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ICTS: Editorials, Perspectives and Recognition Awards

Medawar Prize Acceptance Speech “Connections”

Dubernard, Jean-Michel

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doi: 10.1097/TP.0b013e318191261b
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Dear Mr. President of the Transplantation Society, Mr. Nicholas Tilney—as you know a “Brighamite”—and Dear Mr. Chairman of this great congress in Sydney, Mr. Jeremy Chapman, it is a great honor and a great pleasure for me to receive the Medawar Prize. I would like to express my heartfelt thanks to the Medawar Committee and, in particular, to its Chairwoman, Kathryn Wood. I would also like to thank Carl Groth who nominated me for the prize and who unfortunately cannot be with us today. I was deeply touched by Sir Roy Calne’s kind introduction spiced with gentle humor.

My speech will focus on the multiple CONNECTIONS that bring together individuals involved in the field of transplantation—researchers, doctors, and patients—from all over the globe, on the connections that have led to today’s gathering in Sydney. These connections have a common denominator at the origin of all innovation: IMAGINATION, whether individual imagination—the dream or collective imagination—the myth.

VIRTUAL CONNECTIONS

Virtual Connections or Abiding Myths

So present and so powerful, and yet so impalpable and intangible.

Projections into the future—what happens next?

Or a return to times past—bygone memories?

Back to the memories imprinted in each of us, in the chromosomes of mankind, in simple molecules with eternal life transcending time.

The myth of the Minotaur, undying symbol of transplantation, listening to the music of the heavenly spheres, their vibrations and pulsating rhythms, to the song of the stars (Fig. 1).

FIGURE 1.
FIGURE 1.:
“Minotaure et jument morte devant une grotte face à une jeune fille au voile” ≪ © succession Picasso 2008 ≫, Pablo Picasso, 6 mai 1936 (Musée Picasso Paris). Reproduced with the kind permission of the Picasso Administration.

LONGITUDINAL CONNECTIONS

Longitudinal Connections Relayed Through Time

What is the origin of this gentle rustling breeze, this tradition, running through the city of Lyon, from the time of Alexis Carrel down to Jules Traeger and beyond? Alexis Carrel described the technique of end-to-end anastomoses (1902), experimentally transplanted numerous organs, and published the first limb allograft in dogs (1908); Mathieu Jaboulay transplanted thyroid and adrenal tissue, and later become the pioneer of renal xenotransplantation (pig-to-man and goat-to-man) (1906); Louis Paufique described the maladie du greffon after a series of failed corneal grafts—his was the first well-documented report of clinical tissue rejection (1945)—and Jules Traeger, a nephrologist with an open mind, launched clinical renal transplantation in Lyon (1966), having grasped early on during his career that clinical and laboratory research, including surgical research, were important. In the breeze that ran through Lyon, I captured the waft of past xenografts that could lead us to islet xenografts. My PhD thesis (1971) was on the effect of pepsin-modified antibodies on renal and skin xenografts between two primate species—baboons (Papio Cynocephalus) and macaques (Macaca speciosa) (Fig. 2).

FIGURE 2.
FIGURE 2.:
Specific Connections. (From left to right): First line: Alexis Carrel, Mathieu Jaboulay, Louis Paufique, Jules Traeger, Marius Renard, Philippe Mikaeloff, Joe Murray, Earl Owen. Second line: Henri Kreis, David Sutherland, Roy Calne, Walter Land, Raimund Margreiter, Carl Groth, Marco Lanzetta, Nadey Hakim, Warren Breidenbach. Third line: Bernard Devauchelle, Sylvie Testelin, Benoit Lengele, Xavier Martin, Lionel Badet, Emmanuel Morelon, Olivier Thaunat, Palmina Petruzzo. Fourth line: Tom Starzl, Léonardo Fresi, Clint Hallam, Denis Chatelier, Isabelle Dinoire.

