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Advanced Information on The Nobel Prize in Physiology or Medicin 2006

RNA INTERFERENCE
This year’s Nobel Prize in Physiology or Medicine is shared by Professor Andrew Z. Fire at Stanford
University, California, USA, and Professor Craig C. Mello at the University of Massachusetts Medical
School in Worcester, USA. They receive the prize for their discovery that double-stranded RNA triggerssuppression of gene activity in a homology-dependent manner, a process named RNA interference
(RNAi). Their discovery revealed a new mechanism for gene regulation, and the biochemical machinery
involved plays a key role in many essential cellular processes. Double-stranded RNA synthesized within
the cell can reduce or abolish gene activity by RNAi-like mechanisms. This control system for geneexpression has proven to be important for both the development of an organism and the physiological
functions of cells and tissues. Furthermore, RNAi protects against RNA virus infections, especially in
plants and invertebrate animals, and secures genome stability by keeping mobile elements silent. Today,
double-stranded RNA is used as a powerful tool to experimentally elucidate the function ofessentially
any gene in a cell. The discovery of RNAi has already had an immense impact on biomedical research
and will most likely lead to novel medical applications in the future.

Introduction
The gene expression process is of fundamental importance for all living organisms. Most genes reside in the
chromosomes located in the cell nucleus and express themselves via proteins synthesised inthe cytoplasm.
The genetic material was identified as deoxyribonucleic acid (DNA) in 1944 (ref. 1) and the double-helical
nature of DNA was revealed in 1953 (by Francis Crick, James Watson and Maurice Wilkins; Nobel Prize in
Physiology or Medicine in 1962). At that time, the main problem outstanding was how DNA in the cell
nucleus could govern protein synthesis in the cytoplasm. It was proposedthat another nucleic acid, singlestranded ribonucleic acid (RNA), acts as an intermediary in the process, and the so-called Central Dogma
was formulated, i.e. the idea that the genetic information is transcribed from DNA to RNA and then translated from RNA into protein. The RNA carrying the genetic information was first believed to be the RNA
in ribosomes; for several years the hypothesis wasformulated as “one gene-one ribosome-one protein”. In
1961, Francois Jacob and Jacques Monod presented a visionary gene control model, for which they received
the Nobel Prize in Physiology or Medicine in 1965 together with André Lwoff. In their model, they proposed
that the gene is transcribed into a specific RNA species, messenger RNA (mRNA). Soon afterwards it was
demonstrated that ashort-lived, non-ribosomal RNA directs the synthesis of proteins. Subsequently, Marshall
Nirenberg and Gobind Khorana broke the genetic code and could assign code words (codons; triplets of nucleotides) to the twenty amino acids (they received the Nobel Prize in Physiology or Medicine in 1968 together with
Robert Holley). Francis Crick predicted that an RNA molecule could act as an adaptor between mRNAand the
amino acid, and a short, stable RNA, transfer RNA (tRNA) was soon identified as the predicted adaptor.
For many years, messenger RNA was believed to correspond to an uninterrupted nucleotide sequence in the
DNA. It therefore came as a complete surprise when Phillip Sharp and Richard Roberts showed in 1977 that
the mRNA sequence could be distributed discontinuously in the genome (the splitgene concept; Nobel Prize in
1993). It was known that long RNA molecules (pre-mRNA, heterogeneous nuclear RNA) are trimmed to much
shorter mature mRNAs, and Sharp and Roberts therefore suggested that the mRNA sequences, the exons, are
likely to be cut out from the primary transcript and spliced, while the intervening sequences, the introns, are
degraded. It was immediately realised that the...