The Rise and Fall of Modern Medicine (19 page)

Thus, by 1953, ‘the stage was set', Murray observed, when the twins Richard and Ronald Herrick were referred to the Brigham Hospital. Medical expertise was at hand in the form of the renal dialysis programme for looking after patients with severe kidney failure and Murray had a ‘proven laboratory model' for the proposed operation. Richard Herrick was in the terminal stages of kidney failure caused by an aggressive inflammatory destruction of the kidney known as glomerulonephritis. He was very ill, his body bloated by the water he was unable to excrete through his failing kidneys. He was tired and lethargic because of severe anaemia and was suffering from the intractable itching arising from the accumulation of waste products in the skin. He was also disoriented and confused. His admitting doctor was Frank Parsons from Leeds in England, who was spending time at the Brigham to learn the technique of dialysis. ‘The dialysis went well but it was the most traumatic one I had ever been in charge of. He constantly spat at me (and his aim was good) cursing “Bloody limey”, but such is the power
of dialysis to correct the confusion [associated with] kidney failure that the next day he apologised profusely for his behaviour.'
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On 23 December 1954 Richard was given a kidney from his brother Ronald. ‘The kidney functioned immediately. Richard Herrick's recovery was rapid and complete, exceeding our highest hopes,' Murray recalls.
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Within a couple of weeks he was well enough to be discharged from hospital and promptly married the nurse who had looked after him in the recovery room after his operation. They had two children together, and Herrick survived another eight years before dying suddenly from a heart attack.
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Murray went on to perform several other ‘identical twin' transplants over the following years. Emboldened by his success, he sought to widen the scope of transplantation by borrowing kidneys from close relatives, hoping to suppress the inevitable ‘rejection' by using X-ray treatment to weaken the recipient's immune system. His results, and that of others who tried, were disastrous. The following decade became known as the ‘black years' as every attempt to push the boundaries of transplantation beyond the genetically compatible ended in failure. During this time there were twenty-eight transplants between identical twins, of whom twenty-one survived, but for everyone else it simply did not work. Thus ninety-one patients received a kidney from a blood relative, but only five lived for a year – that is, eighty-six healthy people had voluntarily undergone a major operation to donate a kidney only to see the relative to whom they had given it die almost immediately. As for the 120 patients who were given a ‘cadaver' kidney from someone recently dead, only one lived longer than a year.
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Behind these gloomy statistics lay an even bleaker picture – the manner in which these patients died. One example must suffice – a 21-year-old woman whose kidney failure had been
caused by chronic pyelonephritis (kidney infection), who had been given a transplant from her mother. Immediately after the operation she developed severely raised blood pressure and had multiple convulsions. On the fourth post-operative day a considerable amount of urine started leaking from the transplanted kidney, which required a reoperation. Her white blood count then fell. Despite being kept in strict isolation she also developed multiple abscesses. A fortnight later she started haemorrhaging, requiring a further reoperation, where it was found that one of her arteries had been eroded by the tube draining her bladder. She then took ‘a turn for the worse' because of an acute rejection episode, which it was thought might have been brought on by a further abscess, warranting a third reoperation. Her surgical wounds failed to heal and she developed massive bed sores and acute heart failure. These were followed by hallucinations and a drop in blood pressure. After almost six months of this misery she died in hospital.
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And then came azathioprine.

Back in the late 1940s two scientists, George Hitchings and Gertrude Elion, involved in a cancer research programme at the pharmaceutical company Burroughs Wellcome, postulated it might be possible to prevent cancer cells from dividing by finding a chemical similar in structure to the genetic material DNA but sufficiently different that when incorporated into the cell it would ‘jam the works', preventing the cancerous cell from multiplying – the mechanism of action known as ‘competitive inhibition' (already encountered in the discovery of the drug
PAS for the treatment of tuberculosis).
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This led eventually to the discovery of the drug 6-mercaptopurine (6-mp), which would subsequently be widely used in the treatment of childhood leukaemia (see Chapter 10).

Ten years later Dr William Dameshek, Director of Haematology at the New England Medical Centre in Boston, while searching around for a cure for aplastic anaemia caused by the failure of the bone marrow, treated three patients by transplanting the bone marrow from a close relative – suppressing the inevitable immunological rejection with X-ray treatment. All three patients died rapidly. Dameshek realized – as the kidney transplanters knew only too well – that some alternative method of immunosuppression was essential. He also had considerable experience in treating children with leukaemia with 6-mp, whose admittedly limited efficacy was based on its ability to interfere with the replication of leukaemic cells. Dameshek wondered whether it might also block the replication of the cells of the immune system, and thus act as an ‘immunosuppressant'.

