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Veterinary College Faculty Play Lead Role in New Center for Reproductive Genomics

Cornell University has established the Center for Reproductive Genomics, which will combine basic and clinical research in reproductive sciences on Cornell's Ithaca campus and at Weill Cornell Medical College (WCMC) in New York City, which has one of the country's leading fertility clinics. Infertility affects 10 to 15 percent of couples of childbearing age.

The collaborative center will focus on the genetics of infertility, with specific emphasis on meiosis, the specialized cell division that results in recombination of genetic material and the production of sperm in the male throughout life and eggs in the female fetus, which then develop over 20-plus years.

The center now has about 15 faculty members from the two campuses engaged in collaborations. All consulted on or wrote a $5 million grant proposal that will soon be submitted to the National Institutes of Health to help fund the center. Ultimately, about 100 faculty members from both campuses will be part of the center, which is unique for its distinct focus on genetic mechanisms, said Paula Cohen, the center's director and an assistant professor of genetics in the Department of Biomedical Sciences at Cornell's College of Veterinary Medicine.

"We can now look at how reproductive performance is genetically determined," she said.

The center will target both human and animal health. Observations of the role of genetics in infertile human patients from WCMC can now be studied further through animal models at the Ithaca campus. For animals, fertility studies will help with everything from wildlife conservation to breeding cattle and horses.

"This is an example of a collaborative translational research process that brings together the best of a world-renowned clinical research program in male and female infertility with strong basic research from Ithaca that is likely to grow beyond the sum of its individual parts through its synergistic opportunities," said Peter Schlegel, chairman of urology at WCMC and urologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. Schlegel has led efforts at WCMC to establish the center.

Schlegel and Darius Paduch, assistant professor of urology and reproductive medicine at WCMC's Brady Urological Health Center, have previously shown that up to one-third of men with severe male infertility have defective recombination of chromosomes during meiosis, which can often disrupt sperm production. John Schimenti, professor of genetics in the veterinary college and director of Cornell's Center for Vertebrate Genomics, has taken this discovery one step further by producing mice with specific gene defects that lead to abnormal meiosis, allowing him to examine the genetic basis of similar processes that Schlegel and Paduch observed in humans.

Also, part of Cohen's work aims to answer why defects in male meiosis lead to the death of sperm cells while similar defects in female meiosis preserve eggs. Since these defective eggs survive, errors in female meiosis are responsible for high rates of birth defects in humans, including Down syndrome, for example. To study these genetic processes, Cohen and colleagues have grafted human fetal ovarian tissue into mice. Within 20 weeks, the mice produced tiny human ovaries containing human eggs.

"Normal female meiosis takes 20-odd years in women," Cohen said, because eggs in humans don't mature until puberty. "What we can do now is study the process in a few months in a mouse."

As the genes responsible for disrupting female meiosis are identified in mice, Cohen will work with physicians within the Center for Reproductive Medicine and Infertility at WCMC, headed by Zev Rosenwaks, to find genetic markers in human female patients to determine whether defective meiosis might be causing infertility.

The Center for Reproductive Genomics already has a functional and fully equipped laboratory at WCMC, while the veterinary college handles the center's administrative functions.

"This is an area of research that is important to people on a personal basis," said Cornell Vice Provost for Life Sciences Stephen Kresovich. "The great capabilities both at Ithaca and Weill Cornell to do this type of research make this center a natural fit for the university."

Male infertility database is key to new genetic studies

For the past 13 years, physician-scientists at Weill Cornell Medical College in New York City have been compiling one of the most comprehensive male infertility databases in the country -- with medical background information and blood and testicular tissue samples from more than 2,000 infertile men. The database and new genetic tools are helping Cornell scientists diagnose infertility in patients more rapidly than ever before.

"With this database, we can screen for genetic mutations using DNA from blood, and then -- what is really unique -- we can look at the tissues and compare that with the blood," said Darius Paduch, assistant professor of urology and reproductive medicine at Weill Cornell, who oversees the database.

By building on animal studies that identify gene mutations that lead to infertility, Paduch can look for similar genes in blood samples in the database. When mutations are found on that gene in his human samples, Paduch can see how the mutation in a candidate gene affects an individual's infertility. Such a gene mutation may cause a patient to produce no sperm at all, or sperm may never fully mature.

By Krishna Ramanujan