The Rise and Fall of Modern Medicine (24 page)

Indeed it was not until the mid-1990s that modest improvements of around 10 per cent in survival in patients with some types of solid tumour provided at least some justification for the widespread use of chemotherapy.
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T
he burgeoning prestige of medicine in the post-war years was grounded not only in its substantial achievements, but the perception that some of those achievements – such as heart transplants and ‘test-tube' babies – verged on the miraculous. And it was extraordinary to be able to remove a man's ailing heart and replace it with another, and to facilitate the act of procreation and thus fulfil for the infertile the deep human need to have children.

It is thus only logical to infer that those responsible must be very clever and the possibilities of what medicine could achieve – given sufficient funds – must be limitless. The reality, as seen repeatedly with the ‘definitive' moments of post-war medicine, was rather different. The achievements did not arise from a profound understanding of the nature of medical problems but, more often than not, from chance or luck or some technological development. And the same is true for the events leading up to the birth of Louise Joy Brown, the first ‘test-tube' baby conceived by ‘in vitro fertilisation', usually shortened to IVF.

Fertilisation ‘in vitro' means ‘in a glass tube', to distinguish it from fertilisation ‘in vivo' – in the living body. IVF might seem to be an amazing scientific breakthrough, but is little more than a sophisticated piece of plumbing for women with blocked fallopian tubes, whose eggs cannot pass from the ovary down into the uterus to be fertilised by the partner's sperm. The solution to overcoming the blockage – at least in theory – is obvious: obtain an egg from the ovary, add the partner's sperm, then pop the fertilised conceptus back into the uterus through the cervix with the help of a piece of plastic tube. With luck, it will stick. Nature does the rest – the difficult part – where the tiny fertilised egg grows and multiplies to form a foetus made up of billions of cells, each with its own specialised function. Thus the contribution of human agency through the procedure of IVF in initiating the process is important enough, but it cannot bear comparison with the real miracle – the ineffable mysteries of embryonic development itself.

This sanguine view of the scientific significance of IVF is not intended to belittle the work of those who did so much to make it happen. Rather the reverse: IVF merits its place in the pantheon of great events of post-war medicine on its own account but also because it illustrates better than anything else the essential attributes and multi-faceted nature of the research from which those ‘major events' finally emerged. The first point is how difficult it can be to establish even the simplest facts – that it was indeed possible to fertilise a human egg in vitro. Next there is the crucial role of human personality, and in particular that of its pioneer Bob Edwards, who through the two phases of the development of IVF experienced first nine years and then eight years of bitter disappointment that would have convinced any lesser person to give up in despair. Then there is the essential contribution of the cross-fertilisation of ideas from other
disciplines. Bob Edwards did not set out to find a treatment for infertility because of blocked fallopian tubes. His primary interest in the fertilisation of human eggs was the observation of the earliest stages of human development, and this just happened to coincide with the blossoming of research into the use of fertility drugs in women where infertility resulted from a completely different reason – the failure to ovulate, or produce eggs. Thus IVF emerged from the fusion of two quite separate areas of scientific endeavour. Finally, there was, as so often happens, the singular contribution of technological development, in this case the laparoscope, which permitted eggs to be removed from the ovary without the necessity for a major operation. This made IVF a practicable proposition.

Each of these developments warrants closer scrutiny, but first, to emphasise why IVF was a definitive moment in post-war medicine, comes a description of the culminating event, the birth of Louise Joy Brown in 1978. The dramatis personae in this ‘sensational story of the world's first test-tube baby' are Bob Edwards, Reader in Physiology at Cambridge University; his collaborator Patrick Steptoe, Consultant Obstetrician at Oldham General Hospital; Sheena Steptoe, wife of Patrick Steptoe; and the parents, Lesley and John Brown. Just before midnight on Tuesday 25 July 1978, Patrick Steptoe performed a Caesarean on Lesley Brown and delivered Louise Joy, who weighed 5lb 12oz. Meanwhile, elsewhere in the hospital, husband John Brown was sitting in his wife's room with Sheena Steptoe.

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 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.
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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.
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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.
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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'.
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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:

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.
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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.
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He was, however, unaware that Pincus had conducted precisely the same studies back in the 1930s.

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.'
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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.