He duly asked a new recruit to his department, Dr Robert Schwartz, to study the effects of 6-mp – with results that turned out to be much more interesting than could conceivably have been anticipated. Dr Schwartz hoped that at best 6-mp would block the replication of the immune cells, generally weakening the immune system and thus its ability to reject transplanted organs. But 6-mp turned out to be much more specific than this. He found that when rabbits were injected with the human protein albumin and then treated with 6-mp, not only did they not develop antibodies to the protein, but the rest of their immune system remained relatively unaffected. By analogy, if 6-mp were to be given to patients following a transplant, this might prevent them from developing antibodies to the ‘foreign'
kidney but should not impair their ability to produce antibodies to other pathogens such as bacteria. Thus quite fortuitously Dr Schwartz seemed to have stumbled upon the Holy Grail for which transplanters had been searching for so long – a drug that would allow their patients to tolerate transplanted organs but that would not so impair their immune system as to leave them vulnerable to overwhelming infections.
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The transition from Dr Schwartz's small experiment in rabbits to kidney transplants in humans was made by a young British surgeon, Roy Calne. Calne had become interested in the possibility of transplantation when as a 21-year-old medical student at London's Guy's Hospital he had to care for a teenager dying from kidney failure:

Calne qualified with honours and after two years' National Service returned to Oxford in 1958 as a lecturer in anatomy, during which time he attended the lecture given by Medawar, whose verdict on the practical applicability of his research findings – ‘absolutely none' – has already been mentioned. Soon after moving to London's Royal Free Hospital Calne heard of
Schwartz's paper on 6-mp's ability to induce a state of ‘drug-induced immunological tolerance', and sought out John Hopewell, a consultant surgeon, who had just established one of the first dialysis units in the country for the treatment of kidney failure. ‘One morning I was approached in the quadrangle of the old Royal Free Hospital by a young man [Roy Calne] who told me he was hoping to test the efficacy of 6-mp in combating the rejection of the transplanted dog kidney, and asked if I were interested. I replied enthusiastically.'
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Over the next few months Calne found that giving 6-mp to transplanted dogs improved their survival from around a week to up to six weeks.
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‘These results were sufficiently encouraging to persuade us to conduct a clinical trial,' Mr Hopewell observed, perhaps rather over-optimistically. The first three human transplants using 6-mp were duly carried out. The first two patients died on the third and eleventh days after their operations without the transplanted kidneys having worked. But the third – who received a kidney from a relative – did survive for a few weeks before succumbing, tragically, from widespread tuberculosis, having acquired the infection from his transplanted kidney. An inauspicious but typical beginning.
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Soon after, Roy Calne travelled to the United States to join the doyen of all kidney transplanters, Joseph Murray, at the Brigham Hospital. On the way he took time off to visit George Hitchings and Gertrude Elion at their research laboratory and they provided him with supplies of another chemical similar to but more effective than 6-mp, azathioprine. Three years later, in the summer of 1963, azathioprine brought to an end the ‘black years' – suddenly and dramatically.

The occasion was a conference on human kidney transplantation held in the building of the National Research Council in Washington.
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Virtually everybody involved in transplanting
kidneys was present – a mere handful of twenty-five doctors, surgeons and researchers – epitomising, perhaps better than anything else, what a minority pursuit transplantation was at that time. The reasons were obvious enough to those present, as speaker after speaker rose to describe their results. These included Joseph Murray, who after the first successful kidney transplant on the Herrick twins nine years earlier had gone on to do seven more. But his transplants between the non-genetically identical had been a different matter. Only one out of a series of twelve who had been immunosuppressed with total body irradiation had survived, most of the other eleven dying within a fortnight. Azathioprine appeared to offer the only glimmer of hope, permitting one 24-year-old transplant patient to return to work as an accountant.
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Then there were the two transplant teams from Paris – Professor Jean Hamburger and Dr René Kuss – with only one long-term survivor out of twenty-eight transplants between them. Roy Calne, by now returned from the United States to London's Westminster Hospital, had treated eight transplant patients with azathioprine but only two were still alive.

There was one new face at the conference, Thomas Starzl, from the Veterans' Administration Hospital in Colorado. Though he had only been transplanting kidneys for less than a year, he had managed to clock up an impressive thirty-three. ‘I felt like someone who had been parachuted unannounced from another planet,' he recalls. When it came to his turn to present his results they were greeted with ‘naked incredulity' – twenty-seven of the thirty-three were still alive with functioning kidneys.
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The ‘new boy' had more surviving kidney transplant recipients than everyone else in the world combined. Roy Calne recalls the astonishment of his fellow transplanters and in the evening he along with several others retired to Dr Starzl's
hotel room to go through his records. ‘He was an obsessional smoker at the time and I recall a pyramid of cigarette butts nearly two feet high. In between smoking, he showed his flowcharts [of his patients' progress] . . . it was the first time I had seen this systematic day-to-day assessment of results and I think that was extremely important . . .'
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And how had Thomas Starzl achieved precisely the results that had eluded the veteran transplanters for so long? He too had given his patients azathioprine, but in addition he had treated their episodes of acute rejection with short bursts of very high doses of steroids.
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By the following morning Calne and the other conference participants had realised there was no secret to Starzl's success. They could all achieve similar results. Almost a quarter of a century later, when Starzl reviewed the long-term results of his first thirty-three transplanted patients, he found fifteen were still alive.
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From this moment on kidney transplantation blossomed. It led in rapid succession to liver, heart, bone marrow and lung transplants, though all had their vicissitudes before achieving comparable success rates. There was one further significant development, with the discovery of a second potent immunosuppressant drug – cyclosporine – which emerged as a fortuitous spin-off from a research programme into the antibiotic properties of the fungus
Trichodima polysporum
. Cyclosporine transformed the ‘narrow tightrope' of immunosuppression into ‘a broad plank', markedly reducing the need for steroids and further improving the survival rate.
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