GO FORTH TO THE LABORATORY AND MULTIPLY

THE NEW SCIENCE OF HEALTH: PART TWO; With grandmothers giving birth to their own grandchildren, vanishing sperm counts, libido-enhancing hormones and the male contraceptive pill, fertility is one of science's trickiest areas. Hilary Bower explains all in the second part of our series
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No evidence works as close to the moral pale as the science of reproduction. Since Aldous Huxley painted his apocryphal image of babies grown in bottles, made to measure according to the "Predestinators" command 60 years ago, nothing has been guaranteed to provoke fear, fascination and "fish needing bicycles" jokes more than the possibilities of tampering with procreation.

Deluged with stories of grandmothers having their daughter's babies, post-menopausal women having their own late-life gift, the birth control pill for men, libido-enhancing hormones and vanishing sperm counts, there are plenty who think science is going too far. But for every accusation there is an equally human plea for progress - from people desperate to have children, battling with inherited diseases, or from those who simply want a better way to control their fertility. Essentially it's all the same arena; fertility and infertility are two sides of the same biochemical coin and sperm meeting egg is an amazing chemical reaction. But as researchers are finding out, a lot goes on before Harry meets Sally, and the more we find out, the more there is to know.

While news earlier this month of a 50 per cent drop in the sperm count of Finns in the last decade caused a spasm of predictions about premature extinction, some scientists are starting to believe the old maxim about size - in this case quantity - not being everything, could have more than just comfort value. Damaged sperm, it appears, may be more a problem than not having enough.

Theories on when sperm are damaged and by what, are having little trouble in multiplying. Every month a new culprit is suggested, ranging from cycling and stress to hot baths, excess vitamin E and, according to Dutch research, tight underwear. But the prime suspect for both sperm damage and decimation is a key player in the whole chemistry of reproduction - oestrogen.

Always thought of as the female hormone, oestrogens - or their artificial relations xenoestrogens - are turning up in all sorts of places. Used to soften plastics, as bases for inks in food packaging, in pesticides and in female contraceptive pills, xenoestrogens have been found in water, food and breast milk in what some scientists say are worryingly high levels. Adding weight to the anxiety is evidence that male rats exposed long term to xenoestrogens show a clear drop in sperm production and testicular weight.

But until very recently, the oestrogen theory had one gaping hole. There are no oestrogen receptors in the human male reproductive tract, or at least none that fitted the known female form. Ask anyone what the root of male virility is and they'll probably say testosterone. Last autumn, scientists in Sweden, looking for something else, discovered a new type of oestrogen receptor which they called oestrogen beta (). And, yes, you've guessed it, the male reproductive organs are full of oestrogen receptors.

According to Professor Alan McNeilly, acting director of the Medical Research Council Reproductive Biology Unit in Edinburgh, this development has surprised everyone: "It has given us a whole new view of the world. Now we've got to completely re-evaluate all the theories that have gone before. The realisation that men's testes require this oestrogen to function properly, not just androgen, and that there may be specific ratios between oestrogen and androgen to make everything work, could mean this is the root cause of many problems."

The finding has also opened up a whole new line of investigation in relation to sperm count based on the activities of the special sperm "nurse" cells in the testicles called Sertoli cells. The number of Sertoli cells a man has appears to determine how much sperm he can make and is set while he is still a baby. "This means a low sperm count might not be due to damage to actual sperm - a man may be making a quite normal amount of healthy sperm for the number of Sertoli cells he has. Instead the problem may be that something has reduced the number of Sertoli cells he is born with," says Professor McNeilly, whose unit is currently working on a new test to measure Sertoli cell function. The most popular theory for that "something"? Exposure to environmental oestrogens in the womb. But oestrogen is not the only answer to the conundrum of infertility. There are multiple factors that could affect sperm health as well as a whole stream of unanswered biochemical questions. We know so little about sperm development, says Professor McNeilly. "They're all two sided questions. If we can work out how something is successful then when it isn't, we can work out how to treat it, or we can stand it on its head and see if there's a way to use it to curb fertility. If oestrogen can cause infertility, then its effects can not only be reversed but mimicked for a male contraceptive pill."