SEGMENTAL CONNECTIONS

Segmental Connections or Moments and Persons That Change One’s Life

Marius Renard (1952), the first transplant recipient in France who received a kidney from his mother—a gift of life—on Christmas day and survived for 3 weeks amid intense publicity—a momentous short segment of my life. On that day, I knew I would become a transplant surgeon; Philippe Mikaeloff (1960–1964) and liver transplantation, the long malodorous nights spent in the animal room taking care of dogs, including the dog that survived for 3 months, longer than any other (1963)—a springboard toward the future; Joe Murray (1964–1967), a great source of inspiration to the young clinical research fellow I was then, the quintessence of modesty and intelligence with an unforgettable smile. I had the chance to meet in the Brigham his patient and friend, Charles, who had undergone plastic surgery for severe facial burns with excellent results. Despite Joe’s fears about skin rejection, I had a dream—face transplantation; the Surgical Labs of Harvard Medical School where I performed exciting experiments on the role of humoral antibodies in renal rejection and on intrarenal artery injection of immunosuppressants, including antilymphocyte globulins, to destroy “passenger lymphocytes.” It was in those labs I observed John Brooks prepare islets in rats. Back in Lyon: although very successful in rodents, islet transplantation failed in dogs; yet another dream to nurture—vascularized islets; Earl Owen, who was at the time diluting antigens to induce tolerance and speaking about the “memory of water.” Before anyone else, Earl saw the potential of microsurgery, becoming king in Australia and all over the world: the first index finger replantation, hand surgery, facial and other nerve repair, microvascular anastomoses, and even vaso-vasostomy! The European Microsurgery Workshop we organized in Lyon was the first of a highly successful series that lasted 15 years! Earl, with whom we decided in 1996 in the Bellecour Square in Lyon to take the plunge and perform a hand transplantation, Earl who recruited Clint Hallam, our first patient, and brought him to Lyon—a segment of my life that begun 38 years ago; Henri Kreis with his pioneering vision of transplantology and his obsessiveness that proved so important in the success of the postgraduate Hesperis courses (European Society for Organ Transplantation official course) which we set up 20 years ago—another long segment of my life.

LATERAL CONNECTIONS

Lateral connections – the teams and networks - or why so many of us have the same dreams all over the world at the same time.

Pancreas transplantation with its host of unanswered questions.

The city of Minneapolis where Richard Lillehei performed the first pancreas transplantations; David Sutherland and the open duct technique, David, my dear brother, with “his infectious enthusiasm and determination to make the life of others better by all possible means”; Roy Calne and Paul MacMaster and gastric diversion of the pancreatic juice with portal venous drainage; Carl Groth and enteric diversion of segmental grafts; Raimund Margreiter, with whom I share many of the same interests. Why? We are twins, born on the same day of the same year. His sign of the Zodiac? Taurus, the bull, the fighter. No surprise! Raimund who is so generous and warm-hearted; Walter Land, with whom we attempted the first pancreas transplant in Germany in 1978, in Munich where the first double arm transplant has just been performed by Christophe Hoehnke and Edgar Biemer.

What was the dream? To transform the pancreas into a monofunctional endocrine organ clear of exocrine tissue by blocking exocrine secretion by intraductal neoprene injection. The first clinical attempt in Leonardo Fresi was a success. The organ was easy to transplant and the fibrosis surrounding the islets was minimal in the long term but, alas, there were too many early complications. How to solve the problem? Not by beta-intraductal irradiation, with erbium and the other isotopes we tried, but maybe by brief and superficial alpha-irradiation with boron and neutrinos. However, we never received European approval for this study—an unachieved dream. Another question that continues to nag me: Why does the pancreatic blood flow into the portal vein? After conducting many clinical studies, I still do not understand why.

In a movie, 31-years old, one can see the segmental graft of the donor pancreas beating at the same rhythm as the recipient’s heart. What a symbol!

Hand Transplantation—Other Horizons, Other Teams, and Other Networks

Earl Owen, of course; Nadey Hakim; the enthusiastic and energetic Marco Lanzetta with his capacity for hard work; Palmina Petruzzo, who together with Marco, has developed The International Registry on Hand and Composite Tissue Transplantation; Warren Breidenbach who carried out the second single-hand transplant, 4 months after ours, in Louisville; and Raimund Margreiter who performed the second double-hand transplant, just 2 months after ours, in Innsbruck—always the same ideas, at the same time, all over the globe.

Why transplant a hand? Maybe because the hand contributes to the domination of the human species. The hand that waves, gives and caresses … the hand that picks up, grasps and holds … the hand that writes … the hand that squeezes, punches, fights, and pulls the trigger. All these hands are so important to our identity. In our first single-hand transplant, we no doubt overestimated the psychological consequences of unilateral as opposed to bilateral amputation on body image and certainly underestimated the dimension of the patient’s dream. Functional magnetic resonance imaging shows that, incredibly, in the months after transplantation, the representation of the hand returns as the sensory and motor cortex is reorganized, returning faster in the left cortex of a right-handed patient. Two to three years after a double-hand transplant, our patients could play Mikado, thread a needle, and lovingly stroke their children’s hair. Dreams of “not saving life but giving life”, as one patient said- dreams that were coming true.

