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Research in Multiple Sclerosis

 

Introduction

Over the last year, there have been over 1,500 articles published in medical journals on multiple sclerosis or animal models of the disease. The majority of these articles represent new research into MS, its causes, its mode of action or potential treatments for it. In addition, there has been an even greater amount of new research into cell biology, genetics, the immune system, other autoimmune, inflammatory and neurological diseases, virology and stem cell research - all of which give us a better understanding of the biological environment in which the disease operates.

It is impossible to sum up all of this research in a single essay and, for this reason, I intend to concentrate on those areas which seem to me to be particularly hopeful. This is, therefore, a personal view. This section will take a while to complete but I'm publishing it in installments.

There is no global authority coordinating the MS research effort. This is probably a good thing because it allows researchers to attack the problem from oblique angles and provide novel and unexpected insights into the disease. However, I intend to structure this article as if it were a progress report for just such a global research project. This project would group the research into four areas:

1. Finding the cause of multiple sclerosis
  • Genetic associations with MS
  • Viral and bacterial associations with MS
  • 2. Arresting the progress of the disease

  • Understanding the pathology of MS
  • Treatments that might stop the course of MS
  • Treatments that might slow the course of MS
  • 3. Repairing the damage already done by the disease

  • Remyelination strategies for MS
  • Stem cell treatments for MS
  • 4. Other Multiple Sclerosis Research

  • Treating the symptoms of MS
  • Understanding and assisting with the personal and social implications of MS
  • It seems to me that if the medical profession can achieve the first three of these goals, we can declare multiple sclerosis to be cured. I also consider this list to be in priority sequence - if we find out what causes the disease we will be not only be in a better position to stop the progress of the disease but we may also be able to prevent any new cases. After a single generation, it will become unnecessary to arrest the course of the disease because no one will suffer from it. Similarly, if we can stop the disease in its tracks, we will buy time to repair existing damage without ongoing progress destroying our efforts at repair.

    Of course, those of us who are already carrying significant deficits as a result of MS might wish to reorder these priorities. In any event, researchers are making significant progress in all these areas.

    Finding the Cause of Multiple Sclerosis

    Looking for the genes that convey a susceptibility to Multiple Sclerosis

    Introduction

    Recently, there has been a lot of interest in the genetics of complex diseases such as multiple sclerosis. The human genome has recently been mapped in its entirety and the hope is that this will allow researchers to isolate the genes for such diseases by statistical analysis of affected populations.

    Before looking into where new research into the genetics of multiple sclerosis is going, I think it's a good idea to summarise the background behind these studies.

    Background

    MS is known to cluster in some families and the risk of the disease is significantly increased for people who have close family members with the disease. People with MS have a 10% to 20% chance of having one or more affected relative which is much higher than one would expect for a disease that had no genetic component. Moreover, multiple sclerosis is significantly more common in certain racial groups (white northern Europeans) than others, even when controlling for latitude (another risk factor). The following graph summarises the increased familial risk (from Compston and Coles, 2001):

    Figure: Recurrence risks for multiple sclerosis in families. Data gathered from population based surveys (e.g. Sadovnick et al, 1993; Mumford et al, 1994; Ebers et al, 1995; Robertson et al, 1996; Robertson et al, 1996; Sadovnick et al, 1996 and Robertson et al, 1997.

    Further evidence for a genetic link comes from studies showing a common age of onset (and not date of onset) in families with more than one affected member [Doolittle et al, 1990 and Bulman et al, 1991]. This would seem to rule out a common environmental event such as a virus epidemic causing all the MS in any one family.

    However, it's known that genetics is not the complete story with MS. This is because people with identical genes (i.e. identical twins) both have MS in only 25% to 30% of cases [Sadovnick et al, 1993 and Mumford et al, 1994]. Such data show that MS is not a classical genetic disease in the way that sickle cell anaemia, cystic fibrosis or Huntingdon's disease are - people with these diseases always have a particular genetic configuration and people with that configuration always get the disease. With MS, there must be some, as yet unknown, environmental factor that also contributes to the risk of contracting multiple sclerosis.

