The second component essential for transplantation developed at the Brigham Hospital during this period was an appropriate surgical technique. Here Joseph Murray refined a method first devised by a Frenchman, Alexis Carrel, following the assassination by an anarchist in 1894 of the President of the French Republic. The anarchist’s knife wound had severed the main vein from the liver and Carrel realised the President’s death from massive internal bleeding might have been avoided had there been a means of sewing small blood vessels together. The technique he devised was extremely ingenious: ‘He sewed three equally spaced sutures round the circumference of each of the cut ends of the blood vessels that he wished to join together. By pulling on all three stitches at once the vessel opened up, its end shaped like a triangle, making the task of joining one end to the other relatively easy. Carrel used very fine thread and sharp round needles coated with Vaseline to seal the holes in the vessels as soon as they were made.’6 Now that he was able to repair blood vessels, it was an obvious step for Carrel to investigate whether it might be possible to transplant organs such as the kidney by hitching its blood supply to that of the recipient. In a series of experiments on dogs he removed their kidneys and then retransplanted one of them back.7 They survived, but not for long which, Joseph Murray inferred, was almost certainly because Carrel connected the kidneys to the carotid artery in the neck:
Therefore my first aim was to devise a transplant operation which could produce normal renal function indefinitely [where there was no immunological barrier because the dogs were simply being retransplanted with their own kidneys]. By 1954 I had several animals living over two years on solitary, life-sustaining renal autografts (their own retransplanted kidneys). The key was the implantation of the kidney into the abdominal cavity of the dog and connecting the ureter to the bladder. This eliminated the mechanical and infectious disadvantages of [Carrel’s] previous experiments.8
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.’9 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.10 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.11
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.12
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.13
And then came azathioprine.
George Hitchings, Gertrude B. Elion and the Discovery of 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).14 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 anti
bodies 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.15
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:
‘The consultant told me he would be dead in a couple of weeks so I should try and give him two weeks of reasonable comfort while he was dying,’ Calne subsequently recollected. ‘I knew enough anatomy to realise the kidneys were the kind of organ that you might graft in much the same way that you would graft the branches of a fruit tree or a rose bush, so I asked: “Couldn’t he have a kidney graft?” The consultant physician said: “No. It can’t be done.” I said, “Why not?” He just said, “It can’t be done because it can’t be done.” One of my friends whispered I’d better not ask any more questions.’16
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.’17
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.18 ‘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.19
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.20 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.21 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.22 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 . . .’23
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.24 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.25
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.26
9
1964: THE TRIUMPH OF PREVENTION –
THE CASE OF STROKES
There is no more certain way of increasing the chances of living to a ripe old age (besides, of course, not smoking) than dropping in periodically to see the family doctor to have one’s blood pressure checked and – if it is found to be elevated – taking regular medication to lower it. For, as everyone now knows, if raised blood pressure is left untreated it can burst a blood vessel in the brain to cause a stroke which, if not lethal, can have catastrophic complications including paralysis, loss of the power of speech or many other highly undesirable variations of functional impairment.
The prevention of strokes merits inclusion in the pantheon of the major events of post-war medicine for two reasons. First, strokes are the third most common cause of death, and thus the ability to prevent them is of enormous significance. The second reason is subtler. The need to identify and then treat those with raised blood pressure – or hypertension – expands the scope and influence of medicine enormously. In the past people visited their doctors because they were ill or had some distressing symptoms about which they were concerned. Hypertension changed all this because it usually does not cause any symptoms, so there is no way to know if the blood pressure is elevated other than by visiting the doctor’s surgery. Thus the contentment that comes from feeling healthy can be illusory, concealing the damage being wrought by raised
blood pressure. We now need doctors not only when we are ill, but also when we feel well.
Hypertension is very common (though how common is a contentious matter) and nowadays much the most frequent reason for people to consult their doctor and take medication is for a condition that previously they would never have known they had. Nor does it stop there. For once it is accepted that identifying and treating hypertension is a good thing then the same principle can be applied to any number of other ‘silent killer’ conditions that cause no symptoms – such as raised cholesterol levels, or detecting hidden cancers of the breast or cancer of the cervix by screening. The evolution of this type of ‘preventive screening’ in which doctors screen the healthy looking for disease has led inevitably to the ‘mass medicalisation’ of society. Now everyone, not just the sick, is a potential patient. And it all started with the successful treatment of hypertension.
The word ‘stroke’, which for the young carries the gentle resonance of affection and physical comfort, acquires by middle age the much gloomier connotation of its other meaning – a devastating blow. A stroke is a catastrophe. The damage to the brain cannot be repaired so the only rational approach is prevention. Most strokes are caused by raised blood pressure, which either accelerates narrowing of the arteries to the brain or may cause a blood vessel to burst, resulting in a haemorrhage. Logically, then, drugs that lower the blood pressure should reduce the risk of strokes. They do, and dramatically so, as first demonstrated in 1967 in a famous study of 140 US veterans, seventy of whom received treatment, the other seventy acting as ‘controls’. Just two of the actively treated went on to have a stroke, compared to twenty-seven of those taking a placebo. It is hard to conceive of a more powerful verdict on the imperative of treating hypertension.1
The Rise and Fall of Modern Medicine Page 14