Face Transplantation—Yet Other Teams and Other Networks

Bernard Devauchelle and Sylvie Testelin, maxillofacial surgeons in Amiens, Benoit Lengelé, an anatomist and plastic surgeon in Brussels, and the young lion cubs in Lyon (Xavier Martin, Emmanuel Morelon, Lionel Badet, Olivier Thaunat, and the bellissima Palmina Petruzzo), all the new generation at work.

Isabelle’s face was destroyed. She could not speak, drink, or eat; she could neither smile nor kiss, express neither scorn nor anger; she had lost her identity. The donor’s face was so beautiful that I still see her image among the stars in my dreams. When the clamps were released, the color shot into Isabelle’s white lips. This was one of the most moving and magic moments of my life. The beauty of such a face should not be marred by biopsies, which explains why we placed an antebrachial radial sentinel flap revascularized by the thoraco-dorsal vessels. Near-normal sensitivity was recovered within 6 months, near-normal motricity within 1 year, and identity was restored almost immediately: “They gave me back an identity because when you do not have a face, you are nothing”, she said in an interview. The graft is not a mask concealing the recipient’s identity, nor a mirror that reflects the donor’s image, but a new individual interface with the outside world, a return to social integration.

TRANSVERSAL CONNECTIONS

Tolerance—A Transversal Connection—Or Our Ultimate Common Dream

Roy Calne, who coined “prope tolerance,” and Thomas Starzl, the two high-priests of the modern era of tolerance.

My hypothesis underlying hand transplantation was that hematopoetic stem cells from graft bone marrow could migrate to the thymus and induce T-regulatory cell lines. Many experimental studies using vascularized bone seem to support this hypothesis. Five years after hand transplantation, numerous FoxP3-expressing cells are found in the graft skin. They do not consider the donor’s antigens as foreign and inhibit peripheral blood lymphocyte cytotoxicity. Two months after face transplantation, a small yet significant number of CD34+ donor cells were found in the recipient’s bone marrow. I have the premonition that the concepts of “nanochimerism” and “cryptochimerism” will one day be a reality.

And can we neglect tolerance in the neonate and not form a longitudinal connection with the fathers of modern immunology, with Sir Peter Medawar, of course, and his followers? We are above all doctors, helping patients, especially those who are frail. Treating malformations in children has to be a priority. What can one do when an ultrasound examination three months before birth reveals agenesis of the hand? Or when terrible vascular malformations affecting upper and lower limbs are observed in the newborn? Some arteriovenous facial malformations mean that the children are going to die. Fetal surgery—another dream on our doorstep.

COLLATERAL CONNECTIONS

When Our Dreams and Those of Patients Coincide

Our calling is to fulfill some of our patients’ wildest dreams. Denis Chatelier, the first double-hand transplant patient, had his hands blessed by the Pope in 2000 and planted a Gingko Biloba tree in the park of the French National Assembly during the debate on bioethics in 2004. He congratulated Theodar Kelz, the Innsbruck double-hand recipient, and shook his hands. The first three face transplant patients all had the same dream, to acquire an interface with the outside world that would not arouse gruesome curiosity and make people turn away.

CONNECTIONS: FROM IMAGINATION TO INNOVATION

Virtual, Longitudinal, Segmental, Lateral, Transversal, and Collateral Connections

When individual IMAGINATION meets collective IMAGINATION

When the dream meets the myth

INNOVATION is conjured up and springs forth.

Let’s now return to Sydney in 2008

And to the Minotaur painted by Picasso in 1936,

And take a closer look:

At the Minotaur, the symbol of transplantation—powerful and determined, but sad and lost in his thoughts,

At the dead mare, the symbol of death—beautiful and desperate, her hooves scraping the ground,

At these two hands extending out of the Daedalian maze—Denis Chatelier’ new hands?

At the single hand—Clint Hallam’s graft?

At the quiet, tender, smiling face—Isabelle’s face?

Amazing, isn’t it?

The Minotaur listens to the symphony of the heavenly spheres, to the song of the stars, and responds to the song of a single star.

ACKNOWLEDGMENTS

I thank Tiiu Ojasoo for her assistance in editing this speech.

© 2008 Lippincott Williams & Wilkins, Inc.