The Rise and Fall of Modern Medicine

by James Le Fanu

  Laparoscopy

  Bob Edwards’s investigation on fertilisation involved eggs removed from women while undergoing major gynaecological operations, such as hysterectomies, that involve opening up the abdomen, permitting access to the ovaries. Clearly, if IVF were to become a practicable proposition, some alternative method of obtaining eggs had to be found. The answer is laparoscopy, which requires a small incision below the umbilicus, through which a metal tube is introduced into the abdomen to allow eggs to be removed from the ovary.

  Laparoscopy is now so widely used in gynaecology that it is hard to imagine that back in 1967 Patrick Steptoe was virtually the only man in Britain who had any experience with the technique. He appreciated its considerable potential in clarifying one of the most difficult problems confronted by gynaecologists – how to sort out the many causes of pain in the pelvis by ‘looking inside’ to see whether it might be due to an ovarian cyst, or an ectopic pregnancy in the fallopian tubes, or some other inflammatory condition. Steptoe was also adept at laparoscopic sterilisation – in which the fallopian tubes are tied off – and had advocated its use as a means of observing what was happening to the ovaries during the administration of fertility drugs and thence preventing multiple pregnancies.19

  In March 1967 he published a monograph – Laparoscopy in Gynaecology – describing its many benefits.20 It is not quite clear how Edwards, sitting in his laboratory in Cambridge, heard about Steptoe’s work, but he was struck by its potential as a means of retrieving human eggs for fertilisation. They had a brief conversation on the telephone and met formally at a conference at the Royal Society of Medicine on 6 January 1968. Robert Edwards recalls the moment as follows:

  Sitting in the rows of green chairs facing the raised platform and the lectern were many distinguished gynaecologists and endocrinologists. One of the topics discussed was the disadvantage of the fertility drugs for they led too often to multi-pregnancies. ‘If only the ovaries could be inspected easily beforehand,’ the speaker continued, ‘then we would have advanced warning of multi-pregnancy. We would see how many eggs were growing. Perhaps the new method of laparoscopy could be of use here?’

  People lulled in their chairs. It was an august gathering and the chairman had no need to disturb anybody by bringing his wooden mallet down sharply. But suddenly a distinguished-looking gentleman, sitting in front of me, raised to his feet.

  ‘No,’ he said dogmatically. ‘Laparoscopy is of no use whatsoever. It is impossible to visualise the ovary using that technique. I have tried it.’

  He was suggesting it was just a gynaecological gimmick when, at the back of the hall, a thickset, grey-haired man leapt to his feet evidently impatient with the speaker. He did not actually say ‘Rubbish’ but his remarks were pungent and direct. Forcefully he recounted how, through the laparoscope, not only could the ovaries be seen but also the fallopian tubes and other parts of the reproductive tract. ‘Indeed,’ he continued, ‘the whole abdominal cavity can be inspected. You are hopelessly wrong. I carry out laparoscopy routinely every day – many times over. It is simple and only takes me a matter of minutes.’

  This obviously was the Patrick Steptoe of Oldham General Hospital. I felt immediately, here was a man I could trust and respect and work with. He knew his mind. He was utterly convincing and he offered to demonstrate the slides he had brought along to substantiate his claims. Afterwards in the foyer, near the marble columns of the Royal Society of Medicine, I approached.

  ‘You are Patrick Steptoe,’ I said.

  ‘Yes.’

  ‘I’m Bob Edwards.’21

  Four months later, on 1 April 1968, Bob Edwards made his first trip to Patrick Steptoe’s hospital in Oldham with the apparatus, microscopes and culture fluid to set up his ‘research laboratory’ (in reality an old storeroom) for the fertilisation of the female eggs which Patrick Steptoe would retrieve through his laparoscope.

