UNKNOWN

In May 2008, pioneering physician Sir Roy Yorke Calne delivered a seminar at the 5th International Symposium of the Definition of Death Network in Varadero, Cuba.  Here, he describes the implications of advancements in organ transplantation upon the clinical declaration of death.

INTRODUCTION (CALIXTO MACHADO)

Its a great, great, honor for Cubans to welcome Professor Roy Calne.  He is one of the pioneers in transplant for all history - beginning in the sixties.  His role in immunosuppressive treatment is already known by the whole globe.  There are no words to say that we are really happy and honored to have Professor Roy Calne with us today.

SEMINAR (SIR ROY CALNE)

Professor Machado.  Ladies and gentlemen.  First of all I would like to express my thanks to you and your colleagues for the really warm reception we've had in Cuba, and the hospitality we've received.  It's been a great experience and it's not finished yet.

The achievements of transplantation have been looked at from this painting in Peter Brigham hospital of the first kidney transplant that was successful between identical twins.  And it's interesting to just reflect whether anybody in that operating room imagined that in fifty years time there would be hundreds of thousands of patients receiving transplants, and many of them benefiting in terms of quality of life from the transplant operation.  We had the opportunity of doing an intestinal transplant between identical triplets and we realized that the surgery of all transplants is established and usually successful, but the immunology is still a problem and we have not yet fully understood how to control rejection.

But we did the transplant between the healthy and sick triplet, and eighteen months later they do look alike again.  And it really emphasized to us that without an immunological barrier transplantation would be so easy and straightforward.

Peter Medawar, my hero and friend in transplantation, is the person who showed that rejection is an immunological phenomenon, and also stumbled upon immunological tolerance, which is a way of overcoming it, but with no obvious clinical application at that time.  They got the wrong answer when they did skin transplants between non-identical cattle twins.  Cattle twins share blood in the placenta, one to the other, and this, they reckoned, might be the immunological explanation of why the skin grafts were not rejected.  They expected the skin grafts would be rejected.

And this is one of Medawar's own slides given to me by Leslie Brent when they did the experimental tolerance and the fetal and neonatal tolerance, and I was very impressed with this white feather in a black chicken.  And then the mouse experiments that really led to their Nobel Prize.  Lymphoid cells from an in-bred strain of mice were injected into the fetus of another strain that was also in-bred.  And they found to their surprise that some of the animals died of a mysterious disease and Rupert E. Billingham rightly explained that this was likely to be, and then showed that it was, graft against host.

Now I put these early experiments before you because all of us working in transplantation, we would like to be able to make our recipients temporarily tolerant to the graft, but able to withstand infections, that otherwise the immune system must not be totally paralyzed, but specifically paralyzed.  And so far we have not been able to do this.  And with any attempt to produce tolerance with say bone marrow cells or stem cells, there would be the danger of graft versus host disease which we need to keep in mind.

The first method used to try to stop rejection was X-irradiation.  And this has been very successful for bone marrow grafting, but I would like to draw your attention to the line which reads that a close match of donor-recipient is essential in order to get a good result.  It was, in the 1950s and 60s, and it still is now - fifty years later.

Three patients with stable bone marrow grafts developed kidney disease and required renal transplantation.  They received kidneys from the same bone marrow donor to the recipient who happened to get kidney disease and needed a kidney transplant, and didn't require any more immunosuppression.  So this is long-term tolerance.  And then non-ablative immunosuppression, which was introduced in Seattle, and probably some of you have read in the New England Journal of Medicine, recently its been used with considerable success by David Sachs - the group in Mass. General; have used it in patients with myeloma, with also renal disease.  And again donor and recipient close match was essential.  So the really good cases were human leukocyte antigen (HLA) identical sib to sib transplants.  When they moved to parent to child, one haploid, they didn't find it was so easy to obtain long-term tolerance.

So how does a graft last for a long time?  A French group found that there are regulatory cells, or suppresser cells with markers in a long-tolerated graft.  And they found in a patient's arm, sometime after transplantation, that these cells were in the skin of the recipient - suppresso cells.  And they weren't able to find them anyplace else.  And it looks as if these cells went into the graft and protected them in some way or another.  But the phenomenon has not been fully worked out, but the observations referred to have been published by the French group.

