Billy Rubin

The adventures of a pre-clerkship medical student.

Monday, October 02, 2006

And the award goes to...

Before I began this long journey called medical school, I did some graduate research for a couple years. A large chunk of my research used a technique called RNA Interference (RNAi). It's an amazing piece of technology which allows a researcher to selectively eliminate one gene product. It's like being able to thumb through a phone book and selectively erase one person. All the other names and numbers are left undisturbed except for that one. RNAi is essentially the magnet which allows you to remove the one needle from the haystack.

A simplied mechanism of RNAi is shown here. Put simply short sequences of RNA called small interfering RNA (siRNA) bind to a complimentary region of messenger RNA. This creates a double-stranded RNA which is detected by the cell and "sliced" up. The power of this tool is that the sequence of the siRNA is chosen so that it recognizes only one mRNA sequence. And in this way you selectively remove the mRNA before it is translated into protein/enzymes/etc.

The reason I bring this up is that this year's Nobel Prize in Physiology or Medicine went to Andrew Fire and Craig Mello for "for their discovery of RNA interference - gene silencing by double-stranded RNA". The press release describes their eureka moment:

Andrew Fire and Craig Mello were investigating how gene expression is regulated in the nematode worm Caenorhabditis elegans (Fig. 2). Injecting mRNA molecules encoding a muscle protein led to no changes in the behaviour of the worms. The genetic code in mRNA is described as being the 'sense' sequence, and injecting 'antisense' RNA, which can pair with the mRNA, also had no effect. But when Fire and Mello injected sense and antisense RNA together, they observed that the worms displayed peculiar, twitching movements. Similar movements were seen in worms that completely lacked a functioning gene for the muscle protein. What had happened?

When sense and antisense RNA molecules meet, they bind to each other and form double-stranded RNA. Could it be that such a double-stranded RNA molecule silences the gene carrying the same code as this particular RNA? Fire and Mello tested this hypothesis by injecting double-stranded RNA molecules containing the genetic codes for several other worm proteins. In every experiment, injection of double-stranded RNA carrying a genetic code led to silencing of the gene containing that particular code. The protein encoded by that gene was no longer formed.

After a series of simple but elegant experiments, Fire and Mello deduced that double-stranded RNA can silence genes, that this RNA interference is specific for the gene whose code matches that of the injected RNA molecule, and that RNA interference can spread between cells and even be inherited. It was enough to inject tiny amounts of double-stranded RNA to achieve an effect, and Fire and Mello therefore proposed that RNA interference (now commonly abbreviated to RNAi) is a catalytic process.

Fire and Mello published their findings in the journal Nature on February 19, 1998. Their discovery clarified many confusing and contradictory experimental observations and revealed a natural mechanism for controlling the flow of genetic information. This heralded the start of a new research field.

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