The Rise and Fall of Modern Medicine

by James Le Fanu

  A Sister burst in excitedly. ‘You may come and see your baby daughter now. A porter will take you along. Your wife is fine.’

  ‘What did you say, Sister?’

  ‘You may go to see your baby daughter as soon as the porter arrives.’

  John was speechless. Tears poured down his face. He stood up and banged his clenched fist against a wall. When he regained control, he kissed Sister, he kissed Sheena Steptoe, who was also happily weeping, and ran out of the room. He ran all the way downstairs along the sixty yards of corridor to the operating theatre, followed by the porter and Sheena. There we stood with Louise’s cot on a trolley, the baby was lifted into John’s arms.

  ‘I can’t believe it! I can’t believe it!’ he cried out. ‘I don’t know what to say.’ He gazed mesmerised at the infant, until someone gently guided the baby back into the cot. Lesley Brown was still peacefully asleep [from the anaesthetic], unable to join in the happy delirium all around.1

  The powerful emotions elicited by this account are enhanced still further when it is realised that this cameo was the combination of eight bitter years during which Edwards and Steptoe’s many attempts at IVF had all ended in failure.

  Fertilisation In Vitro

  Fertilisation is much the easiest part of IVF: given sufficient numbers of sperm, a mature female egg and the right culture medium, success can be almost guaranteed. And yet for thirty years before 1969, when Bob Edwards first showed how it could be done, the fertilisation of human eggs outside the body was thought to be impossible. It is a most curious story.

  In 1937 John Rock, the most prominent infertility expert in the United States, anticipated the possibility of IVF in a prescient editorial in the New England Journal of Medicine, ‘Conception in a Watch Glass’ – commenting ‘what a boon for the barren woman with closed [blocked] tubes’ such a treatment would be.2 His article was inspired by the work of a colleague, Gregory Pincus of Harvard University – later to become internationally famous for his role in the development of the oral contraceptive pill – who claimed to have performed IVF in rabbits by taking an egg from one rabbit, fertilising it and then replacing it in another unmated rabbit to produce offspring.3

  Clearly Rock’s next step was to see whether he could achieve in humans what Pincus had claimed to have shown in rabbits. Here Pincus had made another important contribution, having shown that – within a couple of hours of being removed from the ovary and placed in an appropriate medium human eggs began to show the changes in the nucleus indicating they were mature and thus receptive to fertilization.4 So, in the six years from 1938 to 1944, Rock, with the help of his assistant Dr Miriam Menkin, removed 800 human eggs from female volunteers undergoing major gynaecological surgery such as hysterectomy and attempted to fertilise them with human sperm. ‘On the basis of [Gregory Pincus’s] finding we have made numerous attempts to initiate in vitro fertilisation of human ovarian eggs,’ Menkin subsequently reported, but the result was ‘unremitting failure’.5 In 1944 she did manage to get one egg to divide to the two-cell stage, which was duly reported in the journal Science and generated a lot of correspondence from infertile women:

  Most letters came from relatively young women whose fallopian tubes had been surgically removed. A woman from California wrote that when she was twenty-nine, a surgeon while removing her appendix noted her tubes were ‘dried up’ – so he removed them. She hoped for ‘a modern surgical miracle’ that would allow her to have a child. One young woman was devastated when surgery for pelvic inflammatory disease robbed her not only of her tubes and ovaries but of her fiancé as well. He ‘wanted children very much,’ she wrote. ‘We have never married because of this.’ Another had thought she was undergoing ‘a minor operation’ while her soldier husband was overseas to enable her to become pregnant when he returned. Instead she found herself without her fallopian tubes. ‘I have never,’ she wrote, ‘felt this operation was absolutely necessary.’ Her husband, as well, was ‘deeply grieved about their childlessness’.6

  But despite the desperate need expressed in these letters Rock and Menkin felt they had no alternative other than to abandon their research project. If it was not possible to predictably fertilise human eggs, there could be no hope it would ever become a realistic treatment for infertility.

