Worm People and RNAi Interference

2006 Nobel Prize for Medicine: Fire and Mello's discovery
="RNA interference – gene silencing by double-stranded RNA"= This Nobel Laureates have discovered a fundamental mechanism for controlling the flow of genetic information. Our genome operates by sending instructions for the manufacture of proteins from DNA in the nucleus of the cell to the protein synthesizing machinery in the cytoplasm. These instructions are conveyed by messenger RNA (mRNA). In 1998, the American scientists Andrew Fire and Craig Mello published their discovery of a mechanism that can degrade mRNA from a specific gene. This mechanism, RNA interference, is activated when RNA molecules occur as double-stranded pairs in the cell. Double-stranded RNA activates biochemical machinery which degrades those mRNA molecules that carry 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 may occur in plants, animals, and humans. It is part of the regulation of gene expression, participates in defense against viral infections, and keeps jumping genes under control.

=The flow of information in the cell: from DNA via mRNA to protein=

The genetic code in DNA determines how proteins are built. The instructions contained in the DNA are copied to mRNA and subsequently used to synthesize proteins. Proteins are involved in all processes of life, our genome consists of approximately 30,000 genes. However, only a fraction of them are used in each cell. Which genes are expressed is controlled by the machinery that copies DNA to mRNA in a process called transcription. It, in turn, can be modulated by various factors. Around 1990, molecular biologists obtained a number of unexpected results that were difficult to explain. The most shocking effects were observed by plant biologists who were trying to increase the colour intensity of the petals in petunias by introducing a gene inducing the formation of red pigment in the flowers. But instead of intensifying the colour, this treatment led to a complete loss of colour and the petals turned white! The mechanism causing these effects remained enigmatic until Fire and Mello made the discovery for which they received the Nobel Prize. =The discovery of RNA interference=

Andrew Fire and Craig Mello were investigating how gene expression is regulated in the nematode worm Caenorhabditis elegans. 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. 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 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.

=Benefits in biomedical research, gene technology and health care=

RNA interference opens exciting possibilities for use in gene technology. This method has already become an important research tool in biology and biomedicine. Several recent publications show successful gene silencing in human cells and experimental animals. For instance, a gene causing high blood cholesterol levels was recently shown to be silenced by treating animals with silencing RNA. Plans are underway to develop silencing RNA as a treatment for virus infections, cardiovascular diseases, cancer, endocrine disorders and several other conditions. Reference: Fire A., Xu S.Q., Montgomery M.K., Kostas S.A., Driver S.E., Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391:806-811.

Small Biography
Fire was born in Palo Alto, California and grew up in Sunnyvale, California. After graduating from Fremont High School, he attended the University of California, Berkeley, and received his B.A. in mathematics in 1978 when he was only 19 years old.

He applied to the Massachusetts Institute of Technology, where he was accepted and after 3 years of study, received a PhD in biology in 1983 under the mentorship of Nobel laureate Phillip Sharp. Fire moved to England for a few years. He became a Helen Hay Whitney Postdoctoral Fellow and also a member of the MRC Laboratory of Molecular Biology group directed by Nobel laureate Sydney Brenner.

From 1986 to 2003, Fire worked at the Carnegie Institution of Washington’s Department of Embryology in Baltimore. His work on double stranded RNA-gene silencing was published while Fire and his team were laboring at the Carnegie Labs. Fire had the chance to be a professor as well. He tought in the Biology Department at Johns Hopkins University since 1989 and later on joined the Stanford faculty of pathology in 2003. Throughout his career, most part of his work has been supported by research sponsors such as the U.S. National Institutes of Health. He is a member of the two prestigious learned societies:National Academy of Sciences and of the American Academy of Arts and Sciences. He serves on the Board of Scientific Counselors and on the National Center for Biotechnology, and National Institutes of Health.