"The motivation for the study was the genomic application of Sutton's law," said Larry Steinman, MD, professor of neurology at Stanford. "Sutton's law" refers to a bank robber who, upon being asked why he robbed banks, answered, "Because that's where the money is." For Steinman and Jorge Oksenberg, PhD, associate professor of neurology at UCSF, the logic in examining autopsied brains from MS patients to learn about the disease is clear. "It's where the money is," said Steinman.
According to Steinman, collaboration with UCSF on this project was "a direct extension of a 10-year adventure looking at gene expression in the inflamed multiple sclerosis brain to see what's going on in the course of this disease." Steinman and Oksenberg, a former postdoctoral fellow with Steinman at Stanford, shared senior authorship on the paper explaining their findings, which appeared in the Nov. 23, 2001 issue of Science.
With large-scale sequencing, they created a gene library from the brains of people with MS, looking for genes that appeared most often. "We found an abundance of osteopontin in the multiple sclerosis brains - the equivalent of a dozen or more volumes," said Steinman, likening the genes to books in a library.
In MS, inflammation of nerve tissue destroys the myelin covering of nerve cell axons, leaving areas of scar tissue. This patchy loss of myelin in the brain and spinal cord slows communication between nerve cells, leading to symptoms such as muscle spasms, weakness, sensory deficits and visual disturbances.
Two important pieces of evidence presented in the paper indicate that in an experimental model of MS, the degree of expression of osteopontin may be related to the severity of the disease. First, the researchers determined that osteopontin expression varies with the phase of the disease. By inducing an autoimmune disease in rodents similar to MS in humans, they were able to show that osteopontin expression is most prominent in nerve cells near sites of active lesions during acute disease and relapse, but not during remission.
Second, using genetically altered mice lacking osteopontin, they confirmed that osteopontin affects the course of the disease, demonstrating that manifestations of the disease were significantly less severe in osteopontin-deficient mice. The percentage of remissions was much higher in the osteopontin-deficient mice. Moreover, there were no disease-related deaths in this group. It was suggested that osteopontin may influence the evolution of the disease, determining whether relapses and remissions develop.
"With this finding, a major piece of the puzzle is in place," said Oksenberg, "but there is much more work to be done." Steinman added that in addition to osteopontin, a number of other genes found warrant further examination. "We have identified the titles but haven't yet read the contents," he said.
MS affects approximately one million people worldwide, with women being twice as likely as men to have the disease. At present, MS is incurable and the cause is unknown. The underlying problem may involve the inability of the body's immune system to distinguish "self" molecules from foreign molecules.
Postdoctoral fellows Dorthee Chabas at Stanford and Sergio Baranzini at UCSF were co-first authors on this study. Chabas carried out the studies in mice and Baranzini analyzed the large-scale gene sequences. Renu Heller is also a co-senior author for her role in organizing the work through her position at Roche Biosciences.
This study was funded by the National Institutes of Health; the National Multiple Sclerosis Society; the Susan G. Komen Foundation; the Association Francaise Contre les Myopathies; the Ligue Francaise Contre La Sclerose En Plaques; the Assistance Publique des Hopitaux de Paris; and Roche Biosciences.
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