So we have natural tolerance, as I mentioned between cattle twins, experimental tolerance, and then graft, and that's what has interested our group for many many years.  I think that you can regard tolerance a bit like happiness.  There are different causes, it may not always be complete, and we may not realize when we've got tolerance as some of our patients - still on immunosuppression, may in fact be tolerant.  But of course, when tolerance is lost - when happiness is lost - we're very aware of it.  I think the analogy is quite useful, and particularly, that tolerance may not be complete because even in Medawar's experiments, sometimes his skin grafts were rejected late.

Robert Schwartz and William Dameshek published a paper in Nature in 1959 in which they used the anti-leukemia drug 6-mercaptopurine, given to rabbits challenged with a foreign protein.  And they gave them two weeks of 6-mercaptopurine, and the animals produced no antibodies to the BSA, and they still produced no antibodies after the 6-MP was stopped.  And they called it drug-induced tolerance.  And it was after reading that paper that I had been working with X-irradiation in experimental kidney grafts in dogs and finding that X-irradiation was very very unsuccessful, totally unsuccessful, in getting tolerance.

And so I moved to use the 6-mercaptopurine, and some of the dogs lived much longer than the control - so this was encouraging; but it was a long way from getting tolerance.  And in correspondence with the people who made 6-mercaptopurine - George Hitchings and Gertrude Elion at Welcome Research Laboratories in New York - I asked them if they had anything better, and they said they didn't know, but they would give me some compounds.

And then I went to work in the Peter Brigham Hospital Medical School and found that the drug azathioprine sometimes gave really prolonged survival of kidney grafts and we found - my wife and I had to look after these dogs very carefully and get very good quality food from the kitchen of the hospital.  And when they were cared for, some of them lasted for a very long time, and some of them - a few of them - became tolerant after the drugs had been stopped after a year or two.

We started to use azathioprine in England when I went back to England and started at Peter Bent Brigham Hospital, and the early results were very disappointing until steroids were added routinely.  When corticosteroids were added, then some good results occurred.  Our longest patient with a kidney graft received the graft from a road traffic accident - unrelated - they didn't even have tissue typing back then.

From left: Roy Calne, Gertrude Elion, George Hitchings, Donald Searle, E.B. Hager, and Joseph Murray.  The dogs are Tweedledum, Tweedledee, Titus, and Lollypops

And this is 10 years after transplantation, and she looks a little pale, but he had the transplant; and the transplant functioned for 40 years; then slowly its function deteriorated, and the patient is now back on dialysis.  Of course the long-term results of transplants are what really counts, and its the justifications, in my mind, for all the work and trials and error that went into it.

Well the liver turned out to be only interesting from the immunological point of view.  Orthotopic liver grafts in pigs sometimes lasted for a long period of time, and the animals lived without evidence of liver damage.  Although they went through an acute rejection phase first.  The phenomenon is more easily detected in rats than in mice, and its strain specific.  And it's interesting that this rejection reaction appears to be part of the road to tolerance.  Dr. Thomas Starzl, a friend and long-term colleague, did the first liver graft in 1963 in children.  The results were very disappointing, and he gave up for four years and started again in 1967.

And this is the old hospital in Cambridge.  This is where, having worked on liver transplants in the laboratory in pigs, we decided to do liver transplants in patients.  And in 1968, Dr. Francis Moore, one of the pioneers with Dr. Starzl, of experimental liver transplantation - he happened to visit Cambridge where his son was doing a post-doc course, and he came to visit me and it was the day that we wanted to do the first liver transplant.  There was much opposition among my colleagues, as there is when one tries to do anything new, but Dr. Moore persuaded them and he was very great surgical chief who presided at the Brigham for nearly 40 years, and he was my first assistant in 1968 when we did our first liver transplant.

And it was a child's liver to an adult and we used the technique which was 20 years later re-described from Pittsburgh by Dr. Tzakis and his colleagues.  We used it because it was a small vena cava.  Well I guess to give you a few examples of some of the early days of liver transplantation and some of the difficulties that we were faced with and may or may not have overcome.  This is a child who infarcted her liver and we had to wait 24 hours to get a new one for her.  She went into grade 4 come and we wondered whether she would be seriously brain damaged.  Fortunately the next day she was able to take some orange juice, and three weeks later go into convalescence, and a year later the only evidence of brain damage was the wish to take a photograph of her surgeon.  And that has persisted, and she is now 26 years post-transplant.

