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Will Women Be Able to Make More Eggs in the Future?
By Leigh Ann Woodruff, March 1, 2012
The fertility news this week is filled with stories about exciting new research out of Harvard and Massachusetts General Hospital in which researchers located egg-producing stem cells from the ovaries of reproductive age women and demonstrated that these cells can produce what appear to be normal egg cells or oocytes.
The 2012 study, published in February's Advanced Online Publication of the journal Nature Medicine was a follow-up to a controversial 2004 paper published in Nature, which first suggested female mammals continue producing egg cells into adulthood and challenged the conventional theory that a woman is born with all of the eggs she will ever have.
“This study demonstrates that purified mouse egg precursor cells can mature into fully functional eggs that can then be successfully fertilized to produce healthy blastocyst-stage embryos,” says Jonathan Tilly, Ph.D., chief of research for Massachusetts General Hospital (MGH) Vincent Department of Obstetrics and Gynecology and professor, Department of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School (HMS). “We also demonstrated that human egg precursor cells not only exist in ovaries of reproductive-age women, but that these newly discovered cells possess the same features that permit maturation into eggs that are held by their mouse counterparts. The results presented in this new study confirm and extend our previous work on egg precursor cells in adult ovaries, opening the prospect that human assisted reproduction may be provided with new tools to combat infertility caused by aging or insults.”
Can a Woman Continue Producing Eggs?
Since the 1950s, the fundamental belief about human reproduction has been that women are born with all the eggs they will ever have — a finite supply. As a woman ages, this egg supply is depleted until the supply is completely exhausted when a woman enters menopause.
Clinical embryologist Jacques Cohen, one of the founders and directors of the PGD laboratory Reprogenetics and senior editor of Reproductive BioMedicine online, explains that Dr. Tilly's research is challenging this concept of a finite egg supply. He says research into making eggs from stem cells has been going on for about 12 years. "I hope he's right," Dr. Cohen says. "It's exciting research, and it needs to be done. The odds look OK — not simple stuff, this."
In this new study, Dr. Tilly and his colleagues used a new cell-sorting technique and were able to sort and purify egg stem cells from the ovaries of both adult female mice and from the ovaries of reproductive-age women (provided from healthy ovarian tissue from consenting patients undergoing sex reassignment surgery).
The scientists reintroduced the mouse egg stem cells back into the adult mouse ovaries, which led to the maturation of new eggs that could be ovulated and fertilized to become healthy embryos. With the egg stem cells isolated from adult human ovaries, they found that, like the mouse stem cells, the human egg stem cells were able to spontaneously form cells with characteristic features of oocytes, and there were indications that they had progressed through meiosis, a cell-division process unique to the formation of mature eggs and sperm.
The researchers next injected green fluorescent protein (GFP)-labeled human egg stem cells into biopsied human ovarian tissue, which was then grafted beneath the skin of immune-system-deficient mice. When they examined the human tissue grafts after seven to 14 days, they found both immature human follicles with GFP-negative eggs (probably present in the human tissue before the egg stem cell injection and grafting), as well as numerous immature human follicles with GFP-positive eggs, which would have originated from the injected human egg stem cells.
"What's potentially exciting here is that the source of the cell is an egg stem cell," says Dr. Cohen. "So it's closer. That's probably the more appropriate source because you already have developmental aspects on the micro level that resemble a mature egg. What needs to be done next is to really prove on a molecular level that it is very much egg-like, that you can properly fertilize them and that you can get normal development and ultimately birth."
The Ultimate Goal
Dr. Tilly is a co-founder of OvaScience, a private fertility company focused on the discovery and development of new treatments for infertility. “This research conducted by Dr. Tilly and his team at MGH, and exclusively licensed by OvaScience, has the potential to enable the development of new treatment options for infertility,” says Scott Chappel, Ph.D., chief scientific officer of OvaScience. The Boston-based company is doing research on increasing the success of in vitro fertilization (IVF) by enabling a woman to "rejuvenate" her aging eggs with her own high quality mitochondria, which is retrieved from these egg stem cells.
Dr. Cohen says a goal for the technology would be to enable a woman, particularly an older woman, to have a much larger supply of eggs to be used with IVF. "We need a much larger supply — it needs to be five- or 10-fold — because if you just look at the statistics, most eggs are abnormal. We know about the chromosomal abnormalities — they are well in excess of 50 percent in older women; it's highly correlated with chronological age and ovarian age. If you remove aneuploidy, there are still other anomalies that we know very little about."
Ideally, there would be one procedure, such as an ovarian biopsy, that would allow the egg stem cells to be isolated and developed into eggs. "If we can have one procedure and then months later, it would yield 500 eggs, fertilize those and then sort embryos for survival," Dr. Cohen says. "The technology would bring it down to one procedure and nearly an unlimited amount of gametes.
"It's a numbers game," he continues. "Once you improve the numbers game, then your odds go up dramatically."