  The Long Hard Journey to Success

  The second phase of Bob Edwards’s involvement in IVF lasted for a decade, from 1968 to 1978, the last seven years of which were devoted to trying to achieve a successful pregnancy. It came eventually but the disappointments and frustrations along the way were enormous. During all this time both Steptoe and Edwards knew they must be close to their goal but, for reasons that only became clear in retrospect, they could not make IVF work. Their difficulties were compounded by a further factor, illustrated by a map of England, which shows that the ‘commute’ from Cambridge in the south-east to Oldham in the north-west is a distance of 165 miles as the crow flies. As there were no motorways in the late 1960s, the journey had to be made by ordinary roads. For the best part of a decade, when everything they tried seemed to end in failure, Edwards and his fellow scientist, Jean Purdy, were to make that arduous journey several times a year.

  Initially things could not have gone better. They began by devising a fertility drug regime to maximise the number of eggs and ensure they would be retrieved at the right time. In the first half of the cycle women were given three doses of HMG to ‘bring on’ two or three eggs simultaneously. This was followed by one injection of HCG (to mimic the effect of LH) to induce ovulation. Patrick Steptoe then performed a laparoscopy and retrieved as many eggs as possible from the ovary. These were placed in the culture medium, sperm were added and almost invariably fertilisation occurred. The major uncertainty at the beginning was whether eggs fertilised in this way would develop normally, so first they had to be allowed to grow for long enough and then examined under the microscope for evidence of abnormality. There was none.22

  As the time approached to start treating the first patients, the problem of conducting an experimental therapeutic programme over such long distances seemed immense. Bob Edwards recalls:

  The years of constant travelling to Oldham were now beginning to take their toll. The days of sojourn in Lancashire played havoc with my family life. All too often I could see Ruth’s [his wife’s] face cloud over as I had to disappoint the children over some matter or I had to cancel a party at the last moment while I hired a car and dashed northwards complete with equipment and necessities. Jean [Purdy] also had to face similar problems. I always remember returning home on one occasion after a prolonged stay at Oldham and being surprised to discover not only new neighbours in the street but fresh colleagues in the laboratory at Cambridge.23

  The obvious solution was for Patrick Steptoe to move from Oldham to Cambridge. There was a possible vacancy as an NHS consultant at Newmarket General Hospital, which would have cut Bob Edwards’s commuting distance to ten miles. This would, however, require special funds, so they turned to the Medical Research Council for help. Their joint application was rejected on three grounds: ‘serious doubts about ethical aspects of the IVF programme’; ‘a lack of preliminary studies in primates’; and reservations about the justification of using laparoscopy for ‘purely experimental purposes’.

  The grounds for rejection may have been particularly ill-informed, but Edwards and Steptoe had no alternative other than to carry on as before, and to start treating patients in the hope that success – which at the time seemed imminent – would alter the MRC’s view.

  So the commuting started again in earnest. In December 1971, the first patient underwent IVF:

  With a sense of an important occasion Patrick passed a cannula [a thin plastic tube] containing the embryo in its drop of culture medium through the cervical canal of our first hoped-for mother. There was a few seconds’ delay while the fluid dispersed and the embryo was carried into the recesses of the womb. But despite the high hopes of it all, this reimplanted embryo did not stick, pregnancy was not established and with the tell-tale signs of the beginning of her menstrual period we all realised this first attempt of IVF had been a failure.24

  As indeed were all the other attempts over the next six years. The disappointment of these times is difficult to imagine, not least because the success of their preliminary research had shown them that they must almost be there. The validit
y of every single step of the process had been confirmed, only to be frustrated by the failure to get the reimplanted embryo to ‘stick’ into the lining of the uterus to create a viable pregnancy. Recording this period Edwards observes: ‘One after another we had to admit at least temporary defeat, had to telephone an anxious waiting husband and say, “Sorry – we failed again.” T. S. Eliot had remarked on those who are undefeated only because they go on trying. It was only in that sense that we were now undefeated.’

