Why study genes?

If MS isn't an inherited disease, why are medical scientists looking for MS genes? Dr. Stephen Hauser of the University of California, San Francisco is leading a multicenter effort (supported, in part, by funds from the Society) to identify genes that "confer susceptibility to MS." InsideMS asked him what this means.

We know MS involves an attack by the immune system on myelin in the central nervous system. But we still have some significant mysteries. For example, every tablespoonful of human blood contains about 10 white blood cells, called T cells, capable of reacting against myelin. But nothing happens to most of us because these cells remain in a quiet or resting state. In people with MS, however, these white blood cells are different. The myelin-sensitive cells seem to be chronically stimulated. Just a few years ago, we didn't know this.

When white blood cells that are sensitive to myelin are stimulated, they can leave the bloodstream, move through the protective blood-brain barrier, and enter the central nervous system. When they do, they find the structures on myelin that they react against, and this meeting stimulates many other immune cells to move into the brain and cause inflammation. All this makes the immune reaction that much stronger.

Dr. Cedric Raine of Albert Einstein College of Medicine in New York has taken very accurate photographs of what can happen next. The myelin on nerve fibers develops bubbles, and immune cells called macrophages (Greek for "Big Eater") can be seen lurking nearby. Macrophages apparently make myelin bubble up this way by releasing a chemical called a cytokine.

Immune cells react to fragments of protein molecules, and myelin contains more than one protein. In MS, the immune response appears to be against more than one of the myelin proteins. There seems to be a hyperactive immune response to much of the protein structure that makes up myelin.

We didn't know any of this in the 1980s. But until we understand what causes these things, we know we don't truly understand MS.

Enter Genetics

Statistics on populations of people suggest that the risk of developing MS is about 1 in 1,000. The risk of MS in the siblings of a person with MS is significantly higher. It may range from 1 in 20 to 1 in 50. As one moves from sib to first cousin to third cousin, this increased risk drops off. 80% of people who develop MS have no one else in their family with the disease--which means that the risk of inheriting MS is small for an individual. But 20% people with MS do have a relative with the disease. Taken together, it is clear that genes are involved in creating abnormalities that make some people susceptible to MS.

Genes not only direct things like eye color, they also influence how cells function--for example, what specific T cells can react to and if they will respond normally.

Genes are simply sections of DNA and DNA is relatively simple stuff. It has a sugar backbone with 4 chemicals attached, usually called by their initials: A, C, T, and G. The sequence in which A, C, T, and G occur determines the structure of the gene. It's humbling to know that we have the same number of genes as a mouse: about 100,000.

Each cell in the human body has 23 pairs of chromosomes containing approximately 3 billion DNA building block--units of A, C, T, or G. A chromosome contains a great quantity of seemingly inactive DNA--and an average of about 4,000 genes. Each of us has 2 copies of each chromosome, and 2 of each gene, 1 of which is randomly passed down to each of our children.

About 1 in every 100 building blocks is different. These differences define a human's individuality. In genetic screening, we search for the building blocks that are inherited in common by people who develop a specific disease.

Genes on a Hot List

Three U.S. teams supported by the Society and French, British, and Canadian teams have all been studying families in which more than one member has MS, comparing samples of their DNA to see which regions are common only to the family members who have MS. Then we use the science of statistics to test whether the relationships we've found could be produced by chance alone.

This international effort has put at least 19 regions--each containing about 70 genes--on a hot list. While we suspected for some time that no one single gene is responsible for MS, we didn't know it until 18 months ago. Now the research teams are working to confirm these 19 regions.

We've found a number of interesting things. For example, genes responsible for directing T cell attacks are located in one of the regions highlighted by these studies. This supports the understanding that MS is an autoimmune disease.

There are hints that genes associated with MS susceptibility are not themselves abnormal. In fact, some of them may be advantageous to have. But in some combinations, these normal genes appear to predispose an individual to develop an immune system that is highly active against myelin.

The Goal

What matters most is zeroing in on the genes that make a person susceptible to some outside event or events, the not-yet-known environmental trigger that starts MS. Once the genes are identified, it will be possible to determine what proteins those genes make--and then conduct tests to learn what those proteins do.

At the end of the road lies a rational therapy--a therapy directed at a specific, known defect. We may even find something to prevent MS from happening in the first place.

RELATED ARTICLE: Risk of MS

* If no one in the family has MS: 1 in 1,000

* If mother has MS and baby is a girl: 1 in 50

* If father has MS and baby is a boy: 1 in 100

* If a sibling has MS: 1 in 20 to 50

* If a fraternal twin has MS: risk is the same as other siblings

* If an identical twin has MS: 1 in 3

Dr. Hauser is chair and Betty Anker Fife Professor in the Department of Neurology at the University of California, San Francisco.