Dr Martin Brinkworth: The key to our beginning, pathology and evolution

Recently The Independent on Sunday newspaper reported on work that Senior Lecturer Dr Martin Brinkworth is carrying out with scientists at the University of Leeds. They have discovered a unique 'DNA packaging signature' in human sperm, which may act as a key that unlocks an egg's fertility and trigger new life.

Recently The Independent on Sunday newspaper reported on work that Of the 3,000 of you to whom News & Views are distributed, some 450 are likely to suffer from infertility, whether recognised yet or not. The problem afflicts men and women roughly evenly, and for about a third of the former, i.e., ~75 men working at the University, the problem will have no currently identifiable cause (i.e. idiopathic). Infertility thus represents a medical problem of far greater prevalence than, say, diabetes. Furthermore, whilst assisted conception techniques are increasingly available, only around 30% of treatment cycles are successful. Those of us fortunate enough to be able to have children tend to take it for granted, and find it hard to grasp the depression and long-term mental anguish of an unfulfilled desire to be a parent. And because many people, especially men, find it difficult to discuss their fertility, it is an easily overlooked problem.

Despite the embarrassment potential of the topic, there are many very good reasons for studying the intricacies of the male reproductive system. There is considerable public concern about the possibility that environmental, occupational, therapeutic or other agents damage men's production of sperm. There is no rational treatment for idiopathic infertility; some may be helped to father a child by IVF and Intra-Cytoplasmic Sperm Injection (ICSI) but these treat only the symptom while the underlying problem remains. In addition, there is still uncertainty about the extent to which heritable diseases may be induced in a small proportion of offspring produced this way. It is often argued that too much of the burden of contraception is left to women. After several decades of research, a workable alternative to the condom for men is still unavailable. Finally, behind all these biomedical problems remain intriguing, fundamental questions in biology: Why are the testes held outside the body in humans and some other mammals? Why are only the mother's mitochondria (the cell's energy producers) passed on to the offspring? How do mutations produced in sperm contribute to the evolution of species?

Nearly 20 years ago, a paper published in the British Medical Journal made the startling claim that human sperm counts had dropped by 50% over the previous 50 years. This work attracted an enormous amount of interest worldwide and stimulated numerous follow-up studies and hypotheses. As a result, even now, there is widespread acceptance among the public that environmental pollutants are damaging sperm production and that infertility is on the increase. Unfortunately, the study was deeply flawed and seriously misused a particular statistical approach. Nevertheless, the idea caught the attention of the public and media in a way that no amount of dry statistical rebuttal could not. Likewise, the main explanatory theory - that oestrogen-like compounds in the environment were disrupting the development of the male reproductive system - soon acquired the status of gospel. Since then, follow-up studies have found sperm-count declines in some countries but not others, the oestrogen hypothesis has been found wanting and has migrated into a general theory of "testicular dysgenesis" and there is still no agreement about what if any environmental agents may be detrimental to sperm production. There is also no evidence that infertility is increasing. The lack of scientific clarity and the public confusion are very unsatisfactory and need resolving urgently.

Some agents (anti-cancer therapies for example) unquestionably damage the reproductive system in the male. A classic study in the 1970's identified a particular pesticide as causing infertility in farm workers. However, the vast majority of daily-life exposures do not cause particular damage to adult male reproductive capacity. What is much more likely to be responsible (if anything at all) is exposure of the embryo or foetus via the pregnant mother. Much current research focuses on compounds capable of interfering with hormone signalling but there is little evidence yet that these could be effective at the levels at which they are found in the environment. A study we conducted here in Bradford, in partnership with colleagues in Germany, indicated that a DNA-damaging chemical already known to be capable of affecting the adult testis caused damage in embryonic testes at levels up to 50-times lower. Humans can be exposed to DNA-damaging compounds, for example through cigarette smoking, and a couple of recent studies have indicated that men whose mothers smoked in pregnancy are more likely to have testicular defects. This promising lead is therefore something we hope to follow up in the future.

