EVLP. We would then give the transplant case to one of our colleagues because we had to make sure we got it done right. We would give them a perfect lung to transplant. After a while, I realized that I did not want to be tinkering around with a lung for six hours and then have to do a lung transplant operation after that. So that’s where I divided the service model. We trained other people to do it. It created a whole new category of health care workers called organ procurement specialists who go through a course that examines everything a hospital needs to be certified in organ perfusion.

A colleague in Chicago, IL, called to tell me about a very sick patient on extracorporeal membrane oxygenation. He had a marginal lung offer in another state. He asked if we could do EVLP on the lung in Toronto prior to transplanting it in Chicago. We got compassionate approvals from his institution and mine. We flew the lung from Wisconsin to Toronto, repaired it on EVLP, and then flew it to Chicago, where it was transplanted and saved the patient. That experience gave me the idea of the organ repair center. I realized that not only did I not want to do EVLP myself, I did not think every institution was going to be able to do what we were doing at Toronto General.

It’s analogous to the development of blood transfusion. The first blood transfusions were from a healthy soldier in the field to a hemorrhaging soldier, and although they saved lives, you can imagine that they probably killed a few people with transfusion reactions and infections. We now have blood collection centers, which collect blood via standard operating protocols under properly delineated conditions; then it is properly tracked, identified, safety controlled, tested for infection, stored appropriately, and so on. That is where we need to go with organs. Every time there is a donor, up to five surgical teams descend upon one hospital, procure their organs, and then go back to a different hospital. This inefficient process results in variable quality, and a lot of wasted and unused organs. Imagine the model where organs will get picked up; taken to an organ repair center; checked, modified, optimized; and then sent to the recipient who needs it.

We have two organ repair centers in the U.S. so far. One is located in Silver Spring, MD, and is providing EVLP lungs to Duke University, Durham, NC; the University of Maryland, College Park; the University of Pittsburgh, PA; the Cleveland Clinic, OH; and the Mayo Clinic, Rochester, MN. The second is being built in Jacksonville, FL. A third is planned for Phoenix, AZ, with additional gene therapy capabilities. We believe that having centers in Toronto, Silver Spring, Jacksonville, and Phoenix will enable us to provide EVLP lungs to the whole North American continent.

Our next phase is to scale so that the organ recovery technicians can monitor 10 lungs simultaneously rather than one at a time. This is how we are going to scale it. In Toronto, we have used EVLP lung transplant in more than 450 patients. If you put a lung on the Toronto EVLP, the average utilization of the organ is 70 percent. In other words, there’s a 70 percent chance you’re going to get a lung that you’re going to transplant with good results.

Back when you were standing at the bench with your wife, remaking your solution with clean water, did you ever imagine that you would be talking about a “lung in the box” traveling to hospitals all around North America?

No. I knew I was going to work hard and try to achieve great things. I didn’t even realize how my master’s thesis would change transplant at that time. We used to take turns sleeping in the bed next to the post-lung transplant patient in our intensive care unit (ICU) for the first three days. Those patients were so sick with reperfusion injury. The surgical fellows would sit there manipulating the inotropes and vasoconstrictors to just keep the patient alive. When we started using LPD solution, if you did a lung transplant, you would drop the patient off in the ICU with a junior resident looking after them, and then go home and sleep.

You had several successful mentees along the way. How do you mentor your trainees and junior faculty?

The most important aspect of mentorship is the natural connection between the mentor and mentee. We have made mistakes in the past by assigning and insisting on a pairing. I still talk to Dr. Cooper to this day, 25 years later. Your mentor has to be someone you can connect with, someone who cares enough about you, but someone that you actually identify with or admire or want to be like. When students or residents come to you with excitement in their eyes, you want to help them. You need to be careful to not take on too many and to properly look after them. During some of the busiest parts of my career, I sometimes felt that I didn’t do as good a job of mentoring. When it comes to our fellows, I take on trained thoracic surgeons and train them in science. We’ve done great things with the engineering students who don’t even know medicine. They have wonderful insights into developing a machine to support a lung.

What do you think we could do to make being a surgeon-scientist sustainable for surgeons coming out of training right now?

We have many successful examples of them from within our own group. They have succeeded because we function as a team, so they are less vulnerable between grants, and we can help each other.

Do you think the Canadian health care environment makes it harder? I know some of my friends who I trained with along the way have struggled to find a good surgical research job in Canada.

A lot of people ask me why I am at Toronto General Hospital. I’ve been offered some pretty incredible, high-profile jobs in the U.S. The University of Toronto and the University Health Network create a unique, remarkable environment. I can think of no better place on the planet to work as a thoracic surgeon. Our department really values excellent patient care, research, and education altogether. I think we have the biggest critical mass of surgeon-scientists possibly in the world but definitely in Canada. It does take commitment and sacrifice. You want to hire people who can operate, but you’ve got to facilitate it. When you set up new surgeons in the division, they must have predictable OR days so that they can have predictable lab days to meet with their collaborators and their students. More often than not, new surgeons in the division get the leftovers. They are operating Tuesday this week, Friday next week, Wednesday next week. Most of the time, I come down on the division chief, saying, “Wait a minute, what do you mean he doesn’t have a fixed OR day or clinic day? How do you expect him to do two full-time jobs, surgery and research, and you don’t even set him up for success?”

It sounds like you have had multiple careers all at the same time. What do you like to do outside the hospital?

One of the other secrets to success is to have interests outside the hospital and make time to enjoy them. I prioritize spending time with my family. My wife is a surgeon and vice-president of the hospital. My daughter is applying to medical school. We have a house about an hour’s drive away on the Niagara River. We go bicycling, and I play a lot of tennis. I travel a lot for work, and I really enjoy teaching and talking about the work we’re doing.

Any closing thoughts?

I feel very fortunate for the career I have built. Obviously, it does take hard work and talent, but on the other hand, you need to be given the right mentorship and opportunities. Researchers need to be persistent, resilient, willing to take risks, flexible, and adaptable to their environment. Surgeons are at the forefront of disease, and as a result, have insight into the challenges facing medicine in the future.