Mice grow sperm factories 

KENDALL POWELL / Nature 15aug02

Testes grafts could preserve fertility.

Researchers have turned mice into factories producing goat and pig sperm - using testes grafted onto their backs. In future, transplants might preserve the fertility of cancer patients or help to conserve endangered animals.

The procedure involves transplanting a tiny amount of testicular tissue from a newborn animal under the skin of an adult mouse1. "In theory, you can make sperm from any mammalian species in the mouse," says team leader Ina Dobrinski of the University of Pennsylvania.

Dobrinski and her colleagues transplanted the tissue into mice that had deficient immune systems, so that it would not be rejected. Two-thirds of the transplants survived, and the goat and pig sperm produced were capable of fertilization.

"This is an important stepping-stone in the technology for fertility conservation," says Roger Gosden, scientific director of the Jones Institute for Reproductive Medicine in Norfolk, Virginia. Grafts have the advantage of producing potentially limitless supplies of sperm from immature gonads - unlike storing frozen sperm from mature animals.

Sperm to spare

In theory, human testis tissue grafted onto mice could make sperm for young patients left infertile after cancer therapy. But Gosden is concerned that this might risk cross-species virus transmission. Nevertheless, the work might help develop other methods to preserve fertility, he says, such as freezing testis tissue and transplanting it back into a patient.

Other interspecies grafts could help produce offspring from endangered species or valuable livestock, even if only immature males exist. The technique also provides a way of testing the effects of toxins or male contraceptive drugs on sperm development.

Although cross-species transplants of cells from adult testes have been tried before, they failed to make sperm because they did not grow properly. Attempts to grow sperm in a test tube have also been unsuccessful. "Until now, it had not been possible to make completely functional sperm outside the animal," Dobrinski says.

Grafting immature testis tissue appears to work because the host mouse had been castrated, Dobrinski says. This boosts levels of the brain hormones that switch on sperm production, so the young tissue grows rapidly. The technique is expected to work on adult testes grafts too.

The Pennsylvania group will now try the procedure on testis tissue from domestic cats, as a trial for endangered big cats that rarely survive to reproductive age in captivity. Whether eggs fertilized by the sperm would result in healthy, normal embryos, however, remains to be seen.

References

Honaramooz, A. et al. Sperm from neonatal mammalian testes grafted in mice. Nature, 418, 778 - 81 , (2002).

Future of At-Risk Species May Ride on Backs of Mice
Other Animals' Sperm Produced in Rodents

RICK WEISS / Washington Post 15aug02

Scientists in Pennsylvania have created pig and goat sperm inside the bodies of laboratory mice, marking the first time that male reproductive cells have been produced in such distantly related species.

The researchers said they hope to use mice as "bio-incubators" to grow sperm cells for endangered species whose survival is threatened by a lack of sexually mature males. They also want to produce sperm from valuable farm animals without waiting for them to reach puberty.

The technique, in which bits of testicular tissue from newborn pigs and goats were grafted onto the backs of mice, could also provide an unprecedented window through which scientists may watch the mysterious process by which sperm develop in various species -- including humans.

Indeed, several experts predicted yesterday that it won't be long before human sperm are grown in mice -- an advance that scientists and ethicists said could lead to both useful and troubling scenarios.

On the positive side, men who lost their testes before puberty to surgery or cancer treatment might use the approach to sire children: After reaching adulthood, they could thaw a preserved bit of their young testicular tissue, have it grafted onto a mouse and -- after allowing time for maturation -- extract from the rodents healthy human sperm.

But the ability to cultivate sperm from immature testicular tissue could lead to stranger futures than that. It could mean that a boy who didn't survive childhood -- or even a male fetus that was never born -- could someday be a father.

Research leader Ina Dobrinski of the University of Pennsylvania School of Veterinary Medicine emphasized that the team was not pursuing such applications.

"Anything done with humans would have to undergo scrutiny first by ethics boards and the whole nine yards," she said. "This is nothing you'd want to try at home."

Conservationists said they were excited by the prospect of coaxing mature sperm from immature bits of testicular tissue taken from rare or endangered animals.

"With endangered species, you lose some of the animals before they even reach puberty," said Philip Damiani, staff scientist at the Audubon Center for Research of Endangered Species in New Orleans. "Many pandas die right after birth. And if we can get testes material from them that's going to be thrown in the garbage anyway, why not get the material to work with?"

The challenge has been to persuade that tissue to make sperm outside its normal biological environment. In previous studies, scientists had placed sperm precursor cells from rats and hamsters into mouse testes, which then made rat and hamster sperm. But experiments with other species had failed.

The Penn team theorized that sperm precursor cells were more likely to mature in foreign settings if they remained nestled in their own testicular tissue, with all its familiar environmental factors such as hormonal secretions and micro-tubular structures.

They took tiny samples of testicular tissue from newborn goats, pigs and mice -- each sample a little larger than the period at the end of this sentence -- and transplanted them just under the skin of "nude mice," whose immune systems are incapable of rejecting grafts.

More than 60 percent of the approximately 800 grafts survived, and each of those grew from 10 to 100 times its original size and produced mature sperm, the team reported in today's issue of the journal Nature. Some grafts have been producing sperm for more than a year, in concentrations comparable to those seen in whole animal testes. And tests suggest the sperm are normal: Mouse sperm produced by the method fertilized eggs and gave rise to live offspring. (Pig and goat in vitro fertilization is too primitive an art to serve as a valid test of the sperm.)

Among other applications, the system could be useful for studying the effects of toxins and drugs on human reproductive cells, Dobrinski said. Such studies are typically performed on mice and the results extrapolated to humans. The new system could allow tests directly on human reproductive cells in mice.

Larry Lipshultz, a urologist at the Baylor College of Medicine, said he would welcome a sperm maturation system that could make fatherhood possible for men who had lost their testes to cancer in youth. Saved tissues can have hidden cancer cells, so reimplantation into the patient as an adult could be dangerous.

But Lipshultz was one of several experts who expressed concern about using mice as human sperm incubators.

"Does that mouse have viruses or something that will infect the human cells? Are we going to have 'mad mouse disease'?" he asked, a reference to the surprise discovery that the infectious agent behind mad cow disease can also, if consumed, destroy human brains.

The Food and Drug Administration strictly limits the use of biological therapies developed in close contact with animal tissues. Reflecting such concerns, several teams are trying to develop completely artificial culture systems for human sperm and egg maturation from young testicular and ovarian tissues.

Even if the science gets solved, many ethics questions will remain, said Roger Gosden of the Jones Institute for Reproductive Medicine in Norfolk, who tried years ago to grow human sperm in mice, without success, and remains active in the field.

"I do think eventually we'll be able to do it," Gosden said, referring to artificial sperm and egg maturation. Already, he said, some hospitals are preserving reproductive tissues from patients in the hope that scientists will learn how to make them sprout sperm or eggs. But that doesn't mean sex cells should be grown on demand, he warned.

"You could imagine a person wanting to be a grandparent when their child had died before having children," Gosden said.

Gosden did not say that would be wrong. But now is the time to consider it, he said.