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Aging Eggs: Exciting Research Is on the Horizon
We get tired as we age, and so do our eggs — the oocytes don’t have enough energy to go through the rapid cell division for fertilization. It becomes harder to get pregnant naturally and through fertility treatments such as in vitro fertilization (IVF). These aging eggs are more likely to have chromosomal abnormalities known as aneuploidy, less likely to develop into embryos once fertilized, and if they do develop, they are more likely to not implant or be lost through miscarriage.
OvaScience, a Boston-based life science company has set out to find a solution that will increase the success of IVF by allowing a woman to "rejuvenate" her aging eggs with her own high quality mitochondria — the structures that produce adenosine triphosphate (ATP), which is the energy that cells need. "There have been a lot of studies to show that poor quality eggs have less mitochondria or less ATP than high quality eggs," says Scott Chappel, Ph.D., OvaScience's Chief Scientific Officer. "This [technology] is changing the quality of the oocyte by not by doing anything abnormal, because it's basically the patient's own mitochondria that are being put back in."
Embryologist Jacques Cohen, who was one of the first embryologists to examine the distinct differences in oocyte quality of older women, developed a procedure known as cytoplasmic transfer in the mid 1990s. "He postulated that there was something present in the younger woman's oocyte that was not present in the older woman's oocyte," Chappel explains. "So he performed cytoplasmic transfer, where he sucked out very small volume amounts of cytoplasm from a younger woman's [donor] oocytes and injected it into the oocyte of an older woman. And the quality of the oocyte of the older woman dramatically improved, fertilization rates increased, implantation rates increased, and take home baby rates dramatically increased."
Cohen found out that the "active ingredient" in the cytoplasm that improved the quality of the older woman's eggs was mitochondria. "It became understood through animal studies and subsequent studies that after fertilization of the oocyte — when you go to cell division and making new cell membrane, making new chromosomes — that requires a lot of energy," Chappel says. "Even though [the older women] may have had an adequate number of mitochondria, the quality and ability of the mitochondria to make ATP ... the amount of ATP was diminished in the oocytes of mature woman. So [Cohen] had actually transferred mitochondria that were more efficient at making ATP into the older woman."
There was concern, however, with cytoplasmic transfer, because mitochondria has its own DNA, and the resulting children would be genetically linked to three parents. IN 2001, the Food and Drug Administration banned cytoplasmic transfer of third party mitochondria in the United States until lengthy clinical studies could be conducted.
"It was clear that this technology worked, because it dramatically improved success rates," Chappel says. "Everybody in the field believes that this technology would work, but two criteria need to be satisfied." And those criteria are:
- The mitochondria used to regenerate the eggs, need to be autologous, meaning they come from the patient's own body.
- The mitochondria has to be germ-liine mitochondria, meaning that it must have pristine mitochondrial DNA with no deletions or mutations.
In 2004, Jonathan Tilly, Ph.D., co-founder of OvaScience, published a paper in the journal Nature on his discovery in adult mice. He found stem cells that are capable of generating new eggs. "it's been demonstrated that these stem cells exist in humans, and Tilly has published a number of papers to demonstrate it," Chappel says. "We would call them dormant, and then by some process that we don't understand, they begin their development, and they become primordial follicles and alternately they become regular Graafian follicles, and ultimately they are ovulated."
These oocyte stem cells are the source for the woman's own germ-line mitochondria that can be used to rejuvenate her eggs.
Clinical Trial in 2012
OvaScience is planning a clinical trial with two Boston fertility centers during the second quarter of 2012. "This trial that we're about to begin in Q2 is basically a safety and efficacy trial, so this will be the first time that the woman's own mitochondria will be used," Chappel says.
The scientists will enroll women ages older than 35 and less than 42 who have two previous failed IVF cycles in which the reason for failure is not severe male factor, endometriosis or any anatomical issue. In addition, the women cannot have a condition such as diabetes or polycystic ovarian syndrome (PCOS). The women would come in at the beginning of the IVF cycle for a laparoscopic biopsy of tissue from the ovarian epithelium. This is sent to a laboratory, and the oocyte stem cells are purified from the other cells, and the mitochondria is extracted from the stem cells. After the woman's eggs are retrieved, they are fertilized with intracytoplasmic sperm injection (ICSI) along with a "dose" of her own high quality mitochondria.
"The IVF procedure isn't disturbed at all," Chappel says. "The only thing different is that a couple of months before, she had a biopsy to collect the tissue."
"This is one of the first real advances that have been made in infertility treatment in a long time," he continues. "This is changing the quality of the oocyte — not by doing anything abnormal because it's basically the patient's own mitochondria that are being put back in."