  There were no further serious attempts at IVF in the immediate post-war years, though in 1951 one of Pincus’s scientific collaborators, Min Chang, made an observation that might have explained Menkin’s failure: sperm, he argued, first had to be ‘capacitated’, switched on by a chemical in the fallopian tubes, before they were capable of fertilising an egg. ‘It is quite clear that fertilisation occurs when the sperm have been in the fallopian tube for six hours, which is perhaps required in humans for a physiological change in the sperm enabling them to achieve fertilising capacity,’ he wrote.7 It was in retrospect such an obvious explanation but it made the possibility of IVF as a treatment for infertility even more remote. The ‘capacitating chemical’ was not known, so somehow it would be necessary first to place the partner’s sperm in a woman’s fallopian tube for several hours to allow ‘capacitation’ to take place. The sperm would then have to be removed and placed with the egg in the hope that fertilisation would occur. Such a procedure was so impracticable it was not surprising that no one bothered to try.

  The rebirth of IVF as a treatment for infertility can be traced to a single moment in the library of the National Institute of Medical Research in 1960. Bob Edwards, a young physiologist who had been studying the maturation of mouse eggs in vitro, was hoping to extend these observations to human eggs.8 He was, however, unaware that Pincus had conducted precisely the same studies back in the 1930s.

  One morning, in the quiet of that comfortable library, as I read one particular scientific paper I stopped reading and said quietly, ‘Sod it.’ I looked up and nobody had heard me. Nobody in the library at that particular moment was aware of my sudden disappointment, for I just learnt that my discovery was not new. The American, Gregory Pincus, the noted developer of the contraceptive pill, had reported the same results when he had worked with eggs of rabbits in a Cambridge laboratory a quarter of century earlier. He had placed them in a culture solution as I had done, and watched them ripening in the same way. But Pincus had gone one step further. He had done the same with human eggs having removed them from small pieces of ovary. He described how they followed virtually the same ripening programme as rabbit eggs. Research scientists like to be first. I am no exception. I sat in the middle of the Institute library momentarily depressed; the novelty of my discovery had suddenly worn thin.9

  Nonetheless, Edwards reflected, ‘it was simply amazing that no one else had followed up this work for over twenty-five years’. And so, with help from Molly Rose, a gynaecologist at Edgware General Hospital, he obtained a steady supply of human ovarian tissue, taken from women undergoing surgery, in anticipation of confirming Pincus’s findings: that they would ripen over a few hours to a state where they were receptive to fertilisation by sperm. ‘I started with high hopes. After three months I began to feel less certain. Dozens of eggs were cultured. I examined them eagerly after three, six, nine and twelve hours, none of them changed their appearance in any way whatsoever. They gazed back at me. They would not ripen, no matter which culture medium I used. After six months my hopes evaporated completely. Pincus was wrong.’10 The implications of Edwards’s findings were important. He had shown that Pincus must have been mistaken in claiming that it took the same time for human eggs to mature in vitro as it took for mouse or rabbit eggs. That was clear, but the puzzle remained – why did human eggs not mature in vitro? Bob Edwards had no explanation other than to infer that humans were just ‘too different’ from other mammals.

  Two years passed, during which Bob Edwards turned his attentions to other matters. Still,

  I could not help but dream now and then of working on human eggs again. One morning, in 1963, driving to Mill Hill it occurred to me that the ripening programme
in the eggs of primates such as humans might simply take longer than in rodents. Supposing the nucleus changed after twelve hours and only then the chromosomes would become visible? It was just a hunch but it was worth a last throw.

  Again the gynaecologist Molly Rose provided the ovarian tissue from which Edwards was able to extract four eggs.

