Want to freeze-store your ovarian tissue? Grow eggs in your arm? Or use IVF surrogacy to have a baby? All of the above are either available or on the horizon. Alison Motluk talks to Roger Gosden, the man whose work on sheep made possible last year鈥檚 headline-grabbing 鈥渕enopause reversal鈥� on a 29-year-old dancer. Gosden, based at McGill University in Montreal, is currently hard at work figuring out how to culture human eggs鈥�
How is having babies likely to change over the next generation?
I鈥檇 like to think it would be more predictable. It鈥檚 very much a lottery now. About 1 in 6 pregnancies in a young woman will end in miscarriage. In an older woman of 35 or 40, it鈥檚 double that. There鈥檚 a serious incidence of birth defects in our species, about 3 per cent. There are even uncertainties about how long it will take to get pregnant. We are still doing it like cave-dwellers.
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How do you plan to change that?
Most miscarriages are caused by fetal chromosome abnormalities, so if we could improve the quality of egg and sperm, there would be less wastage. There hasn鈥檛 been enough attention paid to preconception care-the idea that problems build up in the antecedents of the fertile eggs and sperm which take many weeks to develop in the body. So there may be ways we can improve the quality of the eggs and the sperm by understanding more about their biology and the sort of agents and lifestyle factors that might harm them. The obvious one is smoking. More and more evidence points to smoking as having harmful effects on the ovaries and the testes, damaging gamete quality and potentially causing mutations. Also the potential to get pregnant varies not only between women and with age, but from cycle to cycle. It probably varies most in the ten years leading up to menopause. We need better markers, hormone levels perhaps, which could predict optimal fertility.
But when you age, your eggs become old and stale鈥�
Well, we have one or two other ideas. For instance, it鈥檚 theoretically possible to slow down the rate at which the ovaries age. This may mean that we can preserve the egg population in the ovary for longer. If we can reduce the rate at which the oocytes in the follicle store start their growth cycle, we would perhaps be conserving those eggs for later in life. And maybe menopause would be later. If we were able to slow down the rate at which the eggs were disappearing so that a woman at 35, instead of having around 25,000, had, let鈥檚 say, 50,000 or 100,000, roughly the level of a woman of 25, would her risk of producing abnormal eggs, including ones prone to Down鈥檚 syndrome, be reduced accordingly? We do have some evidence that the risk of Down鈥檚 may be related not simply to the chronological age of the woman but also to the size of the egg population in the ovary, in a sense to the biological age of the ovary.
Why should the number of eggs matter?
We don鈥檛 know. But we think that as the ovary ages, there are changes in the hormonal relationship with the pituitary gland. Levels of follicle stimulating hormone, or FSH, from the pituitary gland go up, and inhibin levels from the ovary go down. There are probably lots of other subtle interactions going on within the ovary, which are changing as a result of the declining number of follicles. And this might create some sort of disregulation and a less than optimum environment. We don鈥檛 have any proof but it鈥檚 interesting that women who are predisposed to very early menopause do tend to have a higher risk of having babies with Down鈥檚 than others. We do think this is an interesting possibility.
How could you slow down the rate at which eggs disappear?
A contraceptive pill which suppresses follicle development right at the beginning might have the advantage of maintaining a woman鈥檚 fertility options for a bit longer. We don鈥檛 have any candidates yet that might interfere with this early stage, but the theory is robust. The drawback is that a pill, patch, implant, sniffer tube or whatever the best strategy turns out to be for suppressing follicles completely would probably produce menopause-like effects of hot flushes and bone mineral loss, just as if the ovaries had been removed. So it would have to include some oestrogen and perhaps progesterone.
You can freeze embryos. What about freezing eggs?
I don鈥檛 know how many babies worldwide have been born after freeze-storage of mature eggs collected during IVF. At the last count earlier in the year it was about 30, but I guess it鈥檚 gone up. This is a technology that has been much more difficult to develop than embryo freezing.
What makes eggs so hard to freeze?
The egg is poised at a very sensitive moment in its life cycle. It鈥檚 got to undergo fertilisation and nuclear division and set up changes in its membranes within a very few hours, or it becomes over-ripe. Once you collect the eggs, they must be fertilised within a day or so, or frozen immediately after being collected and used immediately after thawing. Otherwise they go off. The egg is a delicate cell-very sensitive to chilling, let alone freezing, and also to the cryoprotectants that we use. It鈥檚 a big cell, which is not really suitable for freezing either. At the moment, the best we can determine, is that for every 100 eggs collected and frozen, about 1 will produce a baby.
