At home Charnley was in a state of despair and the failure was the main topic of conversation. He would arrive back from hospital without a smile even for his young children. He fell asleep from sheer mental exhaustion, and would wake in the early hours. His wife, Jill Charnley, remembers him sitting up in bed with his head in his hands. She felt that ‘everything was grey and there was an all-pervading gloom’.13
Charnley’s despair was, however, mitigated by the surprising reaction of the patients. Once the news got out that the operation offered only temporary relief from their symptoms, he had expected that the number of new patients coming forward would fall off dramatically, but this did not happen. They filled the waiting room in his outpatients clinic just as before and even though told the operation only lasted for two years, they were still prepared to have it. ‘There were others,’ recalls Charnley, ‘when told they would have to have the operation repeated with a new socket of a different plastic material, who made such remarks as “well it was worth it, it was the best few years of my life”.’ These reactions certainly emphasised the pain and suffering caused by hip arthritis and how people were prepared to do virtually anything for it to be relieved. But where was the plastic material to replace the failed Teflon to come from? If it could not be found, then Charnley knew he would have to abandon his operation.
A couple of months after the disastrous revelation of Teflon’s unsuitability, a most peculiar thing happened. The hospital supplies officer rang Charnley’s technician, Harry Craven, to say that he had recently met a Mr V. C. Binns, who was selling gears for weaving machines in the Lancashire textile factories made from a new type of plastic manufactured in Germany. Binns, it emerged, did not know very much about the qualities of this plastic, known as High Molecular Weight Polyethylene (HMWP), but he gave Craven a piece to test on his machine for investigating the wear of different materials. Craven duly showed the material to Charnley, who dug his thumbnail into it and walked out expressing the opinion that Craven was wasting his time. But
Craven had a stubborn streak and persisted with the test: after the first day there were no signs of wear; and only 1/2000th of an inch at the end of two days which was incomparably better than Teflon. Meanwhile, Charnley went to a four-day meeting in Copenhagen and on his return he recalled: ‘My office door opened to reveal Craven, who asked me to come down to the lab . . . down I went to see the HMWP. After running day and night for three weeks this new material, which very few people even in engineering circles had heard about at that time, had not worn as much as Teflon would have worn in twenty-four hours under the same conditions. There was no doubt about it – we were on.14
Not quite. Besides its poor durability, Teflon had also induced a severe inflammatory reaction. How could Charnley be sure that HMWP might not have the same effect? He duly injected a piece under his own skin along with a small piece of Teflon. He reported the result in The Lancet: ‘After several months the Teflon specimens are clearly palpable as nodules about twice the size of the original implant. The HMWP cannot with certainty be detected by palpation which I take to indicate that no reaction has been produced by this material.’ Not only was HMWP remarkably robust, it was much less likely to produce the inflammatory reaction that had cursed the Teflon implant.15
As soon as he had obtained sufficient supplies from the German manufacturer, Charnley was off again. Over the next three years 500 patients were given the new hip. These became the ‘first 500’ though Charnley, not wishing to tempt fate, waited a further seven years – till 1972 – to publish his results. And what results they were! The average amount of pain before operation was ‘severe on attempting to walk, prevents all activity’. This became ‘none’. The average degree of walking disability was ‘time and distance very limited with or without sticks’. This became ‘normal’.16 There were failures and complications – infection, loosening of the prosthesis, ‘unexplained’ pain – but the overall success rate of the operation Charnley put at, typically precisely, 92.7 per cent. His new hip had a further advantage. It not only dramatically relieved the symptoms of hip arthritis, but it also lasted. Charnley deliberately performed his first operations on patients in their late sixties in anticipation that the hip would only have to last at the most twenty years, which indeed it did. Patients reported that their new hips carried on doing sterling work, with almost all remaining completely ‘pain-free’.17
John Charnley died in 1982 at the age of seventy-one. An editorial in the British Medical Journal summarised the monumental nature of his achievement:
Despite the Charnley hip being one of the first joints to be used in large numbers twenty-five years ago, it still reigns supreme – the gold standard. Not one of the dozens of newer, more expensive implants being used by surgeons can match the figures obtained with the Charnley hip in skilled hands.18
More than any of the other definitive moments of post-war medicine, the development of the Charnley hip would seem to conform to the commonly accepted view of how science works. Take a well-defined problem – hip arthritis – devise some appropriate experiments to investigate the difference between the healthy and the pathological, and then, with fastidious attention to detail, come up with a solution whose progress is then monitored in a way that generates reliable and replicable results.
But that is only part of the story. The Charnley hip would never have happened had it not been for the single extraordinarily fortuitous event of the visit by Mr Binns, the ‘travelling representative’ from a German plastics factory, to the supplies officer at his hospital, carrying in his bag the magic HMWP. Then the Charnley hip was as much a triumph of the human spirit as of science, because its final realisation was so completely dependent on the personality of one man. Charnley was a thinking craftsman, skilled with his hands technically and also capable of doing experiments that worked. Clearly these are desirable attributes for someone seeking to design a hip replacement. But he also needed phenomenal willpower and determination – both of which he possessed in abundance.
