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A view from the lab
Roger Gosden
If I were asked to give a title I suppose it would be A View from the Lab, to borrow Steve Jones' title from his newspaper column. I'm a man from the provinces and when I come down to London one of things that I like to do is to pop into galleries, as I did today. One of my favourites is from the National Gallery. It is by Joseph Wright of Derby and is entitled Experiment with an Air Pump. This depicts something that was popular in the eighteenth century which was a bit of parlour science and the middle and upper-middle classes were very interested in scientific experiments. We see in the painting an experiment where oxygen is being evacuated from a chamber and the canary is fainting. You can see lots of interesting reactions to this. One man is presumably the scientist, although he looks more like a magician. The young men and boys are fascinated by the new revelation, asking, 'Whatever is it in the ether that is so important for keeping life going?' Then there are other attitudes which are ones of sorrow at the loss and the cost of the experiment. Then there are other people who are more interested in other things and that's always the way it has been.
Attitudes to science differ according to where people are standing. The same is true in assisted reproductive technology. Attitudes will differ according to whether you are a patient, whether you are part of the medical team or whether you are just an interested on-looker. And that is the dilemma.
A painting by Sir Joshua Reynolds depicts a contemporary of Joseph Wright, called John Hunter, who was a fellow of the Royal Society and a Scots anatomist-cum-surgeon. He did most of his work in London and he was, if anyone can be claimed to be this, the first person to carry out assisted reproductive technology. He was presented with a couple who had an infertility problem. The man had a anatomically abnormal penis and he could not inseminate his wife. Hunter suggested that they collect the semen and inseminate it. The outcome, in the year 1766, was successful. But most interestingly, Hunter never published this work and we only know about it primarily through his brother-in-law who published later. Hunter was concerned about the adverse publicity in the social and religious atmosphere of his day. Hunter would have been amazed now at what can be achieved - and what has been achieved in just the blinking of the eye of history - in assisted reproductive technology. Fertilisation is not just carried out in the test tube between the mixing of germ cells, but all sorts of other things can be done to improve the outcome, perhaps by finding out whether there is a genetic abnormality in the early embryo, or to assist where there are very few sperm by injecting them into the egg.
So the power of assisted reproductive technology seems to be very great. I am going to look at where it is going and what are the attitudes of some of the people who are working in this field.
The attitude to this technology by some is represented by a cartoon which was published in the Sunday Times depicting research in my laboratory in 1994. I must say that I didn't sit for this particular portrait and I think that one has to say that this picture really represents the attitude of those who fear where we are going. There is no important information in there otherwise. No-one, as far as I am aware, is working on the cloning of human embryos and certainly we have never worked on cloning at all. So there is concern about where things are going. But I would say from the vantage of somebody working in reproductive biology that I have views that are not so different from the rest of the population. May I just give you a couple of examples. In a big conference in Greece a couple of years ago there was a debate and the vote afterwards was whether women of post-menopausal age should be assisted to have a pregnancy. Interestingly enough, the people who were there - 2000 people representing gynaecology and embryology - voted it down. They were very conservative on that point. Everyone I know is opposed to gender selection, apart from for medical reasons. It is repellent, as I'm sure everyone would agree here, on any other grounds. So, our views are not so different from the people in the street, though of course there is a spectrum, just as there is outside.
What, then, are the priorities? Are scientists really interested just in the bizarre? Or are we really concerned about people and about understanding one of the most fascinating aspects of the natural world: where we come from, the egg and the sperm. From the point of view of medical treatment, these are the priorities:
Health
In order to help people to have a child, we must be sure that they are not doing more harm to the mother and that the child is normal. Weåve heard about this not just terms of the birth and any physical deformity, but also the psychological well-being of the family and the child in the long-term. The infertile couple often send out a crie-de-coeur because of the sense of loss. It is a real suffering for some people to be unable to have a child. And so it is our responsibility - those who are in the business of carrying out the routine of assisted reproductive technology - to assist those people providing the health cost is not too high. But there are other costs too - the financial cost - and I think it's important for those of us who are in research to try to make this treatment more reasonable in price. Because, after all, this at the moment is a treatment that some people cannot afford.
Efficiency
We have also seen data showing that it is a very inefficient process. There are arguments, of course, that this inefficiency is not much less than nature - human fertility is inefficient - but then maybe we can improve it and reduce the number of cycles that people have to go through. There is not only a cost issue here, but also one of discomfort and physical pain. People measure pain in different ways. People seem to feel pain to different extents but obviously we must try to reduce the discomfort that is associated with treatment.
Genetics
Far from wanting clones, I think what most of us want is a chip off the old block, a child that is a little bit like us but not identical. Most of us would agree that if we had twins, we wouldn't really want to have identical twins. Genetics is important to us - we would rather avoid donor eggs and sperm - and there may be ways in which we could reduce our reliance on them.
The waiting time is another matter for some people, but I would put that at the bottom of my list. There are so many technologies now that have been brought to bear on the business of bringing together eggs and sperm and then transferring them to the most favourable site for satisfactory pregnancy. Indeed, assisted reproductive technology has now got a suitable acronym, ART. But there is some science in it, as I hope you will see!
There are many other acronyms which characterise this particular field. IVF (in vitro fertilisation), IVM (in vitro maturation), IVG (in vitro growth of eggs), ICSI (intracytoplasmic sperm injection) and so on. People wonder where things are going. I don't have time, in a short presentation, to list these, but I am going to give you two topics which are important to me and are being pursued in a number of places around the world and I think are on the threshold of clinical practice. It remains to be seen how widely they will be practised but I hope that it fits in with many of the priorities, representing what I think is mainstream research in this field - not the bizarre, but the common place problems - cost, safety and ethical considerations.