  All I had to do now was wait, wait. I must not look at them too early. The first one I would examine after 18 hours. After 18 hours exactly, I looked and saw alas the nucleus unchanged, no sign of ripening at all. Failure. Impatiently, I looked at a second egg. It was like the first. I had to accept that I had drawn a blank, but I had two human eggs left, I would look at one of them again in six hours’ time – by then they would have been in the culture medium for twenty-four hours. When I next peered down the microscope I could not help but feel elated. Surely something was beginning to move? Just a suggestion but I must be patient. Four hours passed by slowly, slowly, but when I did examine the final egg I felt as much excitement as I had ever experienced in all my life. Excitement beyond belief, at 28 hours the chromosomes were just beginning their march through the centre of the egg. Fine, clear, absolutely visible, a sight to reward all my past efforts. A living, ripening, human egg beginning its programme just as the mouse eggs had done. There, in one egg in the last of the group, lay the whole secret of the human programme.11

  Thus human eggs could indeed mature in vitro; they just took longer. When Bob Edwards reported his findings in The Lancet, he tactfully omitted any reference to Pincus’s work twenty-five years earlier.12

  Here then was another reason – besides Min Chang’s theory of capacitation – to explain the failure of Miriam Menkin’s IVF programme in the 1940s. Taking her cue from Gregory Pincus’s claim of rapid maturation of human eggs she had simply added the sperm too early, before the egg was ready to receive them. Thus, theoretically, fertilisation should be possible if the sperm were added to the egg after twenty-four hours, but first they would have to be capacitated by exposure to the unknown chemical in the fallopian tubes postulated by Chang.

  Perhaps understandably, Edwards failed to anticipate that Chang’s theory of capacitation would turn out to be just as erroneous as Pincus’s observations. As a result he was to spend another three years engaged in futile research. In 1965 Edwards accepted an invitation to travel to Baltimore, where he tried every conceivable method of capacitation, including the addition of small fragments of fallopian tubes to the fertilisation dish, and ‘we even tried to fertilise human eggs in the fallopian tubes of rhesus monkeys, collecting the eggs twelve to twenty-four hours later’. Nothing happened. In six months he failed to fertilise a single human egg. Back in England he repeated these capacitation experiments in female volunteers. The sperm were placed in minute flasks and inserted into the womb overnight in the hope they would be influenced by the ‘capacitation factor’. Again, nothing happened.13 So once more Edwards had come to an impasse; clearly whatever the mysterious capacitation factor might be, it must be presumed to be crucial to fertilisation of human eggs. Until it could be identified there was no hope of further progress.

  Edwards had no alternative other than to turn his attention to other scientific matters – until, two years later, Chang’s theory of capacitation was also shown to be incorrect. Barry Bavister, a colleague of Edwards in the physiology laboratory in Cambridge, found that if hamster sperm were added to eggs in a culture medium containing sugar, bicarbonate and a spot of beef protein, they promptly fertilised. And if it worked for hamsters, why not for humans? It did, and quite spectacularly so – if the human eggs were left for long enough to mature and sperm were added in the right culture medium, then fertilisation almost invariably followed.14 It could hardly have been simpler. The thirty years that had elapsed since Dr Menkin’s failed in vitro experiments back in the 1940s are devastating testimony to the harm caused by false ideas in holding back scientific research.

  Fertilisation may have turned out to be straightforward, but this only serves to emphasise Bob Edwards’s achievement. In any scientific endeavour the decision about which experiment needs to be done must be underpinned by some general philosophical perception of what is likely to work. When Bob Edwards started his investigations in 1960, the philosophical perspective least likely to produce results was that the correct solution was the simplest, because, following Menkin’s studies in the 1940s, everyone knew that the fertilisation of human eggs in vitro was staggeringly difficult to achieve, if not impossible. To move from the supposition that the solution – if there was to be one – was certainly going to be complex to the realisation of its simplicity required him to demonstrate that not just one but the two established ‘facts’ about human fertilisation – Pincus’s work on egg maturation and Chang’s concept of capacitation – were in error.

