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Attack of the Clones

UTHSC researcher leads historic breakthrough in cancer research

August 2003

by Natalie Gutierrez

Cloning - itís shrouded by mystery, intrigue and controversy. When George Lucas introduced the "clone troopers" in his epic film series, "Star Wars," audiences applauded. Last year when Italian fertility doctor Severino Antinori announced that a woman in his human cloning project was pregnant with a cloned human embryo, people werenít so enthusiastic. And long before Dolly, the cloned sheep, was born in July 1996, Shou-Jiang Gao, Ph.D, was hard at work on a cloning project of his own - one that could have people all over the world agreeing on one thing - cloning a virus could save lives.

For the first time in history, Dr. Gao, an associate professor in the departments of pediatrics, medicine, and microbiology and immunology at the Health Science Center, and program leader of the tumor virology program at the Childrenís Cancer Research Institute, and his research team have achieved what scientists across the country have been trying to do for years. They have successfully cloned a complete and productive Kaposiís sarcoma-associated herpesvirus (KSHV), one of the largest viruses known to man and the virus that causes the deadly cancer Kaposiís sarcoma (KS). In addition, they have developed what he calls a "shuttle system" for studying the cancer-causing traits of the virus, thus providing the first successful method for studying why and how KSHV causes cancer. The National Cancer Institute of the National Institutes of Health (NIH) awarded Dr. Gao a $1.6 million grant over five years for his research.

Scientists from England, Germany and Italy and more than 20 research institutions across the country, including Harvard Medical School, Johns Hopkins, New York University School of Medicine, the UC Davis Cancer Center and others, are lining up to collaborate with Dr. Gao on this scientific breakthrough.

"Dr. Gaoís team has made a significant contribution to the study of KSHV," said Zhi-Ming Zheng, M.D., Ph.D., a principal investigator at the NIH. "They are the first to establish this excellent system that will allow us to understand how KSHV genes express themselves and replicate." Dr. Zheng said he and other researchers will use Dr. Gaoís system as a model for further KSHV research.

KSHV, as with all herpesviruses, is a shrewd virus. Many people carrying the virus donít even know they have it. Thatís because it can lie dormant in its host for several years, waiting for the right moment when the hostís immune system becomes weak. Then it attacks, transforming normal cells into cancer cells that wreak havoc on body tissues. The result is KS - a disfiguring rash of often painful, purplish lesions that grow in the mouth and on the skin. In more aggressive cases, KS damages internal organs, such as the lungs, lymph nodes and digestive tract, often proving fatal.

KS was once thought to be a rare disease that afflicted mostly elderly men of Mediterranean, Jewish or African descent. But in the early 80s, cases of KS quickly began surfacing in young homosexual men in the United States. In the last 20 years, the vast majority of KS cases have developed in patients with acquired immunodeficiency syndrome (AIDS). However, just like the human immunodeficiency virus (HIV), which causes AIDS, Dr. Gao stresses that KSHV is not a discriminating virus and should not be labeled a "homosexual" or
"specific racial" virus. Anyone can get it.

Dr. Gao and his colleagues are working with blood and tissue centers to study the KSHV infection rate in Texas. They found that 15 percent of blood donors in Texas were infected, as compared to 5 percent to 12 percent in other parts of the country. Studies also revealed a higher rate of specific strains of KSHV in Hispanic KS patients in South Texas. Health experts are concerned that these figures raise the possibility that KSHV could be transmitted from person to person through blood transfusions during routine operations. Dr. Gao and his team received agrant of nearly $1 millionfromthe NIH for this aspect of their research.

"Dr. Gaoís research is vital and will have a major impact on the testing and processing of donor blood throughout the country," said Dr. Chantal Harrison, professor of pathology at the Health Science Center, who is collaborating with Dr. Gao.

Dr. Gao not only plans on determining whether or not KSHV can be transmitted through blood transfusion, he is on a mission to find the cancer-causing genes of the virus. Thatís where his "shuttle system" comes in.

Unlike the traditional shuttles we know, Dr. Gaoís shuttle is so tiny it canít be seen by the naked eye. His shuttle consists of the cloned KSHV in a Bacterial Artificial Chromosome (BAC), which is like an incubator that allows the virus to grow in bacteria. The BAC serves as a mini-transporter that shuttles the virus from the bacteria into human cells and vice versa. When the virus is in the bacteria, Dr. Gao can manipulate it. In a much quicker fashion than it took him to assemble it, he begins to disassemble the cloned KSHV, pulling its proteins, or genes, apart. Then he shuttles the mutated virus back into the human cells.

Peering through the lens of a high-powered microscope and using some of the latest molecular biology technology, he watches closely to see how each gene reacts among the human cells, waiting for any signs of infection and emergence of cancer cells. With more than 90 genes in the KSHV to study, Dr. Gao has his work cut out for him. But like a gambler at a Las Vegas blackjack table or a noisy slot machine, Dr. Gao is persistent. He wonít quit until he discovers the "winning" combination of KSHV genes that causes cancer in human cells. Once he does, researchers across the country will be able to work on developing vaccines and drugs that target KSHV.

In essence, Dr. Gao is using a virus clone to attack and defeat itself - the recipe for an exciting science fiction novel - except that this scenario is real, with the potential to save thousands of lives.






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