We have also shown that infertile men who nevertheless produce some sperm, have slightly increased levels of DNA damage in those sperm. Whilst that lends weight to the argument above, it may also have implications for any offspring they may be able to achieve as a result of assisted conception techniques. There is certainly a correlation between the amount of sperm DNA damage and success rates in IVF or ICSI. That suggests that high levels of sperm DNA damage would cause a failure of the embryo to develop - but what happens in the case of sperm with lower, but still elevated, levels of DNA damage? The answer highlights a curious paradox in male reproductive toxicology: the higher the damage to the sperm, the less serious the potential outcome. This is because high amounts of damage are likely to cause infertility; lower amounts may permit the development of a child with genetic defects and a higher risk of genetic disease. There is evidence for this from laboratory studies, including some I undertook with Professor Diana Anderson before we were at Bradford, however, there are as yet no comparable data for humans, which would require trans-generational, longitudinal studies.

Treatment of cancer often involves the use of very high doses of drugs (and/or radiation) that can damage DNA of dividing cells. Many of these treatments cause collateral damage to the DNA of the cells in the testis that develop into sperm. As a result, such therapies can be associated with long-term infertility. That is hardly the first concern of someone with such a severe illness, however survival rates for many of these diseases are improving and they often affect young men of reproductive age. There is therefore concern that sperm produced subsequently could be genetically damaged and perhaps pose a risk to the genetic health of future children. A variety of attempts have been made to develop ways of avoiding this but up to now, none has been followed through because of the risk of serious consequences. However, there is a limited amount of encouraging evidence suggesting that the problem may not be as great as feared. Small-scale epidemiology studies on the children of cancer survivors suggest no increase in the levels of abnormality or cancer. Additionally, investigations of mutation rates in the sperm of cancer patients by ourselves and others indicate no elevation of risk as a result of treatment. This prompts the intriguing speculation that there might be a `quality control¿ mechanism in the testis to eliminate damaged cells.

Efforts to prevent DNA damage to testicular cells involve suppression of cell division and this could also be exploited for contraceptive purposes. Over the last 30 years, male contraceptive research has concentrated on the use of testosterone. This has come very close to succeeding but reliability never quite reached acceptable levels. That unreliability, exacerbated by fears that women might not trust men to take a pill, caused the pharmaceutical companies to cease funding the research. Other, non-hormonal, approaches did not get underway while the endocrine strategy was dominant so there is now, perhaps, an opening for alternatives. Based on some recent work in my lab, we hope to target cells just before they develop into sperm and halt their development pharmacologically, work that lends itself to Research and Knowledge Transfer.

In this year of Darwin celebrations and in the wake of our recent International Darwin Conference, it is appropriate to consider what the study of DNA alterations in sperm can tell us about evolution. A collaboration with colleagues at the University of Leeds (and featured by the Independent on Sunday over the summer) has recently uncovered a novel mechanism by which the egg may `recognise¿ sperm DNA from its own species. This implies that DNA not marked in the appropriate way would not be recognised, leading to a failure to develop. That would help drive speciation but it would also mean that errors in the marking in individual sperm would cause them also not to be recognised, and hence could be a cause of some idiopathic infertility.

The level of public interest in reproduction research is extraordinarily high for a science subject and is not even confined to the topics discussed here (lack of space prevents me discussing cloning and reproductive ethics). Furthermore, the commercial potential for agents that assist or inhibit fertilisation is enormous. Added to that, infertility is a major problem in Society, causing distress, a diminished quality of life and clinical depression among thousands. You, like me, may find it extraordinary therefore, that levels of funding are extremely low. Only a tiny proportion of Research Councils¿ budgets are spent in this area; industrial interest is currently negligible; and there are no specialist charities supporting male reproduction research. This last point is particularly scandalous in the light of the healthy profits made by private fertility clinics.