  Understanding Hormones

  Coinciding with Bob Edwards’s lonely struggle demonstrating it might be possible to fertilise human eggs in vitro, there were major developments in the understanding of the female reproductive hormones, both to promote fertility with ‘fertility drugs’ and to prevent conception with the oral contraceptive pill. Four main hormones are involved. The first two, secreted by the pituitary gland at the base of the brain, are follicle stimulating hormone (FSH), so called because it ‘stimulates’ the maturation of the ‘follicle’ or egg, and luteinising hormone (LH), which prompts the ripened egg to pop out of the ovary and start its descent down the fallopian tubes. The two further hormones are secreted by the ovary – oestrogen produced by the ripening follicle, and progesterone from the remnants of the follicle (the corpus luteum) after ovulation has taken place. These hormones were all identified in the 1920s and interact by a mechanism known as ‘negative feedback’, where the hormones secreted by the ovary influence the secretion of the hormones of the pituitary, and vice versa.15

  Put simply, it runs as follows. At the start of the menstrual cycle the pituitary secretes FSH, which encourages the ripening of the egg-containing follicle in the ovary, which itself starts to produce oestrogen, whose levels begin to rise. This oestrogen ‘feeds back’ to cut off the secretion of FSH from the pituitary, permitting the LH to surge upward and precipitate ovulation. The follicle, now emptied of its egg, becomes the corpus luteum that secretes progesterone, which prepares the lining of the womb to receive the fertilised egg. Most commonly, of course, conception does not happen, so the progesterone levels fall, followed by menstruation. Then, in the absence of the negative feedback from the ovarian hormones, the pituitary FSH levels start to rise again, leading to the ripening of the next egg-containing follicle, and so on.

  Both fertility drugs and the oral contraceptive pill exploit this principle of ‘negative feedback’. Thus fertility drugs can be obtained from the urine of women going through the menopause for the following reasons: when the ovaries cease to function, the levels of the hormones they secrete, oestrogen and progesterone, fall precipitously. There is thus no longer any ‘negative feedback’ inhibiting the secretion of FSH and LH from the pituitary, which consequently produce vast quantities of these hormones to be excreted in the urine, from which they can be isolated and given to infertile women to stimulate ovulation. Together, the FSH and LH in the urine is known as Human Menopausal Gonadatrophin (literally ‘sex-organs stimulating’) or HMG.16 Conversely, the pill, containing oestrogen and progesterone, operates on the same principle, but in reverse, exerting ‘negative feedback’ on the pituitary to stop the secretion of FSH and LH, and thus preventing ovulation.

  There is one further important hormone that does not fit directly into this scenario. When the egg is fertilised and conception takes place, it is vital that the lining of the womb remains receptive and is not lost at menstruation. This is initially achieved by the progesterone secreted by the empty follicle, but its function is then taken over by a hormone secreted by the conceptus itself, or more precisely from the early placenta (or chorion), which is known as Human Chorionic Gonadatrophin or HCG, which is
present in large quantities in the urine of pregnant women.

  Thus women whose infertility is due to a failure of ovulation can be treated with fertility drugs derived from these two naturally occurring chemicals, HMG and HCG, found in the urine of menopausal and pregnant women respectively. At the beginning of the menstrual cycle, HMG with its high concentration of FSH encourages the follicle to ripen. Then halfway through the cycle a dose of HCG will, like LH, cause ovulation to take place. This treatment was first suggested in 1954 and introduced in 1960.17

  These fertility drugs are, of course, used to treat infertility due to failure of ovulation rather than blocked tubes, but they would nonetheless be crucially important in the development of IVF for several reasons. First, the considerable publicity associated with their use in the 1960s would have persuaded Bob Edwards that his work on the fertilisation of human eggs might have a practical application in the treatment of infertility that resulted from blocked fallopian tubes.18 Next, the fertility drugs would be of great practical use in increasing the number of eggs that could be ‘harvested’ during IVF, thus making the whole procedure much more efficient. Most importantly perhaps, they focused attention on the need to understand the precise way in which the female hormones interact during the menstrual cycle and, as will be seen, particularly the significance of the role of progesterone in sustaining the lining of the womb to receive the fertilised egg.