Why me? The person with MS must often wonder what factors, unseen and unheard, cause the illness to affect one person but not another, one group of people but not another, and one part of the world but not another. The answer lies in the genetic make-up of individuals and particular ethnic groups. But what are these genes, how do they work, and can they be fixed?
These and other questions are addressed in this issue of MS in focus in which representatives from the leading research teams internationally explain why understanding the genetic basis of susceptibility to MS matters, how this knowledge is being gathered in different parts of the world, what remains to be learned, and what this knowledge means to people who have the disease.
About one person in five (20 percent) with MS has someone else in their family also affected. Since roughly only one in five hundred of the population gets MS, this rate is higher than expected by chance. Everything points to the increased risk depending on being a close relative rather than living together during childhood. Fortunately, the actual risk to any particular relative is pretty low.
So why bother to unravel the genetic story?
Knowing why some people are at higher risk of the disease than others does nothing immediately to help put right the problem, but the main reward should come from the clues provided by understanding what is happening to the brain and spinal cord of people with MS. Until recently, trying to identify susceptibility genes was extremely hard.
Now, thanks to advancing technology, the problem can be approached systematically, with good prospects of success in unravelling the story.
Genes are codes or messages that determine all the features that make one person different from another. They work alone or in groups. Through a complex sequence of events these genetic codes are converted into the proteins from which all cells and tissues are made. Most of these genes show person-to-person variations. Some genes are actually faulty and make defective proteins, but that is not thought to be the situation in MS: rather, the idea is that affected individuals happen to have slight variations, called polymorphisms, that are perfectly healthy genes but – by chance – fit together badly so that the normal workings of cells, especially those that make up the body’s immune system and the brain and spinal cord, are subtly altered.
Once this assortment of badly-fitted genes has come together by chance in the genome (a complete set of DNA) of one individual, it stands to reason that some or all of these factors may be shared within families through the normal mechanisms of inheritance. Put another way, if a particular gene contributes to MS, and two people in the family both have the illness, then it is likely that those two individuals will have inherited the same risky part of the genome. Genetic effects can also be unravelled by making comparisons between people who have MS and unrelated individuals who do not.
This issue of MS in focus tells the story of how medical scientists have worked with people who have MS, especially those in whom there is a family history, trying to identify and map the genes that increase susceptibility. Progress has been slow for several reasons, and many questions have yet to be answered. Where should the search be directed and how should it be organised? Before the Human Genome Project, it made sense to pick sensible candidates from amongst the increasing list of genes that had already been identified. The guesswork was not so inspired, although this approach did identify the HLA (also referred to as the “major histocompatibility complex” or MHC), as containing one (probably the most important) susceptibility gene for MS. HLA proteins are found on the surface of all body cells. They act as a signal to the immune system to confirm that the cell is part of the body and should not be attacked.
Now the Human Genome Project has provided a much improved opportunity for progress. The Project has identified and mapped each and every one of the 30,000 genes we all possess, and has started the process of characterising the differences which occur between individuals, so that a systematic search can be made. We might be overwhelmed by the amount of information coming from modern data analysis techniques, but methods for analysing these data and seeing the bigger picture are also being devised.
Who can help most with this research?
Decisions have had to be made on whether the answers will come faster by working within families having several cases of MS, or by concentrating on people who have the illness whether or not there is a family history. Both can be useful, but in different ways.
Once identified, can the genes be fixed?
There is no possibility for gene therapy designed to insert a brand new set of “better” polymorphisms. In any event, these are healthy genes and are presumably doing a very good job in many other respects.
Is it only risky genes that cause this disease?
Clearly not: these are perfectly healthy structures and the susceptibility, or risk, is just that; something else has to happen that releases the effect of these genes. Triggers, presumably something environmental such as a virus, are what actually set off the disease process.
Sometimes the notion of genetic risk implies blame. Where did these genes come from?
The origins of MS are obscure but it seems to be more common in northern Europeans than other populations, and especially in Nordic peoples. The Vikings have been blamed for distributing the genes that increase the risk. They might have done so, but presumably those genes belonged to their predecessors and did not just appear out of the Northern Mists.
So, here is a mystery that is ripe for solution. Over the next few years, several international research groups are expected to re-screen the human genome with high expectations of finding some, if not all, the genes that contribute to MS susceptibility. The new knowledge is expected to provide even more revelations about disease mechanisms and perhaps help us direct specific treatments to the most responsive individuals. The knowledge will fill in the puzzle and make the big picture on MS ever easier to read, understand, and solve.
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