Classic Discoveries: Gene Silencing And The Discovery Of RNA Interference Print E-mail
Science - Genetics & Genome
Written by TS-Si News Service   
Sunday, 17 August 2008 16:30
Nematodes
 
Return to the RNAi World: Rethinking Gene Expression and Evolution
 
While investigating the genetic workings of the microscopic worm, C. elegans, Craig C. Mello and colleague Andrew Fire, PhD, of the Carnegie Institution of Washington, discovered RNAi, a natural but previously unrecognized process by which a certain form of RNA can be manipulated to silence—or interfere with—the expression of a selected gene.
 
Mello and Fire were awarded the Nobel Prize in Physiology or Medicine in 2006.
 
The discovery, published in the journal Nature in 1998, has had two extraordinary impacts on biological science.
 
• One is as a research tool: RNAi is now the state-of-the-art method by which scientists can knock out the expression of specific genes in cells, to thus define the biological functions of those genes.
 
• But just as important has been the finding that RNA interference is a normal process of genetic regulation that takes place during development.
 
RNAi has provided not only a powerful research tool for experimentally knocking out the expression of specific genes, but has opened a completely new and totally unanticipated window on developmental gene regulation. RNAi is now showing promise in the clinic as a new class of gene-specific therapeutics.
 
The accompnying video is of a Google Tech Talk session conducted by Craig C. Mello on 9 April 2007. Video and abstract courtesy of Google. Time 01:08:54
Washington, DC, USA. A fundamental mechanism inhibits gene expression during translation or hinders the transcription of specific genes. Called RNA interference (RNAi), it targets RNA that is significant for some forms of our innate immune response and plays a key role in regulating development and genome maintenance.
 
RNAi has a selective and robust effect on gene expression, making it an essential research tool in cell culture and living organisms. The introduction of synthetic dsRNA into cells can induce the suppression of specific genes. Large-scale screens that systematically shut down each gene in the cell use RNAi to help identify the components necessary for a particular cellular process or an event such as cell division.
 
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Andrew Fire, SiQun Xu, Mary K. Montgomery, Steven A. Kostas, Samue E. Driver and Craig C. Mello. Nature 391 806-811 (19 February 1998). doi: 10.1038 / 35888  [ Download PDF ]
 
However, this was a hard won understanding. Prior to 1998, there were a number of research findings, generally inconclusive and/or inconsistent, that were suggestive but non-definitive. It took the findings from beautiful experiments, published in Nature (Citation, 1998), to clear up the confusion and set biology onto an important new path.
 
Craig C. Mello (b. 18 Oct 1960) and Andrew Z. Fire (b. 27 Apr 1959), of the Carnegie Institution of Washington [N1], were awarded the 2006 Nobel Prize for Physiology or Medicine for the discovery of RNA interference.
 
Craig C. Mello (b. 18 Oct 1960) and Andrew Z. Fire (b. 27 Apr 1959), of the Carnegie Institution of Washington [N1],  were awarded the 2006 Nobel Prize for Physiology or Medicine for the discovery of RNA interference.
 
C. elegansThe Nobel citation, issued by Sweden's Karolinska Institutet, said the Nobel Laureates "… discovered a fundamental mechanism for controlling the flow of genetic information."
 
 
Mello and Fiore showed that RNA plays a key role in gene regulation by demonstrating in detail how RNA can be manipulated to interfere with — or silence â€” a selected gene's expression.
 
The cell destroys the gene's messenger RNA (mRNA) before it can produce a protein. This effectively shuts down specific genes. A type of RNA transcribed from the genome itself, microRNA (miRNA), works in the same way.
 
The word seminal applies here: this one piece of work opened up an enturely new field in biology, bringing on a revolution in our understanding of biological processes and regulation, including quality control feedback loops and the basis for anomalous birth conditions.
 
Craig Mello revisited the subject of RNAi in a Google Tech Talk [N2]. Please refer to the sidebar for details and a video of the session.
 


[N1] The Carnegie Institution of Washington is now known as the Carnegie Institution of Washington.

In 1902, Andrew Carnegie founded the Institution as a vehicle for scientific discovery. His stated intention was to provide a home to exceptional individuals — men and women with the imagination and extraordinary dedication capable of working at the cutting edge of their fields.

[N2] According to Google, Google TechTalks are designed to disseminate a wide spectrum of views on topics ranging from Current Affairs, Science, Engineering, Humanities, Business, Law, Entertainment, Medicine, and the Arts.

 


Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Andrew Fire, SiQun Xu, Mary K. Montgomery, Steven A. Kostas, Samue E. Driver and Craig C. Mello. Nature 391 806-811 (19 February 1998). doi: 10.1038 / 35888  [ Download PDF ]

Abstract

Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene. Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts. RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression. Here we investigate the requirements for structure and delivery of the interfering RNA. To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually. After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference. The effects of this interference were evident in both the injected animals and their progeny. Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.

 
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Last Updated on Sunday, 17 August 2008 15:15