Multiple sclerosis is not life-threatening, just life-blighting - and incurable.

This autoimmune malady afflicts upwards of 1.1 million victims throughout the world, between 250,000 and 350,000 of them in the U.S. Among its myriad inexplicable features is the fact that twice as many women as men contract MS. The disease becomes manifest between 20 and 40 years of age. During this prime of life, like a thief in the night, it robs its patients of eyesight, joint and limb command, bladder control and mood, among other symptoms and signs.

But MS is a pitiless practical jokester. From time to time all its horrors vanish in what is called remission. Then, just as the patient feels cured, those dire features come back, a little bit worse each time, in a flare-up or relapse. Those wide swings of well-being and emotion, scientists believe, reflect the on-and-off wrapping and destroying of myelin, which ensheaths the neuronal axons in the central nervous system.

"If you demyelinate an axon," observed neurobiologist Gareth John, "it inhibits nerve impulse conduction. And if you remyelinate the axon," he continued, "you restore axonal conduction. So in MS we believe that remyelination, at least early in the disease, is associated with restoration of function, demyelination with loss of function - what you would see in a relapse - and remyelination, restoration of function. So if we can promote remyelination, we might be able to promote restoration of function in multiple sclerosis."

Gareth John, in the pathology department at Albert Einstein College of Medicine in The Bronx, N.Y., is lead author of a paper in Nature Medicine, released online Sept. 23, 2002. Its title: "Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation." Its senior author is pathologist/neuroscientist Celia Brosnan, a tenured professor of pathology and neuroscience at Einstein.

"We reported that the Notch developmental pathway is reactivated in the active MS lesion," John told BioWorld Today. "We know that the pathway is involved in controlling - in fact, inhibiting - oligodendrocyte [oligo] maturation. Our thinking is that perhaps the Notch pathway may similarly restrict remyelination in the MS lesion, thereby inhibiting CNS repair."

Oligos, Astrocytes Call Remyelination Tune

"Oligos," John explained, "are the abundant CNS cells involved in myelination. They produce the wrapping that goes around the axons. Each oligo myelinates multiple axonal segments. Astrocytes, too, are abundant in the brain," he went on. "We know some of their functions but probably not all. They are believed to support the other cerebral cell types - oligos, and neurons. And astrocytes may remove excess neurotransmitters and toxic waste products."

John cited "a couple of novel things in our Nature Medicine article. One, we showed that the Notch ligand, Jagged, is inducible by transforming growth factor-beta [TGF-b], which is a pleotrophic immune system cytokine. TGF induces Jagged, which is one of the major ligands for the Notch pathway. That perhaps is the most important finding of our paper, because it has implications for developmental biology and immunology, as well as putative MS therapy.

"Our second novel finding," John added, "is evidence that the Notch pathway is reactivated in the MS lesion. And we know that TGF-b is present in that demyelinating lesion. It seems to have two functions in the body. It is strongly anti-inflammatory and it also promotes repair. But TGF in excess can promote scar formation. In the lung, liver or kidney, excessive TGF-b is associated with scarring, and inhibition of repair. So we speculate that the same effect might possibly be true in the MS lesion.

"If you knock TGF-b out in mice," John went on, "the mice deprived of that cytokine die off of a multisystemic autoimmune disease. That is, the TGF damps down the immune system. If you overexpress TGF-b in the CNS, you may get excessive extracellular matrix production, which is associated with fibrosis and scar formation.

"We think that the Notch pathway could be one of the mechanisms by which TGF-b may inhibit repair," John pointed out. "But there are multiple factors. It's a very active area of research. There are whole labs that make their livings on identifying these pathways."

John and his co-authors relied on microarray analysis in their in vitro experiment. "Our plan," he recounted, "and originally when we undertook the analysis, was to investigate the molecular nature of a reactive astrogliosis. That is, following CNS injury or inflammation, you see a change in astrocytes - a change in their shape, in the genes they express. Work over the years has indicated that the reactive astrocyte may play a role in CNS repair, perhaps in inhibiting regeneration. We wanted to know what the gene expression patterns were of human astrocytes that had been stimulated with various cytokines that occur in the MS lesion. So we used three cytokines: interleukin-1, TGF-beta 1 and interferon-gamma. We treated the astrocytes with these cytokines and at set time points later, harvested the cells, took their RNA, and looked at their gene expression pattern."

Microarray Assesses Human Fetal Tissues

"There were 9,216 cDNAs on that array," John recalled, "representing 9,182 distinct human transcripts. Our microarray facility is now equipped to analyze 27,000 genes. We obtained our source material, primary human fetal astrocytes, through the fetal tissue resource here at Einstein. The samples came from their clinic to us and we simply cultured them. Overall results of the analysis found that human astrocytes respond to different cytokines with different gene expression patterns. In turn, this suggested a biological function. Each cytokine produced a different pattern of gene expression, implying a different functional consequence for the cell.

"The work in our paper," John noted, "identifies a factor that can reactivate the Notch pathway, and suggests that such reactivation does in fact occur in the multiple sclerosis lesion, with consequences for repair. However, we require proof of concept, so we will push forward in vivo, using a mouse animal model in our further experiments. If the work checks out, if we get the proof-of-concept data that we require, a long way down the line," he concluded, "the Notch pathway could possibly represent a target for therapy designed to potentiate remyelination, and hence recovery of function in MS."