8
1963: TRANSPLANTING KIDNEYS
Far-sighted surgeons in the post-war years realised transplantation offered much the most elegant solution for those whose kidneys were failing. Dialysis, it is true, provided an artificial means of simulating their function but, nature being so much better than anything man is able to come up with, ‘borrowing’ a kidney from another person (or the recently dead) is much the better option. Nor indeed are the surgical techniques particularly difficult, as they involve little more than connecting the blood supply of the donated kidney to that of the recipient.
Nonetheless, no matter how elegant or technically feasible transplantation might be, the surgeon was confronted by an apparently insuperable barrier – how to ‘trick’ the recipient’s immune system into accepting the transplanted organ. For the vital attribute of the immune system is the ability to discriminate between ‘self’ and ‘non-self’, so it lives in harmony with the ‘self’ of the tissues of the body and yet virulently attacks and destroys the ‘non-self’, infectious organisms such as bacteria and viruses – and transplanted organs. The transplanters were thus presented with an apparently insoluble dilemma. They could make the recipient more tolerant of ‘non-self’ kidneys (and so less likely to reject them) by weakening the immune system with drugs or irradiation, but at the price of also compromising its ability to destroy bacteria and viruses, thus exposing the recipient of transplanted organs to the dangers of overwhelming infection.
Success in transplantation was thus qualitatively different from most of the other achievements of the post-war years: whereas the accidentally discovered antibiotics and steroids were ‘gifts from nature’, which just happened to have quite unanticipated benefits, the early kidney transplanters had to come to grips with this most fundamental of biological problems – the immune system’s ability to discriminate between ‘self’ and ‘non-self’.
The practicality of kidney transplantation was demonstrated by the first s
uccessful transplant – between identical twins – in 1953, but this merely bypassed the barrier posed by the immune system, and indeed in the ten ‘dark’ years that followed every attempt to suppress the immune system in the hope of extending the benefits of the operation to the non-genetically compatible was spectacularly disastrous. It began to seem that transplantation was just a cruel hoax, a technique for killing off the terminally ill in a particularly gruesome manner. And yet the far-sighted surgeons were eventually vindicated.
It is not easy to bring together the many strands of medical research involved, but three are particularly significant. This account starts with the work of the British immunologist Peter Medawar, who provided the intellectual framework within which the problem posed by the immunological barrier to transplantation could be understood. Next comes an examination of the practicalities of transplantation developed by Joseph Murray, who performed the first transplant between identical twins at Boston’s Brigham Hospital in 1953. Finally the key that unlocked transplantation – the drug azathioprine – was discovered by George Hitchings and Gertrude Elion. All four – Medawar, Murray, Hitchings and Elion – would eventually receive the Nobel Prize.
Peter Medawar: Understanding the Immune System
Peter Medawar was an exotic in the world of biology. Born in Brazil to a Lebanese father and an English mother, he was tall, handsome and gifted, with a felicitous literary style. His contribution to transplantation was two-fold: he was the first to show that the immune system was responsible for the ‘rejection’ of a transplanted organ; and a decade later he demonstrated that the immune system could be tricked into tolerating transplanted tissues.
In the summer of 1941, Medawar was a lecturer in zoology at Oxford University and, by his own admission, uncertain as to what to do with his life. While sunbathing one afternoon in his back garden with his wife and child he heard the drone of a large bomber overhead. ‘The bomber crashed into the garden of a house about 200 yards away and immediately exploded with a fearful whomp!’ Amazingly the pilot survived, but with terrible burns covering 60 per cent of his body. After the pilot had been transported to hospital, Medawar continued to take an interest in his fate and a medical colleague – who specialised in the treatment of burns – suggested that he should apply his considerable intellect to working out how best to cover the exposed flesh of burn-injury victims.1 Medawar tried various methods of eking out the small remaining amounts of normal skin in the form of skin grafts, but soon turned to the crucial question: ‘I guessed that if one could use what were then known as “homografts” – that is a graft transfer of skin from a donor – the treatment of war wounds would be transformed.’ As he says, ‘it was not a very original thought’, and others had certainly had the idea before.
Medawar studied the matter further in a large burns unit in Glasgow, where he found that, first time round, the skin ‘homografts’ lasted for around ten days, but that a second graft from the same donor was rejected immediately. This is very similar to what happens when the body’s immune system encounters the measles virus. Following first exposure it takes time to build up antibodies so the virus has time to disseminate through the body to cause the characteristic rash. But, second time round, the immunological system ‘remembers’ what the virus looks like and promptly generates the antibodies to destroy it. Hence one never gets measles twice. Medawar published the results of his experiments as ‘The Fate of Skin Homografts in Man’: ‘In this paper we propounded the view that skin homografts were rejected by an immunological process – that is to say by the same kind of specific adaptive responses that daily leads to the elimination of bacteria or viruses or other organisms foreign to the body.’ So now, at least, those who were interested in transplantation knew the nature of what they were up against.2
Peter Medawar stumbled on his second discovery – ‘immunological tolerance’ – after attending a conference in Stockholm in 1948. There, a fellow delegate asked Medawar whether it was possible to distinguish identical from fraternal twin calves.
