For decades, biology textbooks have stated this as fact: “Women are born with all the eggs, or oocytes they will ever have.”1 The assumption — which shapes research on infertility and developmental biology, as well as women’s mindsets about their biological clocks — is that as women age, they use up those reserves they are born with. With each menstrual cycle, egg by egg, the stockpile wears down.
But is it true that women can’t produce any new oocytes in their adult life? Over the past decade, some scientists have begun to question the long-held assumption, publishing evidence that they can isolate egg-producing stem cells from adult human ovaries.
Last week, biologist Allan Spradling of the Howard Hughes Medical Institute and Carnegie Institution for Science, cast a shadow over those findings with a new analysis of the ovaries of adult female mice, which have similar reproductive systems to humans. By his measures of new egg formation, which he has previously studied and characterized during fetal development, there were no signs of activity in the adults.
“Personally, I think it’s quite clear,” says Spradling. “All the evidence has always said this. When oocyte development is going on, you see cysts everywhere. When you look at adults, you don’t see any.”
An oocyte, or egg cell, surrounded by some supporting cells.
The new paper does little to change the direction of those researchers already pursuing the stem cells, though. Jonathan Tilly of Massachusetts General Hospital was among the first to publish evidence that mice and human females have adult germ-line stem cells that can make new eggs.
“There’s so much evidence now from so many labs that have purified these cells and worked with these cells,” says Tilly. “What I don’t find of value is to say these cells don’t exist.”
For now, the two sides remain fractured — Spradling sees weaknesses in the way Tilly and others have isolated cells from the ovaries and suspects that the properties of the cells could change when they’re outside the body. And Tilly proposes that Spradling’s new data could be interpreted in a different way that in fact supports the presence of stem cells.
For women hoping for a scientific breakthrough to treat infertility — or even those simply curious about how their own body works — a consensus on the answer would be nice. But the continued probing on both sides may be just as much a boon to women’s health. After all, it’s questions like these that drive science forward.
In his new study, Spradling labeled a spattering of cells in the ovaries of female mice with fluorescent markers to make them visible and watched them as the mice aged. If any labeled cells were egg-producing stem cells, he says, they would spread the fluorescence as they made clusters of new eggs.
“But you never see clusters,” Spradling says. “Not once.”
In the process of this study, though, Spradling made new observations about how egg cells develop into their final form in female mice, published in a second paper this month. As the precursor cells to eggs mature, they lump together into cysts, a phenomenon also seen in the flies that Spradling has spent decades studying. In flies, one cyst eventually forms one egg. But in the mice, he discovered, those cysts break apart and form multiple eggs.
“This actually leads us to propose a new mechanism for what determines the number of oocytes,” says Spradling. And, of course, that means a better understanding of reproductive biology.
On the side of those who are confident about the existence of adult ovarian stem cells, the field of fertility medicine could be revolutionized if the cells that Tilly has isolated from ovaries can form healthy egg cells that can be fertilized in vitro. These stem cells could also be a tool to study more basic questions on oocyte development and formation or a screening platform for fertility drugs. Tilly is confident enough in the research that he has founded a company, OvaScience, to pursue the commercial and clinical potential of isolating the stem cells.
“The value for the lay public is that we have a new tool in our arsenal,” says Tilly.
Spradling doesn’t argue that continued research in this area isn’t a good thing. “Scientific knowledge doesn’t just come from the proposal of ideas, but also from their rigorous tests,” he says. “I think the most powerful tool we have in medical science is basic research,” he adds, referencing research using cell and animal studies. Investigations of the basics of how and when oocytes form, he says, are the best way forward toward developing ways to improve egg cell formation or development and could even lead to infertility treatments.
So if it finds support from further studies, Spradling’s new work — which states bluntly right in its title that “Female mice lack adult germ-line stem cells” — needn’t be seen as bad news for those dreaming of a breakthrough in understanding fertility. Instead, whether or not egg stem cells end up having clinical value, it’s a step forward in advancing understanding about women’s reproductive biology.
As Spradling puts it: “You have a much better chance of actually helping someone with infertility if you know what the real biology is. Right now, we’re a ways from really understanding the full biology, but we’re making progress.”
1 Direct quote from the third edition of “Human Physiology: An Integrated Approach”, one published by Pearson Education in 2004 and used in medical school classes. Continue reading →