July 25, 2010

summer in Buffalo 2010

As of yesterday, I completed a 7-week research internship at the Jacobs Neurological Institute in Buffalo. If you asked me what I knew about Multiple Sclerosis on June 5th, I would have told you what we had touched upon in Physiological Psychology - basically that it was an autoimmune disease that severely impacts the central nervous system. Over the past month and a half, my knowledge of the disease - and the field of clinical research in general - has been expanded by leaps and bounds.

My original assignment was to assess the recent advancements in the field, and the future directions that research should take. At the conclusion of the internship, the only material I could physically produce was a 1500-word review paper on the pharmacogenomics and pharmacogenetics of MS. My initial feeling was one of disappointment - I couldn't believe that it had taken me 5 weeks to write 1500 words. But when I realized how far I had come in my understanding of the pharmacogenomics of MS, my feelings of disappointment were mollified.

I've read - and understood (!!) - between 30 and 40 primary research papers written since the beginning of 2010 on everything from miRNA (micro RNA) assays, post-translational modification studies, GWAS (genome-wide association studies) to the use of animal models with EAE (experimental autoimmune encephalomyelitis). These are just some of the ways in which researchers have been attempting to further understand both the susceptibility and severity factors of MS in the past few years.

While there are so many interesting things I have learned - some of which I will post about at a later date - I think the most prevalent and intriguing pieces to the MS puzzle are the links we have made to the individual genome. Given that I am boarding a flight back home in a mere 5 hours, I only have the time to talk about one of my favorites for now:

For the past few years it's been widely accepted that, the HLA-DRB1 gene, encoding for the HLA class II histocompatibility antigen DRB1-9 beta chain protein, is associated with MS susceptibility. Just this year, researchers have furthered this belief by proving that the presence of oligoclonal bands in the CSF is significantly associated with the presence of the HLA-DRB1 genotype in a West Australian cohort (Wu, et al. 2010). This was the first study ever to show that HLA-DRB1 allele interactions and dose-effects influence the frequency of oligoclonal bands**. Wu, et al. went a step further to target HLA-DRB1*1501 as not only a strong determinant of MS risk, but also as a predictor of MS severity as measured by the MSSS (MS Severity Score). Furthermore, the HLA-DRB1*1201 allele was linked to less severe cases of the disease. Another study (Zivkovix, et al. 2009) concluded that, specifically, the tag SNP for HLA-DRB1*1501 (rs313588) is present in significantly higher frequencies in MS patients compared to control subjects.

Before heading off to sleep in anticipation of my long-awaited departure from Buffalo, I think it's worth it to mention another study which ties into the above discoveries. In 2008, Hoffman et al. found that the HLA-DRB*1401 and HLA-DRB1*0408 alleles are strongly associated with the development of antibodies against interferon-beta MS therapy. I wonder if this means that they would both be linked to more severe cases of MS? Would that mean that the HLA-DRB*1501 allele also has more antigenic properties in response to IFN-beta? Cool stuff. For a genomics nerd at least...

**http://library.med.utah.edu/kw/ms/mml/ms_oligoclonal.html The presence of OCBs in the CSF usually indicates immunoglobulin production in the CNS, suggesting a case of MS in the patient (as seen on the right)

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