Finding could mean extended fertility
MGH team links mice blood, eggs
Blood and bone marrow contain stem cells that can produce new eggs, researchers reported yesterday, suggesting that someday, women may be able to extend their fertility simply by freezing their blood while young and then defrosting it decades later.
The findings in mice, by a team at Massachusetts General Hospital, showed that stem cells, produced in the bone marrow and carried in the blood, were able to replenish the rodents' depleted egg supplies. The scientists believe that they will be able to show the same process in women.
''We're talking about regenerative medicine here," said the lead researcher, Jonathan L. Tilly. ''We're talking about making your ovaries new again."
In a paper last year, Tilly challenged the idea that women are limited to the pool of eggs they are born with, which diminishes until menopause. His group's findings indicate that mice, at least, draw on stem cells to make new eggs long into adulthood and that the main reason a female's fertility declines with age is not that her initial supply of eggs runs out, but that her stem cells stop making new eggs.
Their new paper, published in the prestigious journal Cell, offers further research showing that adult mice restock their egg supplies. Most important, it shows that when mice are rendered infertile and are then given bone marrow or blood from other mice, their ovaries can generate what appear to be healthy new eggs. The paper lacks what would be the clincher, however: babies produced from the new eggs. That work is still underway, Tilly said.
Colleagues, who heard the broad outlines of the paper earlier this week at a scientific conference, are intrigued, but many remain deeply skeptical.
The paper represents ''a remarkable discovery," but raises so many questions that ''I don't jump on the enthusiasm bandwagon," Dr. R. Jeffrey Chang, director of reproductive endocrinology at the University of California at San Diego, said in a telephone interview.
It is a long way from '' 'Gee, they did it for the mouse' to 'Obviously they can do it for postmenopausal women,' " he said.
Even supporters say Tilly's work must be replicated by other laboratories and developed much further before it can even potentially become relevant for humans. If fully borne out, however, the research could remake the aging woman of the future.
Modern medicine has almost doubled life expectancy, and now ''we may be looking at a 21st-century woman with double the life expectancy and double the reproductive life expectancy," said Dr. Kutluk Oktay, head of fertility preservation at Cornell University's Weill Medical College.
In Tilly's long-term vision, a woman freezes some of her blood at age 20. Then ''you call us on the phone one day and say: 'I'm 42; my ovaries are failing; I want to have my ovaries reinvigorated,' " he said. ''They're your own cells; you don't need anybody's approval. They go right into your blood supply and go right to your ovaries," where they mature into eggs.
Such techniques probably carry ''no down side," no side effects, no invasive procedures, Tilly said.
Other implications abound. In theory, egg stem cells could offer scientists a way around one of the objections to a type of embryonic stem cell research called cloning. Instead of needing to recruit egg donors, who face a slight health risk, the scientists might be able to use egg stem cells to produce in the lab the eggs needed for the potentially life-saving research, Tilly said.
Cancer doctors could learn to tailor chemotherapy to spare the egg stem cells in patients' marrow. Failing that, doctors might be able to offer female patients the option of removing and freezing some cells before their drug regime begins, a far simpler procedure than options like freezing embryos, eggs, or chunks of ovary.
Efforts to help young women who face chemotherapy are ''such a benefit and so needed," said Lindsay Nohr Beck, a cancer survivor and founder of Fertile Hope, a nonprofit group that assists cancer patients with infertility. ''It offers tremendous hope to cancer patients and survivors."
The new work also offers a possible explanation for the long-baffling phenomenon of women with cancer who undergo chemotherapy that renders them infertile and then sometimes give birth years later. If a woman received a bone marrow transplant as part of her treatment, Tilly said, the new marrow could have carried stem cells that eventually replenished her ovaries' supplies of eggs. In theory, if the marrow came from a donor, the baby may not be biologically related to the mother.
After completing last year's paper showing that new eggs formed in adult mice, Tilly's team set out to find the stem cells that had to be their source. The most obvious place to look was the ovaries. They looked in the ovaries for a genetic marker for embryonic egg cells, and, to their surprise, they found only a small pool of these cells in the organ's center, where there are no eggs and only blood vessels that connect to the ovary.
''Nothing made sense," Tilly said. ''So we put our heads against the wall, banged them a few times, and said, 'There's got to be another explanation for these cells sitting in the ovaries.' And then the epiphany happened."
The researchers realized that the few cells they detected in the center of the ovary might not have originated there, but might instead have been passing through in the blood stream.
Tilly's team decided to look elsewhere for the source of the egg stem cells, specifically, in the bone marrow, because cells borne in the blood are derived from bone marrow. Also, recent research has suggested that stem cells in the bone marrow can turn into a variety of types of cells, such as heart or nerve cells.
When they tested the mice's bone marrow for several possible markers of egg stem cells, all were present. Those markers, Tilly pointed out, also turned up in human bone marrow and blood from reproductive-age women, implying that women's blood and marrow may also carry egg stem cells.
If the bone marrow was the stem cell source, Tilly's team reasoned, it should be possible to harvest it from a normal mouse, put it into a mouse that had been sterilized using chemotherapy drugs, and regrow the sterilized mouse's egg supplies. Indeed, two months after a sterilized mouse received the bone marrow transplant, its ovaries contained eggs again, and they remained normal when checked nearly a year later. The ovaries of mice who received no such transplant remained barren.
The next logical step: If blood is the conduit from the bone marrow to the ovary, the team figured, it should be able to replenish the egg stocks, as well. And because blood carries not true stem cells but a later stage, called progenitor cells, it should work quickly. So they destroyed a mouse's egg supply with chemotherapy and gave it a blood transfusion from a mouse that had been genetically engineered to have egg cells that glow green. A day or so later, the sterilized mouse had a few green-glowing eggs in its ovaries.
Still, Tilly acknowledged, ''the big question remains": Can the mice with transplanted marrow or blood get pregnant and bear normal offspring? ''Have we done mating trials? They're ongoing, that's all I can say," he said. The trials are complex and time-consuming, he said, and the team is trying a broad array of permutations. They are trying to mate some mice that have been dosed with chemotherapy, some that have not, some that have received blood transfusions, and some that have received marrow transplants.
If the mouse work is ever to be translated to humans, Tilly acknowledged, the experiments must produce mouse babies, and the babies must be normal. But because the process involves no drugs, he can imagine that once his work is deemed solid enough and confirmed in humans, it could enter clinical use very quickly.
Tilly's work is funded by the National Institute of Aging and others, including the Rubin Shulsky Philanthropic Fund and Vincent Memorial Research Funds. He has applied for three patents based on it, he said. Asked if he had a company to commercialize his work, he replied, ''Not yet."
The new paper appears carefully done, said Frank Bellino, who administers grants on the biology of aging for the National Institute of Aging. But ''what's really lacking now is confirmation from other laboratories," he said.
Tilly's paper last year was so shocking it was as if he was saying the world was flat, said Oktay of Cornell. His reaction now?: ''You say, 'The world is definitely flat and change your travel plans.' "
Carey Goldberg can be reached at goldberg@globe.com. 