The UK Government recently announced its intention to extend the maximum storage limit, for frozen eggs, sperm and embryos, to 55 years across the board (see BioNews 1111). Sarah Norcross, director of the Progress Educational Trust (PET), invited the audience at PET's event 'Advances in Assisted Reproduction: What Can We Expect?' to consider where assisted reproductive technologies (ART) stood 55 years ago. The first IVF baby hadn't even been born. Norcross mused: 'Where will ART be 55 years from now?'
First speaker, Rod Mitchell, professor of developmental endocrinology at the University of Edinburgh, talked about current advances in ART for males. Patients who are unable to produce sperm don't have the option of freezing it for future use. Such patients include children who receive medical treatment that also damages their fertility, such as chemotherapy.
Professor Mitchell explained that we might instead preserve spermatogonial stem cells, as these are present in children as well as adults. This could be achieved by removing and freezing small portions of testicular tissue, where the stem cells are located. In the future, the sperm could be transplanted back into the testes, or used to produce mature sperm in the lab. Such tissue transplantation research is currently on the cusp of clinical development, having recently proved successful in primates.
Professor Mitchell called for clinicians to ensure good service for the so-called 'inbetweeners' – young people who fall between the stage where only spermatogonial stem cells can be harvested, and the stage where mature sperm are present. There are also avenues of research, currently being pursued in animal studies, which could lead to ways of generating sperm that do not need to start from spermatogonial stem cells at all.
Second speaker, Evelyn Telfer, professor of reproductive biology at the University of Edinburgh, addressed advances in the maturation of human eggs in the lab, an area which has been pioneered by her research group. She put her group's research into context with a striking fact: a woman's full egg reserve is entirely formed before birth, but only 0.1 percent of those eggs will ever be ovulated. The rest are lost. This begs the question of whether it is possible to preserve any of the lost 99.9 percent.
In the 1990s, researchers at the University of Edinburgh developed the cryopreservation of ovarian tissue containing immature egg follicles. Since then, more than 130 babies have been born worldwide following transplantation of such ovarian tissue. However, Professor Telfer cautioned that this approach is not suitable for all patients – for example, patients with ovarian cancer cannot risk having ovarian tissue removed and transplanted back into the body following treatment, in case the tissue contains malignant cells. This is why the alternative – in vitro growth of eggs – is needed.
Professor Telfer's group has shown that human eggs can be brought to full maturity using this approach, and she now intends to ensure that the resulting eggs are viable and safe for use. Studies of lab-grown sheep eggs will begin next year. Professor Telfer's group is also investigating how to adapt the maturation process with ovarian tissue obtained from children, from transgender patients, and from patients with chromosomal conditions such as Turner syndrome. Professor Telfer speculated that patients storing tissue now might benefit from future advances, such as the prospect of making mini-ovaries and new eggs from ovarian stem cells.
Third speaker, Adèle Marston, professor of cell biology at the University of Edinburgh, talked about one of the major causes of infertility and miscarriage – eggs that have an abnormal chromosome number, a phenomenon known as aneuploidy. Some 30-40 percent of eggs are thought to be aneuploid, in contrast to 2 percent of sperm. The likelihood of aneuploidy increases with age, and this contributes to a greater chance of miscarriage if women become pregnant in their 40s.
Aneuploidy occurs during meiosis, the process of cell division which creates eggs in biological females or sperm in males. Professor Marston outlined the process, explaining that immature eggs are 'held' in an early stage, each with an accompaniment of proteins to eventually help sort and divide the chromosomes. The deterioration of these 'sorting proteins' over a woman's lifetime may be one of the reasons why aneuploidy occurs. Professor Marston expects that research using embryos and gametes donated by ART patients will help us understand more about aneuploidy, and ultimately that knowledge will be used to provide better choices for patient treatment.
The final speaker, David Albertini, professor of developmental cell biology at the Bedford Research Foundation, Massachusetts, gave a historical perspective on ART. Before 2010, many fundamental discoveries in fertility science started with research in animals, and new technologies moved steadily from bench to bedside. The past decade, however, has seen a steady rise in the prominence of 'add-ons' – optional treatments which purport to improve ART outcomes.
Professor Albertini used this as an example of the science of human reproduction being drawn further into the realm of big business. He also discussed the advent of new frontiers and additional avenues of research, such as genome editing, which in turn give rise to new ethical challenges.
Professor Albertini said that wide-ranging ethical conversations were long overdue, drawing a link between the commercialisation of reproductive technologies, public mistrust of scientists, and fears of a dystopian future society. New technologies could potentially be used for the selection or even the enhancement of human embryos.
Fertility research is now looking at how to make viable gametes from different types of stem cells. Genome editing is set to become more precise. It is now possible to produce embryos containing mitochondrial DNA from a donor. Although this technology was developed to avoid the transmission of mitochondrial disease, some have sought to adapt it into a fertility treatment.
Professor Albertini concluded that ART have much to be proud of – nearly ten million babies have born – but argued that it is time to think about the future of this technology, and its potential both to help and to harm.
After the speakers had finished, there was no shortage of questions from the audience. Some attendees asked whether it was medically or ethically justifiable to have children at the far end of the 55-year storage limit. Professor Telfer said it was unlikely that people would choose to become parents at advanced ages, while Professor Mitchell reminded the audience that gametes or reproductive tissue from very young patients are sometimes being stored, in which case long storage periods are justified.
It was also asked whether science could help a woman with a low number of eggs generate new eggs. Professor Albertini said that while there research into this possibility, the results so far are not promising. It is more feasible to help immature egg follicles mature in the ovary than it is to produce entirely new eggs.
One attendee asked whether cryopreservation affects chromosome stability and meiosis. Professor Marston responded that we still lack an adequate understanding of what the 'normal' appearance of chromosomes in healthy eggs is. Professor Telfer agreed that the science surrounding egg freezing had not advanced as much as is sometimes assumed – there are still many questions to be answered about different techniques, and how freezing affects development.
Further questions covered the low complication rate of egg and sperm collection processes, and what could be done in the future about premature menopause. Professor Albertini reflected that there are now options to preserve fertility that didn't exist 20 years previously, and added that while premature menopause is characterised by substantial and early loss of eggs, ovaries with low egg reserve can still be stimulated to produce eggs for freezing.
As the event drew to a close, a final question concerned whether there is a difference in fertility preservation approaches between the sexes. Professor Mitchell said that there wasn't, except in the sense that research into male fertility lags 20 years behind research into female fertility.
Throughout the event, the speakers struck a careful balance between honest caution and excitement about new possibilities.
PET is grateful to the Scottish Government for supporting this event. Our next online events will be:
'Newborn Screening: What Should Be Screened for and How?' on Wednesday 3 November 2021, register here.
'Reproducing Regulation: Who Regulates Fertility and How?', PET's Annual Conference on Wednesday 1 December 2021, register here.