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In View: People in Transplantation

Dr Andreas Gerasimos Tzakis, MD, PhD, Dhc (mult), Professor of Surgery, Emeritus Director of Transplantation, Cleveland Clinic

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doi: 10.1097/TP.0000000000003807
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Life is short and Art is long; opportunity fleeting, experiment treacherous, judgment difficult

—Hippocrates

You attended Medical School in Athens and then continued your postgraduate training at Mt. Sinai, New York, NY and SUNY at Stony Brook, Long Island. What made you move from Greece to the United States?

AGT: I wanted to have the best Surgical Training.

As a student, I spent parts of my vacations in European Hospitals. I saw that trainees in Europe were exposed to more patients and surgeries than those in Greece. This discrepancy was even greater in the United States. The Surgical Residences in the United States were very competitive and even more so coming from abroad. I excelled in Medical School and the International exams and strongly believed that I could succeed. In America, I could reach for the stars and I was ready for the adventure.

You then continued with a transplant fellowship at the University of Pittsburgh. What formed your interest into transplantation? What were experiences during the interview process at the time?

AGT: After my General Surgery training, I wanted to specialize in liver surgery. At that time, major liver programs were centered in Memorial Sloan Kettering with Fortner, Emory with Warren, and Pittsburgh with Starzl. I always admired Dr Starzl’s work. He was a visionary and had no equal as a master surgeon and innovator.

I applied to work with him and when he invited me for an interview, I was off to Pittsburgh in a flash.

The interview was friendly, but Dr Starzl was not familiar with the surgeons at SUNY Stony Brook who recommended me. He only knew Dr Felix Rappaport who was the director of the Kidney Transplant Program and asked for his letter of recommendation.

I had never met Dr Rappaport since surgical residents did not rotate in Transplantation. He was a pioneer and, like Dr Starzl, brutally truthful. The best he could do was to poll and write a letter combining the opinions of surgeons in the program.

He showed me the letter. It was a mixed review: some thought that I was the best trainee they had ever seen and some the polar opposite. The letter was already sent to Dr Starzl: it was “water under the bridge” Felix said.

I thought that I was doomed.

One night, I was making late rounds when I was paged overhead for an incoming call. It was Dr Starzl’s secretary, Nancy Hartman. Dr Starzl picked up the phone quickly and told me that I was accepted… “if I still wanted the job.” It was a moment I will never forget.

I always appreciated Felix’s rectitude. We became friends and he was a great supporter.

Your training in Pittsburgh under the guidance of Professor Starzl and as a faculty member has been formative in many ways. You have described this time of your life as “blood, sweat, and tears.” How would you describe the mentor style and what made you the expert surgeon that you became?

AGT: Dr Starzl taught by example. He worked tirelessly and had an uncanny ability to see opportunities where others saw failures. He was a superb surgeon and cared deeply for his patients. He demanded total commitment from his team.

His assessment at the end of my training was that “nobody worked so hard and achieved so little.” The truth is that I cared for many patients and learned a lot more than even Dr Starzl realized. In addition, I wrote an article describing for the first time “The clinical presentation of hepatic artery thrombosis.” It showed that the “Achilles’ heel” of liver transplantation was not the biliary anastomosis, as was thought, but thrombosis of the hepatic artery. This article has many citations.

You have been a pioneer in intestinal transplantation, an area that remains most challenging in our field. What do you consider critical barriers in intestinal transplantation today? What do you suggest as a research focus?

AGT: The main barrier remains late intestinal graft failure and patient losses. In many cases, rejections are not diagnosed until the damage is irreversible.

The stomach, jejunum, ileum, and colon act as immunologically separate organs and develop nonsynchronous rejections. Endoscopy is the main diagnostic tool. It is invasive and does not always access the entire graft.

On the recommendation of Professor Jean-Marie Saudubray of the Hospital Necker, we examined serum citrulline as a marker of intestinal rejection.

Citrulline is a nonessential amino acid. It is found only in liver mitochondria and the intestinal mucosa. Circulating citrulline originates exclusively from the intestine. Dr Phillip Ruiz, our lab director, developed a method to measure serum citrulline in a dried drop of blood from a finger stick. It can be mailed as a protected paper sample, much like a stool guaiac.

We were able to define critical values which indicated intestinal damage after transplantation. Like serum markers used in kidney and liver transplantation, this change is not specific for rejection, it can also be attributable to infection or ischemia. Low citrulline levels simply sound the alarm.

Citrulline is a valuable marker. Discovery of additional “early warning” markers should improve the results of intestinal transplantation.

You participated in many “Firsts” during your time in Pittsburgh and later at the University of Miami and the Cleveland Clinic. One of those firsts were 2 baboon-to-human liver transplant. What were thoughts going into this procedure and lessons learned? Fast-forwarding 30 years: what do you see as next steps in moving xenotransplantation into the clinic today?

AGT: I knew, going in, that this procedure was controversial, however if successful would be transformational.

