A team of scientists including Princeton geneticist David Botstein and led by his postdoctoral fellow Michael Whitfield (now at Dartmouth) found more than 2,700 genes with an unusual level of activity in people with scleroderma, which causes painful thickening of the skin, swelling and other tissue damage. The results could greatly improve doctors' ability to diagnose the disease and may reveal possible avenues for treating it.
A surprising result of the study, said Botstein, was that gene activity in patches of skin affected by the disease was indistinguishable from that of unaffected patches. The implication is that the disease is systemic (present throughout the body), rather than confined to skin where symptoms are visible.
Scleroderma, which affects as many as 300,000 people in the United States, typically develops in people in their 40s and 50s. In many cases the symptoms are relatively mild, but in others they can be fatal within 10 years. No current treatments are consistently effective.
Scientists had believed that the cause of the disease would be revealed in symptomatic patches by finding gene activity that was not present in normal tissue, just as cancer researchers look for differences between tumor cells and normal ones. The new study shows that the root cause of the disease is much deeper than the symptoms themselves.
"This is a disease about which very little is known," said Botstein, who helped lead the study at Stanford University and now directs Princeton's Lewis-Sigler Institute for Integrative Genomics. "We have now found that whatever causes the disease is there before the symptoms appear."
In addition, the study showed that skin biopsies from four people with a severe form of scleroderma have consistently and significantly different patterns of gene activity from that of biopsies from people without the disease. A comparison of 12,000 genes in people with and without the disease yielded 2,776 with substantially different levels of activity.
"That, right there, is fabulous. It is a handle on this disease," said Kari Connolly, a professor of dermatology at the University of California-San Francisco, and one of study leaders. "Somewhere in that package of 2,776 genes are the clues we need to look in a more sophisticated way at the many abnormalities that show up in this disease."
The study already has revealed that the disease involves antibody-producing cells, which are part of the immune system. By contrast, there did not appear to be abnormalities in gene activity of skin cells called fibroblasts, which differed from researchers' expectations.
Understanding these differences could allow doctors to diagnose the disease and begin trying treatments well before symptoms become serious, Connolly said, noting that it typically takes patients three years to obtain a correct diagnosis. Information about the particular cells and genes involved also could lead to much more targeted treatment efforts, she said.
The study is scheduled to be published in the online edition of the Proceedings of the National Academy of Sciences during the week of Sept. 29. (The exact date and the date of print publication are to be determined.) In addition to Botstein and Connolly, authors of the study were Michael Whitfield, John Murray, Olga Troyanskaya, Jen-Tsan Chi, Alexander Pergamenschikov and Patrick Brown of Stanford and Deborah Finlay and Timothy McCalmont of UCSF. Whitfield is now at the Dartmouth Medical School and Troyanskaya in the Princeton Department of Computer Science.