RNA interference:

2006 Nobel Prize in Physiology or Medicine to
Andrew Z. Fire – (
born 1959, PhD in Biology 1983, Massachusetts Institute of  Technology.
  Now a Professor of Pathology and Genetics, Stanford University School of Medicine).
and Craig C. Mello - (born 1960, PhD in Biology 1990, Harvard University. Now a Professor of
  Molecular Medicine and Howard Hughes Medical Institute Investigator, Program in Molecular
  Medicine, University of Massachusetts Medical School)

for their discovery of
RNA interference – gene silencing by double-stranded RNA"

     In 1998, the American scientists Andrew Fire (MIT) and Craig Mello (Harvard) published their discovery of a mechanism that can degrade mRNA made by a specific gene. This mechanism, RNA interference, is activated when RNA molecules occur in double-stranded form in the cell. Double-stranded RNA activates a biochemical machinery which degrades those single stranded mRNA molecules carrying a genetic code identical to that of the double-stranded RNA. When such mRNA molecules disappear, the corresponding gene is silenced and no protein of the encoded type is made. RNA interference occurs in plants, animals, and humans. It is of great importance for the regulation of gene expression, participates in defense against viral infections, and keeps jumping genes under control.

     Fire and Mello were investigating gene expression in the nematode worm Caenorhabditis elegans (Nobel Committee Fig. 1). Injecting the normal mRNA molecules (sense RNA) that encodes a muscle protein in the nematodes led to the normal muscle protein and no changes in the behavior of the worms (Nobel Committee Fig. 2). Injecting 'antisense' RNA, the compliment of the normal mRNA, but which can pair with the normal mRNA, also had no effect. But when Fire and Mello injected the paired, double stranded, sense and antisense RNA together, they observed that the worms displayed peculiar, twitching movements. Similar twitching movements were seen in worms that completely lacked the normal functioning gene for this muscle protein. What had happened?

     The sense and antisense RNA molecules met, bound to each other and formed a double-stranded RNA and that double-stranded RNA molecule silenced the gene’s mRNA 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 specific mRNA’s 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 revealed a natural mechanism for controlling the flow of genetic information, which heralded the start of a new research field.

     The mechanism of how RNAi work naturally in cells preventing the translation of normal mRNA was worked out over the next several years (Nobel Committee Fig. 3).  Double-stranded RNA binds to a protein complex, Dicer, which cleaves the dsRNA into fragments. Another protein complex, RISC, binds these fragments. One of the RNA strands is eliminated, but the other remains bound to the RISC complex and serves as a probe to detect mRNA molecules. When an mRNA molecule can pair with the RNA fragment on RISC, it is bound to the RISC complex, cleaved, and degraded. The gene served by this particular mRNA has therefore been silenced.

RNA interference – a defense against viruses and jumping genes:  RNA interference is important natural defense against viruses, particularly in lower organisms. Many viruses have a genetic code that contains double-stranded RNA. When such a virus infects a cell, it injects its RNA molecule, which immediately binds to Dicer (Nobel Committee Fig. 4).  The RISC complex is activated, viral RNA is degraded, and the cell survives the infection. Jumping genes, also known as transposons, are DNA sequences that can move around in the genome. They are present in all organisms and can cause damage if they end up in the wrong place. Many transposons operate by copying their DNA to RNA, which is then reverse-transcribed back to DNA and inserted at another site in the genome. Part of this RNA molecule is often double-stranded and can be targeted by RNA interference. In this way, RNA interference protects the genome against transposons.

RNA interference regulates gene expression:     RNA interference is used to regulate gene expression in the cells of humans as well as worms (Nobel Committee Fig. 4b). Hundreds of genes in our genome encode small RNA molecules called microRNAs. They contain pieces of the code of other genes. Such a microRNA molecule can form a double-stranded structure and activate the RNA interference machinery to block protein synthesis. The expression of that particular gene is silenced. We now understand that genetic regulation by microRNAs plays an important role in the development of the organism and the control of cellular functions.

New opportunities in biomedical research, gene technology and health care: RNA interference opens up exciting possibilities for use in gene technology. Double-stranded RNA molecules have been designed to silence specific genes in humans, animals or plants (Nobel Committee Fig. 4c). Such artificially-made silencing RNA molecules are introduced into the cell and activate the RNA interference machinery to break down mRNA with an identical code. This method has already become an important research tool in biology and biomedicine. Several successful gene silencing experiments in human cells and animals have been accomplished. For instance, a gene causing high blood cholesterol levels was recently shown to be silenced by treating animals with a silencing RNA. Plans are underway to develop silencing RNA as a treatment for virus infections, cardiovascular diseases, cancer, endocrine disorders and several other conditions.