Performing the surgery was a huge responsibility, but I had a “dream team” assisting me: Satoru Todo, John Fung, and Ignazio Marino. The transplant was uneventful; the patient recovered promptly and left the ICU… but not the Hospital. He eventually died of an infection >2 months later. A second patient fared worse. The trial was terminated.

Analyses showed that the liver produced metabolic products (including baboon proteins, uric acid levels, and others) which were appropriate for baboons but had unknown long-term effects in humans. Moving forward, the choice of the liver graft for xenotransplantation must be reconsidered.

The field evolved and is highly sophisticated and exciting. I have been following the work of Dr Joe Tector, who studied Clinical Transplantation with us in Miami and is a leader in this field.

He has published consistent 500-d survival in pig-to-primate kidney transplants. Dr Bruno Reinhart has published similar results with hearts.

The pigs are genetically modified to secure a favorable immune reactivity. All animals are grown in secluded farms.

The next step is the final development of simple immunosuppressive regimens that clinicians and regulatory agencies can support for phase 2 and 3 clinical trials.

The infectious disease aspects of xenotransplantation have been rigorously investigated, particularly considering the COVID pandemic. PERV has been evaluated for >20 y. It is clear that this virus carries minimal risk of human transmission.

However, laser focus must be continued to identify new pathogens; carriers must be removed from consideration as donors.

You did not only have an interest in solid organ transplantation but also contributed critically to the progress in vascular composite tissue allotransplantation with “First” in abdominal wall and deceased donor uterus transplantation. Where do you see the biggest hurdles for uterus transplantation? How would you advice to balance live versus deceased donor uterus transplants?

AGT: There are critical differences between abdominal wall and uterus transplants.

The abdominal wall transplant is effectively “vital.” It has been used for patients with intestinal or multivisceral transplants when the abdomen cannot be closed with native tissues. Without it, recipients are exposed to fatal or incapacitating complications. Ethical approval and funding have not been major hurdles.

Uterus transplant, to the contrary, is an “ephemeral” transplant. It is designed to serve for the birth of 1 or 2 children and then to be removed. It is an option for women with uterine factor infertility.

Ethical approval, informed consent, patient selection, and funding have been approved at institutions where these transplants take place. There is currently no major extramural funding.

The demand is great. Three active clinical US programs have received >2000 unsolicited applications. The early experience has been favorable worldwide. Success, defined as a healthy mother and a healthy baby is achievable with both, live and deceased donors.

The recovery of the uterus from a live donor involves a very tedious dissection which lasts >10 h in the most experienced hands. Its main peril has been preservation of donor ureters. Indeed, every active program using living donors has seen at least one such complication. The safety of the live donor is a serious concern.

Recovery of a uterine graft from a deceased donor is straightforward and does not interfere with multiorgan donation. The procurement in deceased donors takes approximately 1.5 h. Availability of appropriate deceased donors has been the greatest barrier.

I had the good fortune to participate in both living and deceased donor uterus transplants. I believe both need further development. In my judgment, the scale is currently tipped in favor of deceased donors.

You have helped starting transplant programs around the world. Can you share some of those experiences with us?

AGT: Most memorable were 2: starting the pediatric, living donor, liver transplant program at the “Hospital Pequeno Príncipe” in Curitiba, Brazil, and the first multivisceral transplant in Israel at the Schneider Medical Center in Petah Tikva, just outside of Tel Aviv.

The Brazilian experience was straightforward and is a wonderful memory. The team were Julio Wiederkehr from Curitiba, Tom De Faria, Rodrigo Vianna, and myself from Miami. All donors and pediatric recipients recovered uneventfully.

A busy week in Surgery ended with a fun bike ride and dinner at the Rain Forest.

The second experience was very different: nothing was simple.

The recipient was a 10-year-old, blood type A, girl with intestinal pseudo-obstruction and liver failure. I met her during a trip to Israel…

Treatment required a multivisceral transplant. It had to take place in Israel attributable to funding limitations. There was no prior local experience with multivisceral transplants. The transplant team, Drs Ran Shtainberg, Eitan Mor, and Eviatar Nesher asked me to participate in the surgery.

We all realized that the logistics were nearly impossible. There were very few pediatric donors in Israel, let alone of appropriate size and blood type for the recipient girl.

In addition, there had to be enough time for me to fly from Miami to Tel Aviv.

Being in the Holy Land, I hoped that divine intervention would bring about a miracle for this child.

Several months later, I was enjoying the last day of a short trip to Greece with a bike ride on my favorite mountain trail outside Athens. Suddenly, I received a call from Freddy Rosenfeld who represented the Insurance Company of the child. I knew Freddy well because he always took personal interest in every patient he referred to me. There was a pediatric donor available. He was of appropriate size but was O blood type. Should we move forward? The decision of the entire team was unanimously YES!

Freddy sent an Air Ambulance to Athens. The transplant proceeded perfectly. I left the operating room the following evening, just in time to make the nonstop flight back to Miami. I was home the following morning.

The child had a completely uncomplicated postoperative course. Years later, I received her picture in IDF uniform. She is a strong and beautiful young lady. Miracles do happen…

Patients have always been at the center of your work. Can you share your favorite patient story with us?

AGT: As I mentioned, I had a pretty rough fellowship. Dr Satoru Todo and I trained at the same time. At the end of 2 y of training, neither one of us was allowed to do liver transplants in humans.

One day Dr Starzl called us both to his office. He announced that we would be allowed to operate independently under the condition that we always worked together. We alternated roles as surgeon and assistant.

In this particular transplant, I was the surgeon, Satoru was my assistant.

The transplant progressed perfectly until reperfusion of the liver when the patient had a sudden cardiac arrest. We started resuscitation immediately, but after >1 h, there was no cardiac activity. The graft looked very dusky.

The anesthesiologist, a very experienced and respected part of our team pleaded that we stop. She thought, even if resuscitation succeeded, the patient would be brain dead or severely damaged. When we refused to stop, she called Dr Starzl to intervene. It was the very early morning hours.

Dr Starzl came to the Hospital immediately and peeked from the door of the operating room. He asked if I would consider stopping, I responded that I wanted to keep trying. He granted me permission to carry on and left.

After many more attempts, the heart started pumping, the liver perfused well and we were able to complete the transplant. The climate in the operating room was very somber until, as we were transporting the patient from the operating room table to the transport bed, he gained consciousness. As a matter of fact, he recovered completely with no neurological damage!

I called Dr Starzl immediately with the good news. We did not know he was watching us from the overhead amphitheater of the operating room!

The patient is alive and well >25 years later. Hypothermia very likely caused the cardiac arrest, protected his brain, and saved his life.

It also changed my life… After that day, Dr Starzl concluded that I was no longer a trainee, I was now a teacher.

The many awards you have received include not only 3 honorary doctor degrees in addition to some of the highest awards in our field including the 2020 TTS Thomas Starzl Award but also 2 Guinness Book of World Record references. Can you share some of the details of your “World Record” Awards?

AGT: I have been humbled by these honors. They were very meaningful to me because they brought happiness to my family, friends, and particularly my late mother and father.

My father had copies of newspaper and CNN videos of my surgeries and awards. He shared them with his friends. We lived far from each other, but he knew that his work of a lifetime paid off. The ceremonies of the Honorary Degrees were always memorable. The ceremonies in Gothenburg were distinctively formal and unlike anything I experienced.

I had great company: my wife Patricia, Michael Olausson, and his wife Marie. My brother Michael, who years before had obtained his PhD in the Dental School of Gothenburg, made a surprise trip from Greece and joined us. It was an unimaginable dream come true.

You are unique in many ways. In our field, you bridge the generation of early pioneers to those who currently try advancing a regulated, nevertheless exciting field. How would you describe your mentoring style?

AGT: I tried to teach the trainees by example, as Dr Starzl did for me. I taught them that the brain is the surgeon’s most important tool.

I think of an operation like a battlefield where the enemy is the pathology. It must be defeated with the least possible blood loss. This requires careful study, planning strategy as well as decisiveness, vigilance, and adjustments. The surgeon cannot always follow the same steps, there must be a backup plan, one may need to improvise and go behind enemy lines.

The trainees were full participants in all team activities including clinical research. They had opportunities to write manuscripts, develop protocols, and submit grants. What they absorbed in their training depended primarily on them. Career development is a difficult task, it has never been easy or a straight path. They must remember that big problems are also big opportunities.

This was a very intense transplant program including all abdominal organs. There was no time set aside for basic research. Interestingly, several including Joe Tector engaged in very stimulating basic research after their training.

We followed our patients in perpetuity; I am still in touch with many of them.

This is only possible if there is a seamless collaboration with the medical specialists and dedicated nurse coordinators. The patients are the main beneficiaries of such comprehensive follow-up.

An additional benefit is the ability of the team to study patients in the long term. We learned to adjust their immunosuppression and completely stopped it in >100 liver recipients who remain operationally tolerant of their grafts.

It is extremely satisfying to see the fruits of our labor.

You ended your wonderful acceptance speech for the TTS Thomas Starzl Award referencing your Greek Countryman, Hippocrates. “Art” for Hippocrates as we understand it referred to technical aspects rather than “fine art.” As a most energetic, collegial, and friendly emeritus: How do you like to spend your time outside of transplantation?

AGT: I love studying history. There are no more exciting stories than those that really happened!

I enjoy bicycling on and off the road. It has been my favorite past time since childhood. Now, with modern technology, I even like bicycling indoors!

I am finalizing the “One Shot,” a stapling device that can do anastomoses of hollow viscera with just one move! It is based on the roll over sleeve technique that I described in 1990. After many failed attempts, I work with an incredibly gifted engineer and have developed a functioning device. It can be seen on YouTube under “Zakease: One Shot Surgical Stapler.” It is currently being converted for use in laparoscopic and robotic surgeries. It is our dream to bring it to clinical use.

I like to watch the Ocean and dream. Love of the sea, dreaming and adventure originate from my Greek genes.

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