Another controversial puzzle is exactly when do sperm become genetically mature? This question is at the crux of one of the newest forms of in- vitro fertilisation - intracytoplasmic sperm injection or ICSI. Sperm take 60 to 70 days to develop from a round cell into the characteristic tadpole-like shape. Starting out in the small lobules of the testes, they move through a tube called the epididymis, ending up in the vas deferens from whence they will be launched into ejaculate during orgasm, for their date with destiny.

In a substantial number of infertile men, however, this maturing process goes wrong and though their sperm are fertile, they're either not good swimmers or can't penetrate the egg. To get around this, the ICSI technique extracts a single mature sperm, either from ejaculate or the epididymis and fires it directly into an egg using a fine needle - eliminating any need for swimming or penetration.

Around 200 babies were born using ICSI in 1996 and many doctors expect it to become a routine procedure available in every IVF clinic in the near future. But this technique has opened a whole can of ethical and scientific worms.

Roger Gosden, Professor of Reproductive Biology at the University of Leeds, and a driving force in the field, explains: "By applying very powerful techniques of reproduction to people who would never normally reproduce, we may be bypassing things that normally happen in the natural selection line.

"At our current level of knowledge, we don't know for sure that singling out one sperm to win the egg race won't have serious implications for later health, not least the risk of perpetuating infertility. Research from Belgium where, due to different scientific regulations, thousands of ICSI babies have been born, is reassuring in that it has shown a very only a small increase in the number of babies born with an extra X or Y chromosome." But despite this being a relatively minor abnormality that also occurs in natural born children, it is linked to impaired fertility. ICSI may beget ICSI.

But even more controversial than mature sperm ICSI is the use of immature sperm - called spermatids - taken directly from the testes for the injection. The method has been pioneered by Dr Simon Fishel of Nottingham University's Research and Treatment Unit in Reproduction, who, in January 1996, shepherded into life Susan Louise Oxburgh, the first English baby to be born by immature sperm conception and one of only six babies worldwide.

"The technique could be a breakthrough for men who are unable to create mature sperm or whose `pipes' are blocked or compromised by, for example, cancer therapy," says Dr Fishel.

Susan's birth has divided reproductive scientists. Some say far too little is known about the genetic maturity of spermatids to guarantee success, a stance that is also backed by the human Fertilisation and Embryology Authority which recently suspended human trials with spermatids in Britain and sent researchers back to animal models for more evidence of safety. Others, however, say animal models can only tell us so much.

Writing in the Progress Education Trust journal, an organisation which examines medical and ethical issues in reproduction, Dr Fishel says his studies and those of other molecular biologists show the genetic make- up of immature sperm is "to all intents and purposes, identical to that of the fully formed sperm". Up to seven generations of healthy offspring have been produced through normal intercourse from mice born by spermatid injection, he adds.

"No matter how much animal research is done, the first series of treatments performed with sub fertile couples will always be a leap in the dark. We can never extrapolate with absolute certainty from animal models to eventual outcome in humans."

The only way of producing categorical data, says Dr Fishel is to "proceed slowly" with human trials. "This will allow patients and their practitioners to accept the risks of undergoing treatment in the hope that it will successfully result in a child while eventually producing the only data that really counts."

This debate is characteristic of this emotionally-charged area of research. With an ever-increasing group of infertile patients, desperate to have their own child, pressure to move closer to the cutting edge of research is enormous. But just as enormous are costs of unforeseen outcomes, not just at birth, but 10, 30 and 50 years on.

The controversy is not limited to immature sperm: another technique on the brink of human testing is freezing ovarian tissue and re-implanting it later in life. And while this may smack of women trying to better nature by extending their reproductive years, there are sound clinical reasons for such a technique.

Up to now it has only been possible to freeze-store embryos and not eggs. Despite multiple attempts, only five children have been born worldwide from a frozen egg.

But embryo IVF can produce fundamental problems. It means a women has to have a partner or, at the very least, a consenting sperm donor, and be over the age of puberty when their fertility is threatened. The threat often comes from cancer treatment which means that as well as coping with the anxiety of traumatic treatment, women also have to undergo the stress and discomfort of hormonal stimulation cycles. For children, the options are virtually zero - even if eggs could be frozen - because ethics do not allow hormone stimulation to be given a child.

