Tom Starzl, as he was known, will be forever recalled, researched, and googled for his profound impact on Transplantation. He pioneered liver, small bowel and multivisceral transplants. In the process, he revolutionized He patology and Immunosuppression. Among the amazing things he gave us, are:

Tom Starzl, as he was known, will be forever recalled, researched, and googled for his profound impact on Transplantation. He pioneered liver, small bowel and multivisceral transplants. In the process, he revolutionized He patology and Immunosuppression. Among the amazing things he gave us, are:

• An understanding of liver physiology and liver regeneration
• Liver transplant, as standard therapy for end stage liver disease.
• Multi-drug immunosuppression: standard management now for all organ transplants
• Successful transplantation across perceived barriers of genetic and racial dissimilarity.'
• Chimerism – ‘the epiphenomenon that continues to be researched.'
• Tolerance - an achievable goal following solid organ transplant.

The Nobel Prize eluded him, although he received every possible honor for original science, on offer in the world during his lifetime. At his 90th birthday celebrations, in Pittsburgh, before an international crowd of his former Fellows, the US government confirmed his stature by naming an entire week in his honor. I was seeing him again after 10 years, and thought he looked more frail than before. Starzl, at 6 feet tall and 155 lbs, had always looked frail. The iron will was hidden– like the ore beneath the picturesque hills of his adopted hometown. His steely toughness was evident to those who encountered or crossed him as he tackled the most complex problems of his time in medicine, surgery, and the allocation of precious resources. His endurance was legendary. He was still working, at ninety, and we thought the Old Man is going to live long enough to force the Swedish committee to give him the honor he deserved, but that was not to be. A week before his 91st birthday he went home after work, exhausted, fell asleep, and did not wake up.

He had spent his lifetime in pursuit of truths never before revealed to man. At the beginning of his career, however, financial difficulties common to ill paid residents of his time almost derailed him into private practice. The movie of a 14 hour operation he performed in 1958 while still a Fellow - successful repair of an occluded aorta, revascularising all abdominal organs – became a smash hit at the Annual Conference of the American College of Surgeons the following year, establishing him as a surgical star. Thirty years later, people who had seen that movie still asked him about it. But his own assessment of the operation, was that it was, “… an inherently inconsequential contribution”. The paper he had really gone to read, about liver transplantation in dogs, did not attract much notice. His presentation did not go well because of his “inexperience in public speaking”, and his low self esteem was worse for not having hospital privileges to see patients. He was, by his own admission, the designated “dog surgeon” and “rat doctor” at Northwestern, Chicago, surviving on scholarships and grants.

Transplantation was not Starzl's primary interest. His research background was in neuroscience as a medical student on PhD/MD track. As a resident in John Hopkins he was part of Alfred Blalock's unit, caught up in the race to start open heart surgery. He first got interested in the liver while actually trying to investigate diabetes and the fate of insulin conveyed via the portal vein from the pancreas. The liver was in the way, and removing it might help. The experiments failed, and might have ended his career as a research scientist, if he had not in the process become adept at keeping dogs alive after total hepatectomy. Sewing in a new liver was relatively easy for Starzl after this formidable procedure, and he proceeded to do that, swerving from diabetes to cutting edge transplantation research. Later, by elegant operations he would show that the liver depended for its survival on portal flow; and the 'hepatotrophic factors' that came in portal blood could not be reliably partitioned to support an auxiliary liver transplant – technically an easier undertaking. The more daunting operation of orthotopic liver transplant would require getting used to. It is regarded even today, as perhaps the most complex operation routinely performed. The reason it is routine is because Starzl did not try to pursue the “Spectacular Surgery” paradigm, preferring instead to perfect, simplify, and teach the technique to protégés who he expected would strive to exceed their guru.