    It would also seem that a susceptibility for developing MS doesn't involve individual faulty genes but would seem to involve several very common genes working in concert with each exerting a mild to moderate effect. This is because no genes have been found that are always present in people with multiple sclerosis and all the genes that are loosely to moderately associated with MS are also common in the general population. There seems to be no such thing as a gene for multiple sclerosis. Instead, susceptibility to MS would appear to be genuinely polygenetic with several different genes contributing to it.

    If all this were not confounding enough, it would seem that there are several different configurations of genes associated with multiple sclerosis. For example, one gene, called HLA-DR (DRB1*1501), has been repeatedly associated with MS [Olerup and Hillert, 1991 and MS Genetics Group, 1998] but not everyone with the disease has this gene. Conversely, HLA-DR (DRB1*1501) is common in caucasian populations. This same story would appear to be the case with all the other genes loosely associated with MS.

    Nor do genetics studies everywhere reveal the same pattern of gene association with MS. For example, studies in Sardinia seem to show that different HLA genes are associated with multiple sclerosis risk than in northern Europeans [Sotgiu et al, 2002 and Marrosu et al, 1988]. Comparative studies between Japanese and causcasian people with MS also show different gene frequencies in the two groups [Spurkland et al, 1991, and Begovich et al, 1980]. This and other data suggest that MS may be different diseases with similar presentations even in the same geographical location.

    And that's not the end of the puzzle either. Genetic changes can occur after conception - for example, the position of genes are shuffled around in the DNA to make the large repertoire of T cell receptors and antibodies needed to deal with the large number of potential viruses and bacteria that a person will be faced with. Further changes happen when retro-viruses insert their DNA back into the DNA of infected cells. Such changes are known as post-genomic changes. Because there is a large element of chance in such changes, it is unlikely that all the DNA in all the cells of identical twins is, in fact, identical.

    The following table summarises what we have discussed so far:
     

    1. Identical genes - different MS status
    2. Similar MS status - different genes
    3. Polygenetic - several different genes contributing to MS susceptibilty
    4. Different geographical locations - different genes associated with MS
    5. Post-genomic changes
    6. Is MS one or more than one disease?
    7. Unknown environmental factor(s)

    Where is MS genetic research going?
     
     

    http://www.vard.org/jour/02/39/2/baranzini.htm
    http://brain.oupjournals.org/cgi/reprint/121/10/1869.pdf
    http://www.medscape.com/viewarticle/413731
    http://www.medscape.com/viewarticle/417572
    http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobtype=pdf&artid=21725
    http://www.rosettabio.com/publications/docs/MS%20Paper%20(Nature%20Medicine%20May%202002).pdf
    http://www.faseb.org/genetics/ashg99/f1406.htm
    http://www.ucsf.edu/msdb/r_ms_candidate_genes.html
    http://www-gene.cimr.cam.ac.uk/MSgenetics/GAMES/Docs/Summary.doc
    http://www.jneurovirol.com/pdf/6(s2)/s10-s14.pdf
    http://www.jneurovirol.com/pdf/6(s2)/s15-s17.pdf
    http://www.msaustralia.org.au/conference/stewart_graeme_day4.pdf
    http://www-gene.cimr.cam.ac.uk/MSgenetics/GAMES/
    http://www.ucsf.edu/msdb/r_ms_genetic_disease.html
    http://www.mult-sclerosis.org/news/Apr2002/FullTextTheGeneticsOfMS.html

    HLA links:
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3263109&dopt=Abstract
    http://www.nationalmssociety.org/Research-Prat.asp

    quantitative trait loci (QTL) analysis - microarrays
     

    Viruses and Multiple Sclerosis

    http://www.mult-sclerosis.org/news/Jan2002/FullTextVirusesAndMS.html

    Arresting the Progress of Multiple Sclerosis
     
     

    Repairing the Damage Done by Multiple Sclerosis
     
     

    Other Multiple Sclerosis Research
     
     

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