‘My dear fellow,’ I said in the expansive way one is tempted to adopt at international conferences, ‘in principle the solution is extremely easy: just exchange skin grafts between the twins and see how long they last. If they last indefinitely you can be sure they are identical twins, but if they are thrown off after a week or two you can classify them with equal certainty as fraternal twins.’ I went on somewhat injudiciously to say I would be happy to demonstrate the technique of grafting to the delegate’s veterinary staff if he were to get in touch with me.
A few months later Medawar received a letter reminding him of his promise and informing him that the twin calves were all under observation at an experimental farm forty miles from Birmingham.
Without a doubt I was morally committed, so we travelled by car to the farm with the right surgical instruments, drapes and local anaesthetics. The skin grafting presented no difficulty but the results were not at all what we had expected. All the cattle twins accepted skin grafts from one another for as long as we had them under observation. Some of these twins must certainly have been non-identical (i.e. fraternal) because they were of different sexes.
So why had Medawar’s prediction been proved wrong? He inferred – rightly as it turned out – that something must happen to the immune systems of twin cattle while they were still in the womb together so they could subsequently ‘tolerate’ each other’s tissues. By now at London’s University College, Medawar resolved to investigate the matter further: ‘Our ambition was to bring about the immunological phenomenon that occurs naturally in twin cattle, to reduce, even abolish, their power to recognise and destroy genetically foreign tissue.’ Accordingly he inoculated mouse embryos with ‘foreign’ cells from adult mice from another strain. Then, after the embryo mice had been born and reached maturity, they were grafted with skin patches taken from the strain of mice to whose cells they had been exposed while in the uterus. Theoretically these grafts should have been rejected in the normal way ten to twelve days later. But they were not. ‘We felt we were on to a genuine phenomenon to which we gave the name “acquired immunological tolerance”, for we had artificially reproduced the immunological tolerance we had observed between cattle.’3
This finding could scarcely be turned to practical use, as Medawar himself acknowledged during a lecture in Oxford several years later when asked by one of the audience – a young surgeon, Roy Calne – whether he could see any clinical application of his studies. He replied, ‘Absolutely none.’4 ‘Rather,’ he wrote in 1982, ‘the ultimate impact of the discovery of tolerance turned out to be not practical but moral, it put new hearts into biologists and surgeons who were working to make it possible to graft kidneys from one person to another.’
Joseph Murray and the First Kidney Transplant
In 1953, a year after Peter Medawar reported on his mice experiments and the phenomenon of ‘acquired immunological tolerance’, Joseph Murray performed the first successful kidney transplant between identical twins. The close proximity of just over a year might imply some connection between the two events, but there was none. Joseph Murray’s first transplant had emerged from a research programme into kidney diseases that had been going on since the war at the Brigham Hospital in Boston, where the two other essential requirements for transplantation besides the solution to the problem of immunological rejection had been developed: kidney dialysis and the necessary surgical expertise.
The first dialysis machine for the treatment of kidney failure was built by the Dutch physician Wilhelm Kolff in 1941, in the extremely adverse circumstances of Nazi-occupied Holland. If the kidneys suddenly fail, as may occur following very severe infection or an episode of shock, they will often recover, usually within a fortnight, if the patient can be kept alive through two weeks of not passing any urine. This essentially means that some way must be found to remove the accumulating waste materials in the blood, mostly urea. Kolff’s initial method involved removing blood from a vein – 50ml at
a time – and passing it through a cellophane-wrapped drum, which rotated through a bath of fluid into which the excess urea was absorbed. The ‘treated’ blood was then replaced back in the arm, and a further 50ml removed, and so on. It was a very time-consuming and laborious process but the results were sufficiently encouraging for Kolff to build a proper dialysis machine. This was not easy for, as he recalled, it was ‘quite a problem’ to make an artificial kidney ‘when nothing could be bought freely and many materials could not be had at all’.
Altogether Kolff treated fifteen patients during the war, only one of whom survived – a 67-year-old woman with acute kidney failure who was actually treated just after liberation. ‘It is significant that this patient, at least in our eyes at the time, was not considered to be a very useful member of society,’ he recalls. Indeed she was transferred from the local prison, where she had been incarcerated for being a Nazi collaborator. After eleven and a half hours of continuous dialysis she emerged from her coma, and according to Dr Kolff ‘the first comprehensible words she spoke were that she was going to divorce her husband, which in time she did’.5
Kolff then moved to the United States, where his dialysis machine so impressed the physicians at the Brigham Hospital that they set up the first formal renal dialysis programme. Dialysis would prove very important for the transplanters. It gave them the experience in dealing with the complex biochemical and haemodynamic problems associated with kidney failure, so they were able to monitor and assess the results of their transplants. Further, dialysis was essential to keep a patient alive while waiting for the operation as well as for ten days or so afterwards, giving time for the transplanted kidney to work.
The Rise and Fall of Modern Medicine Page 13