Starzl was among the first to recognize that the key to success in transplantation was immunosuppression. Accordingly, he temporarily diverted his focus to kidney transplants. The technically simpler operation of kidney transplant, lent itself to precision with intra and post op management. Radiation could immunosuppress, as observed in Hiroshima, but sick patients with renal failure often died when irradiated. The mustard gas derivative 6–mercaptopurine, a 'gift' from the earlier World War, worked better, especially in combination with steroids - recognized by Medawar, at Oxford, to help skin grafts survive.

He was by this time done with the politics of Chicago, and working in Denver. Energized perhaps by the rarefied air of the 'mile high city', Starzl hit his stride, combining clinical and experimental work. His first series of kidney transplants, the largest ever at the time, provoked a gasp of astonishment, heard across the world wherever transplant science had started and faltered in the search for twins as donors. Starzl had succeeded in genetically non identical transplants - regarded impossible in 1963 – and “invigorated” the field by proving they worked. He attempted the first liver transplant in 1963, and succeeded only 4 years later. It is important to note that his early donors were non-heart beating (NHB) cadavers, as brain death was not at the time recognised in law. Ischemic tissues provoke a profound innate immune activation, and the tools to combat this were 50 years away. The early deaths were probably due to primary non-function, which even today makes liver transplant from a NHB donor daunting. Altogether by the time he left Denver for Pittsburgh in 1981 he had performed 165 liver transplants and over 1000 kidney transplants. He had become Professor and Chairman of the department of surgery, gone through a painful divorce and remarried, this time to his lab assistant, almost thirty years his junior. The Czechoslovak – German – Irish – African – American combination proved powerful, and durable. Joy Starzl remained by his side for the next 36 years, a bubbly effervescent and contrapuntal presence, true to her name and true to the end.

Moving to Pittsburgh in 1981, Starzl focused on Transplantation full time. He took cyclosporine, a nephrotoxic discard at the time, and figured out how to make it work using blood levels to individualize each patient's dose. It led to phenomenal improvements in outcome, and liver transplantation was recognized in 1983 as no longer “experimental”. The commitment of the university was total, and the return on investment Starzl brought was equally spectacular. In 1993, University of Pittsburgh Medical Center (UPMC) built a new research block, connecting to the hospital, and spent as much as England and France together could muster for the Channel Tunnel. Patients from all over the world flooded the hospital. Royalty, and heads of governments, were managed by Starzl's Fellows - an eclectic crowd from every corner of the globe: Japanese, Chinese, Koreans, Greeks, Italians, Spaniards, Swedes, Canadians, Argentines, Brazilians, Mexicans, and of course Indians. The Indian contingent had a reputation for clinical skills and surgical technique, and most importantly was the core group behind Tacrolimus. Vijay Warty, Venkat and Ashok Jain were the ones Starzl and John Fung, newly appointed Director of the Starzl Transplant Institute, depended on to push Tacrolimus through to FDA approval in 1994.

With Tacrolimus came an explosion of small bowel, pancreas, and multivisceral transplantation. Starzl exasperated everyone by refusing to conduct randomized controlled trials with the now established Sandimmune, and it took the pundits the rest of the millennium to accept he was right all along. Tac was the better drug, and Pittsburgh the Mecca of transplantation. Starzl publicly crowned Satoru Todo the best surgeon in the world, and went back to the research lab to work on the Holy Grail of transplantation: Tolerance. Or the ability of a graft to survive without (or with very little) immunosuppression, while the recipient retained the immune capability to fight off infections.

Earlier, Starzl had steadfastly refused to accept tissue matching (HLA antigens) as the basis for transplanting solid organs. Apart from there being not enough evidence that it was necessary, he knew it would discriminate against minority populations in deceased organ allocation. He found an unlikely ally in Terasaki, the HLA pioneer, who accepted, at great personal academic loss that for solid organs there was no need to match HLA.

He observed 'chimerism': the survival and coexistence of donor and recipient cells in peripheral blood and tissues. Thus, a male who had received a female donor's liver could have circulating female WBCs (with Barr bodies), several years later. He knew instinctively, that this was significant. Transplanted organs were not just a spare part, but were actively engaging the immune system of the host, and might perpetuate their own survival. This could possibly explain why a liver transplanted into someone with hepatitis C could survive undamaged by the virus for the recipient's life span, and kidneys transplanted into diabetics could function unaffected by the blood sugar abnormalities they were exposed to.

