A Possible Step Toward Setting the Biological Clock

By Rob Stein
Washington Post Staff Writer
Monday, April 13, 2009

Scientists have produced strong new evidence challenging one of the most fundamental assumptions in biology: that female mammals, including women, are born with all the eggs they will ever have.

In a provocative set of experiments involving mice, Chinese researchers have shown for the first time that an adult mammal can harbor primitive cells in her ovaries that can become new eggs and produce healthy offspring, they reported yesterday.

While much more research is needed to confirm and explore the findings, the work raises the tantalizing possibility that it could someday lead to new ways to fight a woman's biological clock, perhaps by stockpiling her egg-producing cells or by stimulating them to make eggs again.

The findings could also help speed stem cell research by providing scientists with a new source of eggs, which are crucial for producing embryonic stem cell lines tailored to individual patients and diseases but are difficult to obtain.

"This is a very big deal," said Roger G. Gosden, director of reproductive medicine at Cornell Weill Medical Center in New York, who was not involved in the research, published online by the journal Nature Cell Biology. "It is quite dramatic."

Some species remain fertile through their lives, and men produce sperm daily. But for at least a half century the dominant scientific tenet has been that women and all other female mammals are born with all the eggs they will ever have, and that stock is slowly depleted with age. For women, the belief has been that most of their eggs are gone by the time they reach middle age, prompting menopause and leaving them infertile.

Although several studies in recent years have raised questions about that belief, those claims remained highly controversial. The new research marks the first time scientists have obtained cells from an adult mammal that appear capable of producing new eggs and healthy offspring.

"If you are looking to disprove that females cannot make new eggs, this paper proves it. It's a really significant paper," said Jonathan L. Tilly, a professor of obstetrics, gynecology and reproductive biology at Harvard Medical School who published some of the most controversial research suggesting that women remain capable of producing new eggs. "This is the smoking gun."

Other researchers, however, remained cautious, saying the Chinese work needs to be repeated more carefully in mice and other species to validate the findings. Even then, it would remain far from clear whether there are any practical implications for women, some experts said.

"The aging process of the human egg differs fundamentally from that of the mouse egg," said David L. Keefe, a professor of obstetrics and gynecology at the University of South Florida. "Except at Disney World, humans are not large mice."

For the study, Ji Wu of Shanghai Jiao Tong University in China and colleagues removed ovaries from mice and sifted through millions of cells to identify a small number that appeared to have characteristics of female "germline" stem cells, which theoretically would be able to become eggs.

After identifying those cells, the researchers reported, they coaxed them to multiply in the laboratory. Those obtained from newborn mouse ovaries continued to multiply for more than 15 months and those from adult ovaries for more than six months. A series of tests appeared to confirm that they were indeed precursor cells for eggs, the researchers reported.

They then tagged the cells with a jellyfish protein that would make them glow fluorescent green so they could be traced, and injected them into the ovaries of other mice that had been rendered mostly infertile with chemotherapy drugs.

Some of the mice were then killed so their ovaries could be examined, which revealed that at least some of the fluorescent green cells had indeed matured into eggs. Other mice that got the cells were allowed to breed naturally and produced offspring. Tests showed that many of the offspring also contained the green tag, which the researchers said demonstrated they were conceived from the transplanted egg cells. Tests found no evidence that the offspring, or the next generation, were abnormal in any way, the researchers reported.

"The results are very significant," Evelyn Telfer, who studies cell biology at the University of Edinburgh, wrote in an e-mail. "Of course there are always aspects of any work that needs clarification, but this study appears pretty solid and I am sure that several groups will be poised to try and replicate this work."

Other researchers have claimed to have identified such cells in human ovaries. If that could be confirmed, and if they behave similarly to the mouse cells, they could offer a host of new options for infertile women.

"You could gain control over how fast the clock will tick," Tilly said.

Women who need to delay childbearing might be able to bank their egg stem cells for use later in life, for example. Some are already doing that with their eggs, but that process is currently highly inefficient and unreliable.

The work would be especially helpful to women who are facing sterilization as a result of cancer treatment. Although some researchers have succeeded in preserving ovarian tissue from such women and reimplanting it to allow them to have children, that approach has had limited success.

If women who are infertile because of their age still harbor such cells, scientists may be able to find a way to activate them to produce new eggs, several experts said.

"We have lot of patients who cannot get pregnant because they have run out of eggs or their eggs are of poor quality because of their age. The only option they have is adoption, which is not so easy, or egg donation, which means their child would not be their genetic child," Cornell's Gosden said. "The research means egg donation from a fertile woman might not be necessary because she could have her own genetic child engineered from her stem cells."

But Gosden agreed caution was important.

"Although this is a dramatic study, these are huge claims. They therefore accordingly should attract the most searing scrutiny," Gosden said.

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