Another patient who, while we were doing a ward rounds, went into septic shock and permanent coma, the X-rays show what looks like lung under the diaphragm, but it is, in fact, gas gangrene of the liver and we had to take the liver out, do a porta-caval shunt, and the next day we were very fortunate in having a liver sent to us from Germany.

And in those days there was a lot of collaboration between different units because there weren't many units doing transplants, and the patient recovered from the coma but rejected the liver because it was the wrong blood group.  And then she sat for her portrait to be painted, she had, by now, had three liver transplants.  And she requested to have a fourth.  And 6 late years later she sent this photograph, and she must be now about 15 years post-transplant.

We had terrible trouble with bleeding and we would send the blood specimens to the hematology department, and they would say the blood's normal; and we would say it's not normal.  And eventually I had to persuade the hematologist to come and see in the operating theatre, and she said she didn't know where it was.  I said you walk along the corridor and when you see blood coming under the door, that's where I'm working.

And she came in, saw the bleeding, and then immediately set up in the operating room, monitoring the bleeding/clotting factors of the patient.  And from then on blood loss became much less, and now it's not usually a problem at all.

In the early days we used to take the sick liver patient to the hospital where the donor had died, and that was unsatisfactory logistically, and then we used to rush all over the place - sometimes in planes and helicopters to get a liver.  We went to Holland once, we didn't ask for a policeman, but he came to escort us.  And he got friends ... a few more friends ... and then at tremendous speeds drove to Schiphol airport, and then we had to wait 20 minutes because the pilot was having his lunch - so it wasn't really necessary.

Now I want to mention warmly Dr. Jean-François Borel - who discovered the immunosuppressive effect of cyclosporine; and had great difficulty in persuading the company Sandoz to develop it.  He talked at many meetings trying to persuade people to be interested in it, and one of them, my colleague, David White, heard about cyclosporine and suggested that we might like to look at it in experimental animals and one of our Greek research fellows Dr. Kostakis found that he got excellent results from heart grafts in rats.

But only when he found how to use the drug, and he dissolved it in olive oil - his mother had said to him that Greek olive oil was a good solvent for cyclosporine - even then we had difficulty to persuade Sandoz to give us cyclosporine, but eventually we found that it was a very effective immunosuppressive in dogs with kidney grafts.

And this pig just had an orthotopic heart graft treated with cyclosporine and a year later given cyclosporine in cat food - which tasted better.  We found, with a number of these pigs, that we could stop cyclosporine and they were tolerant.  So although people have said cyclosporine would prevent tolerance; in fact - in some cases - cyclosporine could actually produce tolerance.

This was the first child ever to be treated with cyclosporine with a kidney graft, and I started using it without any steroids because I had had such bad experience with giving steroids to little children.

Now this, I think, is a very important slide (below).  It happens to be liver transplants in Europe, but it could be liver transplants in America, it could be heart transplants in Europe, it could be kidney grafts.  The point is that until cyclosporine was available, there were hardly any transplants done, the results were very bad - 50% of grafts failed by a year; and there were about 10 centers worldwide doing transplants.

After cyclosporine, within a few years, there were over 1000 centers worldwide doing transplants.  So cyclosporine was the watershed - as you all know, cyclosporine is a very useful drug, but not a miracle drug; but it did change the perception of transplantation among our colleagues.  And so instead of people saying transplants are a waste of time, they're expensive, and the results are terrible; now they would say this is something our patients might actually benefit from.

A photograph of a little child treated with cyclosporine for a liver graft.  A year later - his father keeps pigs as a farmer.  Then, some years later, he and the pigs have grown.  And now he's a farmer himself.  And I think this again shows the justification of all the trials and tribulations of doing organ grafting.

There was an operation we did of transplanting a combination of heart, lungs and liver - all very exciting from the surgical point of view, but far more exciting is that 10 years later the patient was doing quite well.  And then she thought everything was so good that she stopped taking immunosuppression and she developed chronic rejection of the lungs the following year.