What about immature eggs?
The work started when I was in Edinburgh in 1993 and 1994. We鈥檇 been doing work with sheep and other animals to see if we could freeze-store the ovary-or at least biopsies of it. The sheep is quite a good model for humans. Both ovaries were removed from a group of sheep. Then the cortical skin, which is rich in the most immature-or primordial-follicles, was removed by peeling it away. That part was freeze-stored. Several weeks later, it was returned to the original site. It was only a very small part of the original ovary that was returned, just the outer part-and only a part of that. Blood specimens were taken every week or two to measure hormone changes and we found that all of these animals had normal cycles almost identical to normal animals for at least two years. Some lambs were born, proving the technique was effective. If we could do the same in people, we鈥檇 be delighted, of course. That鈥檚 what we鈥檙e aiming for.
What did last year鈥檚 鈥渕enopause-reversing鈥� procedure on the 29-year-old dancer tell us about the viability of this in people?
Proof of principle. In many ways she was not an ideal patient because she had a complex medical history and the tissue was not frozen in our centres. Kutluk Oktay carried out the procedure generously in the hope of doing some good.
Will the day come when a young woman heading for university looks ahead and thinks, well, it鈥檒l be at least ten years before I get round to having kids, so just as a precaution, I鈥檒l bank some eggs now?
I think so-for a minority. I could certainly imagine if a woman had to undergo an abdominal operation anyway, say for an appendix, and if she had a family history of early menopause and no immediate intention of trying to get pregnant, why not save a few eggs on ice? Maybe age 20 is the optimal age. We don鈥檛 know. The more we know about ageing and fertility, the earlier ageing seems to begin affecting the quality of eggs. A woman would always have to undergo some operation, but it might be quite minor if we could use the procedure in routine IVF, which is to suck the eggs out of the ovaries using a needle. It takes about fifteen minutes, so it鈥檚 pretty low risk.
What if you can鈥檛 replace enough tissue in the ovary site to restore a normal cycle?
Another possibility is to transplant the tissue into a site such as the forearm, so even if it was a child鈥檚 tissue and it was a small amount, by transplanting it back into a site that was very easily accessible you get the hormonal changes occurring and you can easily remove the eggs for IVF.
What about growing eggs up outside the body altogether?
That鈥檚 the ultimate aim. We have been working on it for years and it鈥檚 very difficult-much more so than growing embryos. The reason is that the maximum time we need to keep a human embryo in culture for IVF procedures is only five to seven days. For half of that time, the embryo is being sustained by a molecular programme laid down in the egg so it鈥檚 already got its endowment of protein and energy. The conditions of culturing embryos are not really very demanding. However, if we鈥檙e starting with the most immature, the primordial egg, then we鈥檙e looking at a growth time of more than six months. During this time it enlarges a hundredfold and changes from a cell which is very undifferentiated into one that can be fertilised and divide. There are many other subtle underlying molecular changes such as the setting of genomic imprints, so that the appropriate chromosomes are expressing the right genes. So we have to try to match normal conditions as closely as possible to be confident. There are a lot of changes going on that could be upset by a less than optimal environment. And although there鈥檚 progress being made with culturing animal eggs, particularly those of rats and mice, to some extent with farm animals, and a very little with human, we are a very long way away from having a routine procedure. Being able to grow eggs in vitro would be as big a breakthrough as any in reproductive technology.
Apropos other breakthroughs, has anyone taken ovarian tissue from one woman and implanted it into another woman?
Historically, the answer is yes-a century ago, when people didn鈥檛 know about transplant rejection, didn鈥檛 have HRT and were attempting to reverse premature menopause with grafts from young women鈥檚 ovaries. There were even claims of success, including pregnancy, but we don鈥檛 know if they were just lucky with the tissue match. I have carried out ovarian transplants which showed that unless there is a good match, there is a strong chance of rejection. I am looking at the question again of whether the transplant would work after a short period of immunosuppression.
And the $64,000 question. Can stem cells be made into germ cells-eggs or sperm? Has anyone anywhere tried it?
I hear a rumour-but no more yet!
Do you think people will ever give up the cave-dweller natural option for artificial reproduction-just for convenience?
Some already seek this option-though to my knowledge they have been turned down. One of my colleagues has been asked by couples if they could use IVF surrogacy to have a baby-the effects of pregnancy on a career as a model was too much. I suppose if assisted reproduction became more efficient and produced fewer abnormal embryos, more fertile people would see virtue in using it. After all, we have stopped using our brains to do complex arithmetic since pocket calculators became so easily accessible.