Of Mice and Kids (and Piglets)
It sounds like something out of Greek mythology, or maybe Kafka: One male animal (in this case, a mouse) produces the sperm of a pig. Or a goat. Or another mouse.
It happened recently at the School of Veterinary Medicine, under the direction of Dr. Ina Dobrinski, assistant professor of large animal reproduction, who describes it as the first report of complete spermatogenesis from tissue grafted across species. The results, which were published in the August 15 issue of the journal Nature, have important implications for preserving the germ lines (embryonic reproductive cells) of endangered species and animals that have not reached sexual maturityeven for the study of male contraceptives.
Dobrinski and her colleagues took tiny graftsup to one cubic millimeterof testicular tissue from newborn pigs, goats, and mice and grafted them onto the backs of mice. (For all the pig germ cells knew, they were still in the pig, says Dobrinski. The mouse, on the other hand, provided temperature control, oxygen, nutrients, and hormones to the tissue, thereby serving as a little bio-incubator.) As many as eight miniature testes developed in that surprisingly hospitable environment, and the sperm they produced, using in-vitro fertilizationyielded new piglets, kids, and baby mice.
Dobrinski and her colleagues used newborn-animal tissue, which has the greatest growth potential and is less sensitive to hypoxic damage associated with transplantation. But the implications go far beyond just facilitating the laboratory experiment. Previously, she notes, there was no way of achieving sperm production from immature testesand thus no way to propagate the genetic heritage of a sexually immature individual. Now there is.
Normally, by freezing sperm, only a finite number of differentiated germ cells are available, Dobrinski explains. But by doing the tissue transplants, which contain spermatogonial stem cells, they can potentially produce sperm foreveror as long as the host lives.
The process of making spermspermatogenesisis very complicated, says Dobrinski, and until now it has not been replicated in a laboratory. As a result, our ability to study and manipulate sperm production has been very limited, and most of what we know is based on studies in rodents that are often not a good model for other mammalian species or humans, she adds. Therefore, we were looking for a system to make spermatogenesis from different species more accessible to manipulation.
Dobrinski notes that some scientists, including Dr. Ralph Brinster V60 Gr64, the Richard King Mellon Professor of Reproductive Physiology, had shown that germ-cell transplantation from rats and hamsters into mouse hosts could result in sperm production. Until now, however, this was not possible for phylogenetically more distant species like pigs, goats, or primates. And while she and others had tried to transplant isolated germ cells from species other than rodents into mouse testes, we never got sperm production in the mouse host.
There are several major areas of application for this research, says Dobrinski. First and foremost is to better understand and subsequently manipulate spermatogenesis in a variety of mammalian species. (That ability could aid studies on the effects of male contraceptives and other drugs on sperm production in the target species without having to use an entire pig or bull or primate.) The second area of application is to be able to produce gametes from immature individuals and therefore preserve their genetic material. That, she explains, can be very important for the preservation of endangered species when animals are lost before they reach puberty and no sperm can be retrieved, or for valuable farm or laboratory animals that die before reaching sexual maturity.
Finally, this research may someday provide a way to help individuals who have to undergo irradiation or chemotherapy for cancer during childhood and are subsequently rendered infertile. By preserving a small piece of testis tissue before treatment, and subsequently using it to produce sperm, those individuals could have an opportunity to have their own [biological] children even if they become infertile. But, she concludes, this last application requires a lot more work on safety and ethical considerations.