June 18, 2013
By Donna Peck
|David Albertini, Ph.D.|
David Albertini, Ph.D., has spent most of his career trying to understand one of life's most mysterious cells: the oocyte, which eventually matures into an egg cell.
Albertini, who is a professor of molecular and integrative physiology and a member of the University of Kansas Medical Center's Institute for Reproductive Health and Regenerative Medicine, is using the most advanced technology to shed new light on precisely what happens when an oocyte divides and how the oocyte receives support from other ovarian cells. Albertini's research is contributing to scientists' understanding of human embryo development and may guide future approaches for treating infertility and enhancing the use of stem cells in regenerative medicine.
Oocytes first arise in the fetal ovary and remain in an immature state for many years in most female mammals. They mature within a structure known as the ovarian follicle, which resides along the outer boundary, or cortex, of ovaries. During each reproductive cycle, several follicles begin to develop. In humans, only one oocyte per menstrual cycle will become a mature egg to be ovulated from its follicle.
Early on in a woman's reproductive life, most oocytes have chromosomes in pristine condition, resulting in eggs that have the correct chromosomal complement. But as women age, the quality of their eggs deteriorates, and an increasing number carry chromosomal abnormalities, leading to increases in birth defects such as Down's Syndrome.
"There is a very pronounced increase in the number of chromosomal defects in the oocytes of women by the time they reach their early thirties," Albertini says.
For years, researchers have been puzzled about why chromosomes in aging oocytes begin to malfunction. Albertini says the technology allowing scientists to observe the behavior in live oocyte cells didn't exist until recently.
"Before, we could study non-viable oocyte cells under a microscope, but that didn't give us much insight into the cell division process of a live oocyte," Albertini says. "But now we have special microscopes that allow us to see the molecules of live cells in detail and observe the flow of particles when a cell divides."
Albertini and Rong Li, Ph.D., a professor of molecular and integrative physiology at KU Medical Center and a researcher at the Stowers Institute for Medical Research, were able to see firsthand the molecular mechanisms that lead to oocyte maturation. Among other things, they observed that for an oocyte to mature into an egg, it needs the support of the cells around it. Their observations were published in the March 2013 issue of Nature.
"It requires a tremendous amount of energy to transform an oocyte into an egg," Albertini says. "The machines within the oocyte that drive cell division need the help of cells around it to tell it what to do and how to do it."
When an oocyte begins meiosis (the process by which the nucleus divides in all sexually reproducing organisms during the production of spores or gametes), homologous chromosomes, which have genes for the same traits in the same position, form pairs and exchange genetic material in the process known as recombination or crossing over. During the first meiotic division, one member of each pair of homologous chromosomes moves to each end of the cell, and the cell divides. Each of the two cells produced by the first division has just one set of 23 chromosomes. The two daughter cells then undergo the second meiotic division. In the human female, just one of those four daughter cells will become a functional egg.
This process of moving and extruding the chromosomes requires energy in the form of ATP (adenosine triphosphate) that the oocyte is unable to produce. Instead, the cells surrounding the oocyte make large amounts of energy during the process of ovulation and deliver these high energy products through channels that connect the ovarian cells directly to the oocyte. Albertini likens this to filling up the gas tank before taking a long trip. For the egg, the fuel acquired from these cells will be consumed in the process of making an embryo.
Albertini says it is only with the assistance of surrounding cells that the machines within the oocyte are able to push and pull the chromosomes apart during meiosis. He calls it "filling the ooycte's gas tank."
Albertini and Li suggest that as a woman ages, the cells around the oocytes that assist in meiosis also age. When the support cells are no longer able to help the oocytes through the cell division process, it can have a negative effect on chromosomes as they try to separate from one another at each division.
These new studies are helping identify the properties of a "good egg" - which is a key to the production of healthy embryos and babies. In fact, Albertini is an international leader in the rapidly growing field of fertility preservation, which is opening new doors for patients whose fertility may have been compromised due to treatments for cancer.
"Advances in the technology for freezing oocytes or ovarian tissues have reached a point where those patients unfortunate enough to have had their oocytes damaged as a result of radiotherapy or chemotherapy may soon be able to reproduce once their disease has been managed," Albertini says.
Albertini says although there are differences in oocyte development in mice and humans, these latest discoveries are significant.
"I'm optimistic that these new insights into the molecular cell biology of oocytes from rodent models and humans will contribute to advances in the treatment of infertility and the field of regenerative medicine."
Albertini's research is funded by the National Institutes of Health, the March of Dimes Birth Defects Foundation, and the Eshe Fund.