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Why do some people infected with the hepatitis C virus develop liver disease while others do not? Do genetic factors determine who will develop fibrosis and cirrhosis of the liver? Why do some patients infected with the hepatitis C virus stay healthy after liver transplant operations while other patients rapidly develop cirrhosis?
Dr. Michael Katze and his colleagues at the UW's Center for Functional Genomics and Hepatitis C Virus-Associated Liver Disease are applying advanced techniques in genetic research to try to answer these questions. Katze, professor of microbiology, directs the Center where work is done in collaboration with Drs. Nelson Fausto, David Gretch, Robert Carithers, and the Institute for Systems Biology.
The hepatitis C virus was discovered in 1989. About three percent of the world's population, including about four million Americans, is infected with the virus. In Washington state, nearly 100,000 people may have the virus, and 75,000 of those infected may not know it.
The virus is spread primarily through contact with infected blood. Approximately 85 percent of chronic infections are caused by either intravenous drug use with shared needles or through blood transfusions performed before1992. Now, effective tests screen for the virus in the nation's blood supply.
Because the progress of liver disease caused by the virus may span 20 years or more, widespread intravenous drug use in the 1960s and 1970s has resulted in an explosion of hepatitis C-related diseases in recent years.
The virus damages the liver slowly and often without obvious symptoms. Treatment with a combination of the drugs interferon and ribavirin is effective in only 35 percent of the cases. About 1,000 patients in the United States receive liver transplants each year as a result of cirrhosis and cancer caused by the virus.
The virus is difficult to study. Researchers are unable to grow the virus in tissue cultures, and there is no suitable animal model in which to study the progress of the virus. Chimpanzees can be infected with the virus, but they do not develop significant liver disease as a result.
These challenges have led researchers to look for new tools to understand the virus. Among the techniques being applied at the Center are microarray analysis, proteomics, and bioinformatics.
Tools such as DNA microarrays allow the simultaneous analysis of the expression of tens of thousands of genes in a tissue in a single experiment. The technique enables researchers to examine which genes are underexpressed or overexpressed in serial liver biopsies from patients with recurrent hepatitis C after liver transplantation. Investigators hope to determine if there is a difference in gene expression between individuals who do and who don't develop fibrosis, cirrhosis and cancer of the liver.
Many researchers once believed that understanding the human genome would answer all or most questions about gene and protein expression.
"The idea that gene expression totally controlled the amount of proteins in the cell went out the window," said Carithers, professor of medicine, Division of Gastronenterology. "Instead, scientists discovered that the process was more complex, because proteins quickly degrade, or become converted to another protein, or combine with each other."
The Center is applying a science called proteomics, the study of how proteins carry out fundamental cell activities.
Bioinformatics refers analyzing of enormous amounts of research data on computers. A single computer chip can now complete complex genome analyses of a scope that would have demanded a Cray supercomputer a few years ago. Katze and Carithers refer to bio-informatics as the "computational piece of the puzzle" that allows scientists to interpret the data they have collected.
"The significance of the research at the Center is that it combines the most advanced techniques in clinical, genetic, proteomic and computational work," said Carithers.
The National Institute on Drug Abuse (NIDA) and the National Institute on Allergies and Infectious Diseases (NIAID) fund the Center.
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