The first one is in vitro maturation of eggs and the second is ovarian tissue storage and conservation. These are given by way of example rather than a global impression of what the mainstream research is at the moment. One of the major problems in this whole field is the scarcity of a mature egg, ripe for fertilisation. It is the rarest cell of the body. You can't get any rarer than only one cell once a month and then only for 35 years or so. So it is often the limiting resource and not always are they fully fertile either. Increasing ways of producing normal eggs and making the best use of them is a high priority.
Many will be familiar with what happens in conventional IVF already. It is a lengthy process and there are different types of protocols. If we start with the menstrual period, it can take six weeks before we can collect the eggs. That involves various treatments to suppress the woman's own hormones, then giving hormones by injection - FSH (follicle stimulating hormone). Much of the cost is involved here. Maybe half of the cost of IVF is based upon the FSH because it is a rare and precious hormone. Then there is treatment with another hormone to activate the egg which is then collected by ultrasound. Then the egg is fertilised, the embryo stored for a couple of days and then transferred.
In vitro maturation (IVM)
What in vitro maturation involves is bypassing the conventional IVF process. Current IVF practice is not necessarily here for all time, but is developing. Even people who object to in vitro maturation will see that there are some advantages to progress in research that will actually reduce some of their worries. There are two protocols involved in IVM. One is to do without the hormones altogether - no injections - which would reduce the cost of treatment by half. This would be suitable for perhaps polycystic ovary patients or perhaps for other patients just to give a light course of treatment. The latter would have more widespread use but has yet to undergo serious clinical testing.
We don't have any data yet to show a comparison of conventional IVF with IVM, but research protocols work very well with animals. In fact there is a bovine embryo technology out there which has quite a respectable rate of success in producing calves from eggs that are just sucked out of the ovaries. The protocol for humans would involve a short series of injections followed by egg collection, placing the eggs in vitro, fertilising them and then the embryo will be grown. There are various technical questions about how this might be optimised but I won't go into those. Basically what IVM involves is collecting the egg while it is still immature and developing that egg in vitro to the stage where it can be fertilised. Normally this occurs while the egg is still in the ovary and it is activated by a hormone. This is done routinely in animals. And indeed there are a few viable human pregnancy records around the world from this sort of technology. The advantages are:
- to maximise the egg harvest
- to minimise the cost
- to avoid hyperstimulation syndrome
- to avoid many visits to the clinic
There is also the conservation of fertility: we could make better use of the eggs. Were it possible to cryopreserve the eggs at this immature stage (which may be more successful than presently with the mature egg) that would make a big impact too because it would reduce our reliance on embryo storage. There would also be more eggs for research.
Ovarian tissue storage
What about conserving a woman's egg supply and so reducing our reliance on donor eggs which are a scarce resource? One of the major problems at the moment for a young cancer patient who overcomes her disease is that she may be permanently rendered infertile. The reason for this is that egg numbers, which are declining with age naturally, decline much faster. The cancer treatment - drugs, radiation treatment - accelerate that ageing process. So the numbers are reduced drastically and she will have an early menopause. One way that we may be able to overcome this problem is by storing the eggs. We are not talking about the mature ones which are ripe for ovulation, but the bulk of them which are at a so-called primordial stage, resting eggs of which a woman of 30 will have tens of thousands in her ovary. Most of these are around the outside of the ovary and can be harvested by just a little biopsy, rather like skinning the ovary. In that material there is an enormous reserve of eggs which can be stored using conventional freezing methods and then returned to the body.
Patients have tissue in store at the moment, but we don't know if it is going to help them. I'm pretty sure that it will work, but we cannot say with what rate of efficiency. All I can say about returning the tissue to the body, which will be a graft to restore nature, is that we know from animal experiments that it works with lambs born from frozen sheep embryos. In the latest series of experiments, 100% of animals which had frozen ovaries had regular ovulatory cycles for nearly two years and even after that they still had eggs left in their ovaries. So it seems that ovary storage may be an option which will reduce reliance on some of the alternatives and will restore nature. In the longer term, it may be possible to do everything in vitro rather than returning the tissue to the body. Perhaps we could grow the eggs up in vitro rather like in the mouse. But as I emphasise repeatedly, this sort of technology is probably 10 to 20 years off and in the meantime we can only say to patients that we may be able to return the tissue to their bodies by a grafting operation.
This sort of technology could of course have other implications. This has been the history of assisted reproductive technology, that what has been devised for one particular purpose, just as it was originally by Edwards and Steptoe, can be applied in many different ways. So for this particular technique - the conservation of ovarian tissue for cancer patients - there are other diseases where tissue destruction occurs such as endometriosis. There are other conditions of premature ovarian failure or indeed normal ageing. People could put their ovaries on ice, provided they were frozen early enough, and then retrieve them later, because we presume that the eggs remain in suspended animation throughout that time. Then there are other, perhaps more bizarre - though not so bizarre when you start to think about them - situations where someone may want to help their child by inter-generational egg donation, such as the case of a mother who had a Turner's syndrome child with sterile ovaries who cannot have a baby of her own but would make a very fit mother in every other sense. Some have had egg donation, but if her mother could put a bit of her tissue on ice, maybe for 10 years or longer, then she could have that tissue back where the eggs could be collected for transfer to the child.
I don't know how you feel about that. I haven't sorted out in my own mind what should be done and I was quite unprepared for this when it was suggested to me. But one thing I do believe very strongly is that because the technology could be applied to circumstances where there are objections, we shouldn't say that other people who could benefit from this technology should be denied it.
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