April 29, 2002
STANFORD, Calif. Using microarray technology, researchers at Stanford University Medical Center have uncovered thousands of genes that may be involved in multiple sclerosis. Although some of the genes are new, others were known genes that had previously been thought to play roles that were unrelated to MS. These results could lead to new treatments and help clarify previous observations about the disease.
'Weve been bumping around looking at a few genes,' said Lawrence Steinman, MD, professor of neurology and neurological sciences. 'Now there are hundreds if not thousands of other genes that may be critical.' This work will be published in the May issue of Nature Medicine.
MS occurs when cells of the immune system target their attack on cells that insulate neurons in the brain. The disease generally progresses in stages with an acute attack followed by a recovery or chronic phase in which the insulating cells degenerate and scar tissue builds up. Eventually, the disease can lead to paralysis and sensory disturbances such as blindness or deafness.
Steinman looked at which genes were being expressed in both acute and chronic attacks and compared them with the genes active in normal brain tissue.
To do this, Steinmans team isolated messenger RNA from acute, chronic and normal brain samples (mRNA is produced by active genes and can be used to identify which genes are being expressed in a given sample). They then exposed the mRNA samples to a gene chip a glass slide dotted with human genes. If a sample contained mRNA corresponding to a gene on the chip, it would bind to the spot and produce a visible signal. The bigger the signal, the more mRNA, and therefore the more actively the gene is expressed in the sample.
With this technique, Steinman picked out thousands of genes that were expressed at either higher or lower levels in MS compared to the normal brain sample. Some of these genes were exactly what Steinman would have predicted, including the immune-stimulating factors called cytokines. 'We would expect to see angry, inflammatory cytokines in acute MS and scarring in chronic MS, and indeed thats what we did find,' he said.
But he also had some surprises. Steinman found genes expressed at high levels that had previously been found only in bones, in allergic responses and in pregnancy. He said that with only 30,000 genes to work with, the body may reuse genes for many roles. 'Multiple purposes may be the rule,' he said. He expects that future gene-chip experiments will turn up additional known genes playing previously unknown roles.
Some of the unexpected proteins Steinman found may help resolve previous observations about MS treatment. In the past, people have found that both pregnancy and allergy can prevent MS, he said, but nobody understood why. Among the genes that were overexpressed was a histamine receptor and proteins associated with pregnancy. These results could lead to the regular use of antihistamines to treat MS. 'It sure is easier to start with a drug thats approved for over-the-counter use,' Steinman said.
He also intends to test novel proteins for use in preventing MS. To verify that proteins found in this study could lead to possible cures, Steinman tested two treatments in a mouse model. In one, he created a mouse line that was prone to developing MS but lacked a gene that was overexpressed in chronic MS. These mice had fewer signs of the disease during the chronic phase than the MS-prone mice that still had the overexpressed gene. He also injected MS-prone mice with a protein found in the acute phase of the disease and saw a delay in the onset of MS in the mice.
The complete list of genes that are overexpressed or underexpressed in acute and chronic MS will be published online in conjunction with the paper. Steinman hopes other researchers will scrutinize this list and devise their own novel treatment strategies. 'There will be a lot of people who might mine this data for real nuggets,' he said.
Primary authors on the paper include Stanford postdoctoral researchers Christopher Lock, MD, PhD; Guy Hermans, PhD; Rosetta Pedotti, MD; and Andrea Brendolan, MD. The research was done in full collaboration with Renu Heller, PhD, at Roche Biosciences, who was instrumental in developing microarrays for analyzing tissue from human diseases.
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