June 27, 2005.
Pittsburgh Tribune-Review, PA.
The Mother Goose nursery rhyme has three blind mice.
University of Pittsburgh Cancer Institute researcher Robert W. Sobol Jr. accidentally created hundreds of them.
Sobol, who came to Pitt three years ago from the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., has invented mice with cataracts that scientists can turn on and off simply by changing their diet.
He believes his mice could provide answers about what causes human cataracts, the most common cause of blindness worldwide.
Sobol also hopes they could be used to test drugs that would delay and prevent onset of the disorder and be cheaper than lens-replacement surgery, which costs Americans $20 billion annually.
A cataract is a grey-white film that covers the lens of the eye, obscuring vision and causing visual impairment or blindness. Usually the consequence of old age, the condition affects an estimated 20 million adults in the United States.
As a molecular biologist, Sobol didn't plan to study eye disease.
In fact, he didn't know too much about it until several years ago, when he made a fortuitous discovery while working for NIEHS. Sobol had set out to investigate the role of an enzyme called DNA polymerase beta, or pol beta, in repairing genetic damage.
Repair enzymes like pol beta fix the thousands of mistakes in our DNA that occur every day in each cell of the body from the harmful effects of the sun's ultraviolet rays, environmental toxins and X-rays. This helps to prevent genetic damage that could lead to cancer.
More than 30 percent of tumors have abnormal levels of pol beta, suggesting its importance in keeping cells healthy, said Sobol, now an assistant professor of pharmacology at the cancer institute's Molecular & Cellular Oncology Program.
"Something is going on with this enzyme, but for what reason, no one seems to know," he said.
Scientists often try to figure out what an enzyme does by knocking out its function in aptly named "knockout" mice. Then they try to determine how the knockouts differ from normal animals.
But learning about pol beta has proven difficult because mice without the enzyme die within a matter of minutes. Having too much pol beta can lead to genetic damage in mice -- although not enough to kill them.
"Initially, you would think having too much of a good thing would be great, but that's not always the case," Sobol said.
Sobol genetically engineered a mouse strain that makes excess pol beta so he could study the crucial enzyme.
Then something surprising happened. An animal technician noticed every mouse Sobol bred with too much pol beta developed white, cloudy eyes within four days of birth.
"Every single mouse that had the gene had white eyes," Sobol said. "There was complete concordance in hundreds of them."
A veterinary pathologist used miniature eye-exam instruments to confirm what the researchers suspected: The mice were developing cataracts.
Sobol's experiments marked the first time anyone had made a direct link between this common eye disorder and changes in a DNA repair protein.
He also designed his mice so they could stop making pol beta by eating food laced with an antibiotic. Withdrawing this food jump-started pol beta production. As the enzyme turned on and off, Sobol observed, so did the progress of the cataracts.
He published his findings in the scientific journal DNA Repair in 2003 and listed the mouse breed on the Federal Register as a government-owned invention available for commercial licensing.
"This is a nice tool to look at what's going on in cataracts," said Ellen Liberman, program director of the National Eye Institute in Bethesda, Md., which is part of the National Institutes of Health. She is not connected to Sobol's research. "I'm sure someone is going to pick up on this model."
Sobol's blind mice went undiscovered by vision researchers until October.
That's when he happened to be stationed next to Dr. Michael Gorin at Pitt's Science2004, the university's showcase of science and technology held each fall.
Gorin, an ophthalmology professor at the UPMC Eye & Ear Institute, learned about Sobol's mice with cataracts at the annual event, which brings together scientists from across disciplines to share their work.
Gorin referred to the unlikely meeting between a DNA-repair expert and ophthalmologist as "an act of serendipity."
"It was immediately clear to me that (Sobol) had something that was very powerful for ophthalmology research," Gorin said. "His ability to convert mice from having clear lenses to developing cataracts under very controlled circumstances may give us a way to explore what causes cataracts in a scientifically rigorous fashion."
A collaboration between the two researchers is in its early stages.
They plan to seek grant money from the National Eye Institute to use Sobol's mouse to better understand mechanisms that affect the severity and rate of cataract formation and perhaps test new treatments for the disorder.
Sobol recently landed a five-year, $1.7 million grant from the National Institute of Aging along with scientists at the University of Texas Health Science Center at San Antonio to study how changes in pol beta levels that develop with age affect the body.
To prepare for this work, he is breeding hundreds of his genetically engineered mice at the Hillman Cancer Center in Shadyside, a task which could take months and thousands of dollars.
"We think this is a really valuable model, so we're in the process of scaling up the mice again and getting our analysis under way," Sobol said. "The more we study this mouse, the better understanding we will have about how these genetic changes are connected to the onset of cataracts in humans and maybe find a new way to prevent it."
Jennifer Bails can be reached at firstname.lastname@example.org or (412) 320-7991.
Source URL: http://www.pittsburghlive.com/x/tribune-review/news/s_347840.html.
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