Of Mice and Menopause

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The conventional story of female fertility has never made a whole lot of sense. A few months before the birth of a little girl, textbooks have said for 50 years, her ovaries contain about 1 million egg cells each — all that she will ever have. Those numbers only go down as eggs deteriorate or get washed out of the body during menstruation. Finally, when a woman is about 50, they're essentially gone, signaling the hormonal changes known as menopause. The story fits the evidence. Autopsies prove that women have lots of eggs to start with and that the number steadily declines. But in evolutionary terms it seems strangely inefficient to have all those eggs sitting around for decades, slowly going bad. Men, by contrast, churn out new sperm all the time. Insects make new eggs too, well into maturity. "Fruit flies know fresh eggs are better than stale," says Jonathan Tilly, a reproductive biologist at Harvard Medical School and Massachusetts General Hospital. "So why shouldn't mammals?"

But maybe they do. According to a report by Tilly and several colleagues in last week's Nature, mice, at least, have specialized stem cells in their ovaries that make new eggs throughout the animals' lives. The scientists have found circumstantial evidence that the same might be true for humans. And that could — though it's theoretical at this point — lead to powerful new treatments for infertility and perhaps even for staving off menopause. "If it's true," says Roger Gosden, scientific director of the Jones Institute for Reproductive Medicine in Norfolk, Va., "it's as big a paradigm shift in ovarian biology as Dolly and cloning were for embryology."

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Rewriting basic biology was the last thing on Tilly's mind when he and his colleagues began their research. They were interested in prolonging fertility, but as experts in cell death, or apoptosis, they were looking for ways to keep the limited supply of eggs limping along longer. "We assumed the dogma was correct," he says. Indeed, they found that the egg cells in adult-mouse ovaries are constantly dying off — but at a remarkable rate of up to 1,200 a day, or about a third of the total. "By the existing dogma," says Tilly, "they shouldn't last more than a few weeks." Simple arithmetic suggested that the eggs were being replenished.

But simple arithmetic isn't a strong enough argument for such an astonishing proposition, so the biologists conducted several experiments to test it. In one, they looked for and found cells that appeared to be undergoing meiosis, the type of cell division peculiar to sperm and egg cells. They also detected the activity of a gene involved in that process. Then they dosed the mice with busulfan, a cancer drug known to kill the stem cells that produce sperm. Three weeks later, there were virtually no eggs left, suggesting that the drug had found a similar stem-cell target in the ovaries.

Finally, in an especially ingenious experiment, they used mice genetically engineered to carry a jellyfish gene that glows a faint fluorescent green and transplanted normal ovarian tissue into them. If the mice really did have egg-producing stem cells, some should migrate into the new tissue to generate new, green eggs — while the follicles that enveloped them, coming from normal tissue, would be white. "That's exactly what we saw," says Tilly.

The result will have to be confirmed by others before it's fully accepted, although many scientists are already pretty well convinced. But even if it's true for mice, says Gosden, "you have to beware of extrapolation to humans." Tilly's group does have at least one indication that humans have something similar going on: women treated with busulfan almost always experience premature menopause, compared with fewer than half of women taking other cancer drugs. Says Tilly: "This is definitely a hint that these cells do exist."

Even if they do, it will be a while before anyone benefits from this research. Scientists will have to figure out how to purify ovarian stem cells, then transfer them into depleted ovaries to see if they can restart egg production — first in mice, then, if possible, in humans. But if they can, Tilly envisions all sorts of benefits. You might extract the cells and freeze them, and if a woman got cancer, you could reintroduce them after chemotherapy shut down her ovaries. Or you might freeze some of the vigorous stem cells in a young woman so she would have a reserve supply as those in her body aged and weakened. Or, if you could keep existing stem cells viable longer, says Tilly, you might stave off the discomforts of menopause by staving off menopause itself — without dangerous hormone-replacement therapy. It's all wildly speculative so far. Says Tilly: "This isn't the solution to anything yet. We're on the ground floor. But maybe we're finally in the right building."