After much work in the lab, and the failed bone-marrow + solid organ transplants of the '90s, Starzl introduced “Tolerogenic immunosuppression” in the 21st century: lymphocyte depletion prior to revascularization of the graft, and maintenance with a single drug – low dose tacrolimus only. He showed that clinical toleand might have ended his careerrance was achievable. His works on tolerance endures, has inspired many, and are a chapter in the Starzl story which continues to be written.

To quote Joy Starzl, “…nobody who spent time with Thomas Starzl could remain unaffected. He will be greatly missed”.

PERSONAL RECOLLECTIONS:

To comply with an editorial request to mention some personal  anecdotes of working with Starzl, and, not wanting to burden the reader with maudlin memories, I add the following briefly:

My acceptance to the Pittsburgh Fellowship was by the simple process of writing to Starzl, and sending him my CV. Replies were courteous and prompt, and his assessment was I was a suitable candidate for his Fellowship program. (I had at the time, worked 12 years as a general surgeon, been a Hepatobiliary fellow with Leslie Blumgart, and done 6 months with Paul McMaster in multi organ transplant at Birmingham UK).There were several foreign graduates like me at Pittsburgh, handpicked by Starzl. The State Board couldn't or didn't enforce licensing requirements for a Transplant Fellow.

Following a heart attack and a CABG operation, he handed over Administrative control to John Fung by 1992. Licensing rules immediately changed for foreign graduates. I had to satisfy the Board that I had a Faculty appointment in my own country (I was Associate Professor, Bangalore University at the time), plus 20 indexed publications. The Fellowship was regarded the toughest in the US at the time, with over 400 liver transplants per year. Five Fellows joined with me in July 1993, and by December four quit. In January of 1994 the other survivor had a heart attack while on ICU call! (He was admitted to CCU, had an angioplasty and bounced back into the fray to everyone's relief).

Starzl was closely involved with everything that went on in the unit. He would always attend the research meeting on Monday and several of the weekly meetings where clinical work was reviewed. He would show up unannounced to see patients on the floor and the ICU, resulting in a scramble to present the patients he had come to see. I enjoyed these encounters. His wall charts (mandatory for every patient) were succinct and gave him all the information he needed at one glance. His analyses, his instructions, his words, were an education better than anything ever written, or what I had ever read.

The hot topic at research meetings was Tolerance, and how to make our clinical management “tolerogenic”. We would admit patients Starzl had transplanted decades earlier who were off all immunosuppression, to do studies of their chimeric profile : how much of their donor's cells were floating around in areas other than the transplanted organ. It was like science fiction.

Operations were done to a drill. Every surgeon in the unit operated exactly the same way. It was the way, we were assured, and that Starzl himself had operated. Individual technical preferences –

“Starzl’s wall charts, mandatory for every patient, were succinct and gave him all the information he needed at one glance. His analyses, his instructions, his words were an education better than anything ever written, or what I had ever read.”

That most toxic surgical variable - were eliminated. Soon I was also operating the same way, giving up whatever I had learned or acquired along my surgical journey up to that point.

Since then, I have changed, as the operation of liver transplant itself changed and evolved. But one thing has remained: the surgical knot that Starzl insisted on; and when I see someone operating, I immediately know if we share a surgical “ancestor”. The first throw is 'square' and snug, the second, a 'granny' which you cinched millimetrically onto the first knot. Then two 'reefs', for a total of four knots.

The preferred material: “four-zero” silk, prone to breaking unless handled delicately. You had to throw these knots reliably and with speed through long operations at all odd hours of day or night. No knot could slip, break, or tear tissue. This was just one example of what Starzl meant when he said success in liver transplant was achieved not by some great flash of brilliance but by obsessive attention to detail.