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Surrogate Fathers New Scientist 31 Jan 98

ONE of the world's leading reproductive biologists has applied for funding to transplant cells from human testes into those of mice. The aim is to create mice that produce human sperm. "The first time you say to anyone that we want to produce human sperm in mice, they look at you with frank horror," says Roger Short of the Royal Women's Hospital in Melbourne. But once people overcome their initial gut reaction, he claims, many accept the proposal. Developments in IVF now mean that many women with fertility problems can conceive. But men who produce little or no sperm have scant hope of becoming fathers. In many cases, says Short, the cause may be a mutation in one of the genes on the Y chromosome that control spermatogenesis-the producfion of sperm from germ cells, which are known as spermatogonial stem cells. Being able to study human spermatogenesis in a laboratory animal may help researchers to work out why the process fails in many infertile men. And if the genetic fault lies with the Sertoli cells that nurture developing sperm, transplanting germ cells to a mouse with healthy Sertoli cells might even allow mature sperm to form. Short's proposal was inspired by a paper published in 1996 by a team led by Ralph Brinster of the University of Pennsylvania in Philadelphia, which showed that rat spermatogonial stem cells could produce mature sperm after being injected into the testes of mice with defective immune systems (Nature, vol 381, p 418). Before Brinster's announcement, Short's team had transferred spermatogonial stem cells from one rat to another. Short now intends to repeat Brinster's rat-to-mouse transplant, to see whether the sperm produced can fertilise a rat egg-a key test that Brinster did not do. Short then aims to transplant human cells. New Scientist approached Brinster to comment on Short's proposal and to discuss his own work, but he declined to do so. Short has applied to the US National Institutes of Health for funding, and has already won ethical approval from his local animal research committee. He has yet to present the project to the equivalent committee covering human subjects. However, Short says that the human germ cells would come from routine biopsiesthose taken prior to surgery to reverse vasectomy, for instance. The men would be briefed about the experiment, and their consent would be required. Bioethicists contacted by New Scientist agree that the biggest obstacle is likely to be the "yuk" factor that Short has already encountered. However, there are some safety concerns if sperm produced in mice were ever to be used for IVF. The first is that human sperm that develop in a mouse Qtestis might undergo changes that could produce congenital defects. Secondly, mouse retroviruses could infect the spermraising similar fears of viral contamination to those that have dogged attempts to use animal organs for human transplants. David Shapiro, formerly executive secretary of Britain's Nuffield Council on Bioethics, says that strict monitoring for safety should be required at every stage in the technique's development. But he fears that s-)me fertility researchers may be tempted to rush ahead. "There's this gung ho attitude of let's have a go," he says. In the long run, the technique could also run up against the biggest taboo in modern biology. Short believes that the work could ultimately help make it possible to correct the genetic defects that can disrupt normal spermatogenesis. But this would require altering genes in the human germ line. For the time being at least, he says, no ethical committee would sanction such a procedure. Peter Aldhous

LONDON Jan 30 98 - Expert Conceives Plot to Make Men out of Mice

An expert on reproduction is hoping to use mice to produce human sperm in a development that could transform fertility treatment, New Scientist magazine said yesterday. Roger Short, of the Royal Women's Hospital in Melboume, has already applied to the US National Institute of Health for funding. He has won approval from his local animal research committee, but has not received the go-ahead or even presented the project to any cormmittee for human trials. "The first time you say to anyone that we want to produce human sperm in mice, they look at you with frank horror," he told the magazine. He said he believed many people would eventually accept the idea. New Scientist said while many women with fertility problems can now conceive thanks to 'in-vitro fertilization, men who produce few or no sperm have little if any hope of becoming fathers. Being able to monitor human sperm production in laboratory animals may help researchers to work out exactly why the process fails in many infertile men. New Scientist said the problem may relate to a genetic fault within the Sertoli cells, which nurture developing sperm. Mr Short believes transplanting those cells in the human testes responsible,for the production of sperm - so-called germ cells - to a mouse with healthy Sertoli cells could allow mature human sperm to form. For the experiments, Mr Short says human germ cells would be taken from consenting patients during routine biopsies, such as those taken before surgery to reverse vasectomy. Although the project is still a long way from approval, it has already sparked safety concerns. Biologists are worried that human sperm developed in mice might undergo genetic change that could produce defects, and that viruses from mice could infect sperm and be passed to humans. REUTERS