The Rise and Fall of Modern Medicine (25 page)

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

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

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.

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.

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: