Dr. Robert W. Sobol Jr.

Speaker: Robert W. Sobol, Jr., University of Pittsburgh

Robert Sobol, PhD University of Pittsburgh

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.

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Pitt researcher Robert Sobol
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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.
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"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.
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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.
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"It was immediately clear to me that (Sobol) had something that was very powerful for ophthalmology research," Gorin said.
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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.

University of Pittsburgh Cancer Institute researcher Robert W. Sobol Jr.http://topix.net

Robert Sobol, PhD

ROBERT W SOBOL UNIVERSITY OF PITTSBURGH CANCER INSTITUTE

PITTSBURGH, May 4, 2004 - Robert W. Sobol Jr., Ph.D., assistant professor of pharmacology at the University of Pittsburgh School of Medicine, has received a $250,000 award from the Susan G. Komen Breast Cancer Foundation for a project that seeks to identify the mechanisms that trigger tumor cell death in order to improve the ability of a promising breast cancer treatment.

Dr. Sobol, who joined the University of Pittsburgh Cancer Institute (UPCI) in 2002, focuses his research on the identification of mechanisms that may improve the ability of a frequently used chemotherapy agent, temozolomide (TMZ), to damage the DNA of cancer cells.While TMZ is an effective treatment for many cancers, its ability to destroy cancer cells depends on how effectively it can damage the DNA of these cells, preventing them from multiplying and causing them to eventually die.

"Tumor cells, unfortunately, are quite robust and can often repair the damage that chemotherapy causes to their DNA," said Dr. Sobol."In order to improve the efficacy of chemotherapeutic agents for breast cancer, we need to develop ways to subvert the ability of cancer cells to repair themselves.I am hopeful that our project will lead to discoveries of promising new approaches that improve the efficacy of therapy by identifying the mechanisms that control cancer cells' ability to survive."

Dr. Sobol explained that the ability of cancer treatments like TMZ to destroy the DNA of tumor cells depends, in part, on the expression of a tumor-suppressing gene called p53.While p53 prevents normal cells from turning into life-threatening tumor cells, it is damaged in most cancers, and damage to the p53 gene correlates with worse clinical outcomes for many cancer patients.

Dr. Sobol's team discovered that, when deregulated, a gene expression pathway called base excision repair (BER) - integral in repairing damage to tumor cells - dramatically improved the tumor cell killing abilities of TMZ regardless of the status of the p53 gene.In other words, when BER is deregulated, TMZ caused a strong anti-tumor response in breast cancer cells independent of p53.

In the current project, Dr. Sobol seeks to further identify the mechanism in the BER pathway that can trigger cancer cell death independent of p53."If we can discover the mechanism that triggers cell death in the BER pathway without relying on p53, we can facilitate even greater therapeutic efficacy of drugs such as TMZ," said Dr. Sobol.