This is a patient - a very interesting personal story.  He was an Englishman with an English pop group in America, visiting, and he's walking in New York and an old lady was set upon by thieves to rob her.  And he went to the rescue of the lady, and he got stabbed and the thieves ran away.  He had blood transfusions and some years later he came to us with Hepatitis C and a large hepatoma.  So he was a very worthy case for a liver transplant, although not a good indication.  But he's done well, and I'm really happy this good samaritan has managed to benefit from transplantation.

Our longest patient with a liver transplant is 34 years now, but he also had a huge tumor that was more than 10 cm in diameter and he was hepatitis B surface antigen positive.  I met him recently and he said if he came now for a liver transplant with those indications, he would be sent away because there were contra-indications.  So this shows how the exceptions may be very interesting and important and of life importance to this patient.

Then another multiple organ transplant - a patient with Gardner's syndrome, desmoid tumors in all the abdominal organs.  When we removed the diseased organs there's nothing left - just the aorta, the upper and lower cava, the esophagus and the ureters.  And we transplanted en bloc the liver, kidney, pancreas, stomach, duodenum and small bowel.

Now the patient's stomach didn't start working for two months, and then the patient started eating.  At 6 months he looked good, then he ate too much and became fat.  Then at 6 years, a very tragic Christmas, his wife asked him to climb up a ladder and change the decorations, and he fell off the ladder and hit his head and died from a cerebral hemorrhage.  And that was really a terrible tragedy for both the family and for us for a patient who survived that major operative procedure.

The miracle of Saint Cosmas and Damian has been recorded in many churches, and this is a very beautiful painting by Friar Angelico which is in the San Marco Museum in Florence, and it shows the operation underway to transplant the leg.  And the patient is very optimistic because he has two shoes waiting for after the operation.

A patient of Dr. Raimund Margreiter, who is a friend of mine who is head of surgery in Innsbruck, is a policeman who had his hands blown off by a terrorist bomb, and he lost three liters of blood.  And three or four years later he had a double hand transplant from a cadaver donor.  And there is the patient riding a motorcycle with his new hands.  He can work a computer, he can write - and he gave a paper recently - 7 years after a double hand transplant.  And he is an amazing man.  He worked so hard at his physiotherapy, and the results have been excellent.

But what is interesting, from the neurological point of view, is that scanning the brain shows that the portion of the brain that looks after hand movements and hand sensation - it atrophies after an amputation; but what nobody knew until this operation had been done, was that it could grow again after a successful transplant.  So the plasticity of the brain can be demonstrated as a neurological phenomenon.

And the face transplant that had so much publicity in France.  So it would seem that just about anything can be transplanted, but we still have trouble with immunosuppresion, we still have terrible trouble with insufficient donors, and our success in transplantation means that now everybody wants a transplant who might benefit from it, and we're not able to provide this.  So all over the world there is a shortage.  And when there is a shortage of anything, particularly when it is life-saving, there is a danger of corruption and criminal activities, and how to get fair distribution.  And that, of course, is part of what we will discuss in this meeting.

Dr. Paul Terasaki gave me these three slides which I think sum up part of this concern:

If a wife is willing to donate a kidney to her husband ...

... as part of a divorce settlement ...

... in exchange for the house, the kids, and the car ...

... would it be acceptable as an emotionally related donor, or unacceptable as a compensated donor?

And I'll leave that for you to decide.

So the Pope attended the transplant meeting in Rome, the last Pope - Pope John Paul II, and spoke very strongly in favor of transplant and organ donation, but he also spoke very strongly against embryonic stem cell work.  And this derived yet another controversy for those who want to see different aspects of transplantation develop, or even cell, or gene engineering.  And there are still many shades of opinion for which way we should go.

I put this as my last slide.  It is a tribute to the Nobel Laureates in transplantation (left - clockwise: George Hitchings, Gertrude Elion, Joseph Murray, Jean Dousset, Alexis Correl, Peter Medawar) - but the real hero is the donor (right).  Whether it is a live donor who gives a kidney or part of a liver, or a cadaver donor - where the relatives, or the donor in their lifetime, have had this charitable gift of life that they wished to bestow to someone else.

So I'll finish with that tribute to the organ donor.

Thank you very much for your attention.

All images presented herein were provided by Sir Roy Calne, and are used with permission.  All Portraits (with the exception of the painting by Friar Angelico) are original works by Sir Roy Calne