Monday, January 09, 2006

RNA interference

2006 started out rather badly for me, as I was sick as a dog when the ball dropped (specifically, a dog with an adenovirus infection). Now a week later I feel mostly better, but I'm still coughing a good bit, especially when I try to go to sleep. Anyways this has gotten me interested in current research for curing diseases, and in particular a new technique that I had heard about for the first time earlier in 2005: RNA interference. It is a very neat technique that has apparently been around for hundreds of millions of years in eukaryotes - helping them to fight viruses and aiding in gene regulation - but we only discovered it existed quite recently.

Here's the idea. In general a virus will slither up to a healthy cell and insert it's genetic code (either DNA or RNA) into it, and this code will then instruct the cell's ribosomes to produce the proteins needed to construct many more copies of the virus. Some viruses belong to the double stranded RNA (dsRNA - see virus classification) group, which insert complementary strands of their RNA into the cell, and many other viruses use dsRNA during their life cycle. The presence of dsRNA in a cell is a sign of viral attack, since the normal messenger RNA (mRNA) produced in the nucleus is single stranded, and fittingly it is this dsRNA that the cell's RNA interference mechanism uses to fight back against the viral infection. When the Dicer enzyme finds a long dsRNA segment, it will cut out a short chunk from it, around 20 base pairs long, thus destroying the original dsRNA (the short excised segments are called small interfering RNA - siRNA). Furthermore, other proteins will then join with the siRNA segment, forming a RNA-induced silencing complex (RISC). The RISC molecule becomes activated when one half of the siRNA double strand is peeled off (which requires some energy to break the hydrogen bonds). Now the activated RISC will check with other messenger RNA strands, and if it finds a sequence that complements it's own siRNA strand then it will chop that mRNA segment in two, destroying it. Thus introducing a dsRNA segment that corresponds to a particular gene into a cell will result in the suppression of that gene, a surprising result if one doesn't know about the mechanism that lies behind it (as it was at first - gene therapies that were intended to increase the purple pigmentation in petunias ended up producing white flowers...).

RNA interference should allow for all sorts of great targeted attacks against the bacteria and viruses that stalk us. Any pathogen that attacks us will necessarily use genes that we don't - thus we should be able silence those genes, and the illness as well, by introducing the corresponding dsRNA segments. That said, while initial trials have shown promising results and more are in the pipeline, we probably won't see widespread RNAi therapies for another 10 or so years, as they will have to go through FDA approval and so forth. In the near term the most exciting aspect of RNAi will be it's use in decoding the genome: essentially by targeting one gene at a time and turning it off with RNAi and seeing the resulting effects in the cell, you can figure out what that gene does.

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