Freezing a tiny strip of ovarian tissue, the size of piece of paper left by a hole punch, complete with its thousands of minute eggs, and sewing it back when the time is right, may change everything for such women. The international trail blazer of the technique is Professor Gosden. While turn-of-the-century surgeons experimented with grafting whole ovaries to counteract the menopause, Professor Gosden says that now just a sliver from the outer layers of tissue will do because that's where the primordial follicles are stored - the rest of the ovary is just scaffolding.

It is thought that the primordial follicle is a better stage to freeze- store because there are not a lot of specialised structures that can be damaged. The tiny eggs, which are less than 1 per cent of the volume of mature eggs, also have a long period of growth ahead of them to complete their maturity and repair any damage.

"We're ready to test this in humans now - we have quite a lot of patients whose tissue has been stored, now we're just waiting for them to grow up or to come through their disease. In sheep, just sewing the tissue near the Fallopian tubes has been enough to make the cycle start up," says Professor Gosden.

Such technology could have far-reaching implications and not just for those whose reproductive life may be damaged by disease. "Women could be fertile well in their seventies and eighties, but you really have to ask who'd want to be? There is a view that although the women's average life span has been steadily creeping up, the menopause has stayed stubbornly fixed at around the age of 51. You could also say there's a mismatch and if we are extending lifespan, why not extend reproductive life as well?" asks Professor Gosden, who adds: "My personal view is that with more women wanting to have children later, and growing evidence that the risk of conceiving children with genetic diseases increases the older the parents are, it's people in their forties and fifties we should be helping to have healthy children, rather than those in their eighties."

To those who think it could mean eternal youthfulness and sexuality, Professor Gosden cautions that ovaries produce oestrogen in much larger amounts than an HRT dose and adding years of unnatural exposure to it could increase the risk of breast cancer.

According to Juliet Tizzard, director of the Progress Educational Trust, the obvious benefits of ovarian transplants are being held back by society's contradictory opinions on older mothers: "With more women wanting to reproduce later in life and increasing evidence that egg quality matters, you'd think something that allows women to harvest and store eggs from their twenties would be seen as useful. But no, men get a pat on the back if they father a child in their sixties or seventies but older mothers are frowned on. The closer we get with technology, the more worries surface about whether older women can be good mothers."

But there are other potential worries lurking, including the possibility of re-importing lethal cells of diseases, such as leukaemia, within the transplanted tissue. The only way to rule this out is to grow eggs from the primordial follicles into mature eggs in the laboratory -what's known as in-vitro maturation and the subject of some of the most frenetic activity in embryology today.

The question, says Professor Gosden, is what to put in the water?

"We would recover a piece of ovarian tissue in a biopsy at any age, but 95 per cent of eggs would be at the primordial stage with five months growth ahead of them - we don't know yet what they need in terms of nutrients and support to make them grow."

Even using mature eggs close to their natural ripeness, only a handful of human babies have been born from eggs coaxed into maturity in a Petri dish - though the technique works well in animals. One baby mouse has been born from a primordial follicle grown into an embryo in a lab. Growing eggs could revolutionise traditional IVF, says Professor Gosden, bringing costs to a fraction, removing the need for uncomfortable and sometimes risky hormone treatments, and solving the scarcity of donors problem.

What of Huxley's babies in bottles - the wombs that could be the logical extension of growing eggs? Still science fiction, thanks to the complexity of the placenta. Thank goodness some might add.

But not Juliet Tizzard. She says to ensure real benefit, society has to stop being appalled, and start thinking clearly. "We're often horrified by the idea of things that when we really think about them often have quite significant benefits. Artificial wombs are a good example - everyone recoils from the image of baby in a bottle without thinking at all about how the technology might be used. The most obvious benefit would be for people whose only option right now is surrogacy with all its emotional physical and logistical problems. For women without a womb or who can't take a baby to term - an artificial womb could be a wonderful advance. We've got to stop being so horrified and sit down and think things through."

! Next week our series concludes with the science of delaying death

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