  In November 1973, Bob Edwards reported their first eight attempts at achieving pregnancy with IVF had been ‘without success’.25 A new tack was called for. He inferred that, as the difficulty was in getting the embryo to stick, then presumably the lining of the womb was not being adequately sustained by the progesterone secreted by the corpus luteum in the second half of the cycle. He decided, fatefully, to ‘support’ the second part of the cycle with a progesterone supplement, Primolut. This did not work either in the ten or more further attempts at IVF over the following two years. Finally, in the summer of 1975, when on holiday, Edwards received a telegram from Patrick Steptoe: ‘Pregnancy test positive. Ring me urgently. Patrick.’ ‘This pregnancy was a major advance for us,’ Edwards subsequently recalled. ‘It was decisive for we now knew that the fertilisation of the embryo in vitro and the method of replacement were good.’ Sadly the pregnancy turned out to be an ectopic and had to be removed surgically.26 Further attempts with the progesterone support in the second half of the cycle were also unsuccessful and it occurred to Edwards that perhaps the reason they had managed to achieve their one and only pregnancy was that the embryo had implanted in the fallopian tubes, whose lining is not extruded like that of the uterus during menstruation. If this was the case, then Primolut was clearly not ‘supporting’ the lining of the womb as intended – but paradoxically, they were later to discover, it was actually working as an abortifacient, accelerating the loss of the lining of the womb. Little wonder that this phase of IVF research had proved so unsuccessful.

  There seemed no alternative other than to start all over again. From the beginning of 1976 several approaches were attempted, including changing the types of fertility drugs used, trying to initiate fertilisation in the womb by replacing the egg and the sperm together, and finally dispensing with all supportive medical treatment and seeking to simulate as closely as possible what happens in nature. This last strategy was the one that finally brought success.

  The theoretical advantage in using the fertility drugs HMG and HCG was that they both increased the yield of eggs and determined the moment of ovulation, so that Patrick Steptoe knew when to intervene – thirty-six hours after the HCG injection – in the knowledge the egg would be ripe and thus ready for fertilisation. But perhaps, reflected Edwards, these features of the IVF programme that seemed so essential were actually the problem, interfering in some subtle way with the vital process of implantation. If so, it would be necessary to dispense with them. The prospect of dispensing with fertility drugs would not only reduce the yield of potential eggs but also mean that Steptoe and Edwards’s work would now be determined by the natural rhythm of the woman’s own menstrual cycle. They did not intervene in the first part of the cycle but let the woman’s own FSH ripen the egg-containing follicle in the ovary. After ten days they started to monitor the level of LH in the urine, knowing that when it surged upwards, towards the middle of the cycle, ovulation would take place twenty-four to thirty-six hours later. This then determined the time when laparoscopy could be performed and the egg could be retrieved, which could be at any time, including the middle of the night.

  Lesley Brown was the second woman to be treated with this new regime, in November 1977, and three other pregnancies followed soon after. Two of these subsequently aborted, one tragically following amniocentesis at twenty-one weeks and the second due to a chromosome abnormality. The considerable adverse publicity had this latter baby been born alive – with the false inference that the abnormality resulted from her manner of conception – would have done enormous damage to the prospects of IVF.

  That left two live pregnancies after ten years of endeavour: Louise Joy Brown, born in July 1978, and in January 1979 a boy, Alistair.27 The remarkable feature of the ten years of research that culminated in these two live births was that in the end it all turned out to be so simple. The first ‘test-tube’ baby was thus made possible by four simple pieces of technology: a method of measuring LH in the urine to detect the ‘LH surge’; laparoscopy to obtain an egg; a culture medium in which the conceptus would grow for a couple of days; and finally a thin plastic tube for its relocation back in the womb.

  Almost immediately following the birth of Louise Brown, the wheel of IVF treatment turned full circle. First other investigators, and then Steptoe and Edwards themselves, returned to using the regime they had originally started with back in 1971. In 1981, in Australia, Alan Trounson and his colleagues reported four successful pregnancies using the fertility drug Clomiphene to boost the number of ‘harvestable’ eggs in association with HCG to promote ovulation. These along with several other modifications established the basis of the success of IVF throughout the 1980s.28

  Thus to their chagrin Steptoe and Edwards realised that their original strategy back in 1971 had been the correct one. Had they persevered rather than ‘adding in’ Primolut to sustain the second half of the cycle they would almost certainly have been successful much earlier. We know this now, but should not overlook the fact that this ‘mistake’ exemplifies the essential problem of scientific research. By definition, it involves tapping away at the boundaries of the unknown in anticipation of the breakthrough. IVF posed a particular problem because its success rate is naturally low, so it was difficult for Steptoe and Edwards to know when or if their procedure was correct. So, just too hastily, they changed their original technique by adding Primolut, but now their failure was due to an entirely different reason. And so on.

  The point here is that scientists never know why something is not working until they come across something that does. Whatever might appear obvious in retrospect never is at the time. This necessarily leads to the second aspect of the scientific achievement – the human side – the moral courage that sustained them during the inevitable disappointments of trying to make sense of the, as yet, unknown. The reward for Steptoe and Edwards was that the two children born at the end of their seven years of travail became 40,000 pregnancies in the following two decades.29 Further, IVF, it soon emerged, could be extended to treat many other types of infertility as well, including ‘unexplained infertility’ and male infertility resulting from a low sperm count. Virtually everyone now knows of couples whose lives, which otherwise would have been ‘blighted by barrenness’, have been immeasurably enriched – thanks to Steptoe and Edwards – by the ability to have children.

  12

  1984: HELICOBACTER – THE CAUSE

  OF PEPTIC ULCER

  This twelfth and last definitive moment of post-war medicine seems much the least significant. In 1983 a young Australian doctor, Barry Marshall, reported the presence of an ‘unidentified curved bacillus’ (a new type of crescent-shaped bacterium) in the lining of the stomach, subsequently named as helicobacter (literally, helix-shaped bacillus), which turned out to be an important cause of several diseases of the upper intestinal tract including gastritis (inflammation of the lining of the stomach), ulcers and stomach cancer. Marshall’s discovery may be of considerable interest but is not in the same league as, for example, the decades of endeavour that led to the cure of childhood leukaemia or transplant surgery. Its inclusion in this pantheon requires a brief justification.

  The therapeutic revolution of the post-war years had quite different effects on the pattern of disease in the young, the middle-aged and the old. The young were the major beneficiaries of the control of infectious diseases with antibiotics and immunisation. Their serious medical problems now mainly result from either inherited diseases such as cystic fibrosis, problems associated w
ith prematurity, accidents, or allergies such as asthma. At the other end of the age spectrum, the elderly are vulnerable to diseases of the circulatory system and cancer, which are powerfully age-determined (that is, caused by ageing of the body’s tissues), or to the ‘chronic degenerative’ diseases, such as arthritis and cataracts.

  To put it crudely, modern medicine has squeezed the major burden of illness to the extremes of life – among the very young and the old – and in general most people from their teenage years up to their fifties or sixties are remarkably resiliently healthy. This brings into focus the singular peculiarity of the illnesses that do occur in the middle years, such as diabetes, rheumatoid arthritis, multiple sclerosis, schizophrenia, Parkinson’s, and many others. By definition these are not related to age but rather seem to strike out of the blue. The unifying feature of all these illnesses is that their cause is not known.

  They must have a cause; there must be some reason why the nerves in someone with multiple sclerosis should be damaged, or the joints in someone with rheumatoid arthritis should become chronically inflamed. But, despite prodigious efforts and vast sums spent on medical research, their origins remain profoundly enigmatic.

  There is thus a vast ocean of ignorance at the heart of medicine. The causes of the common diseases of middle life are simply not known, and self-evidently, without knowing their cause, they can be neither prevented nor cured. Certainly in some the symptoms can be alleviated by one or other of the drugs discovered in the post-war years, such as chlorpromazine in schizophrenia or cortisone in rheumatoid arthritis, but these are palliative, in that they fail to resolve the underlying pathology in the same way that antibiotics get to grips with infections.