【资源】The Nobel Prize in Physiology or Medicine 2006

The Nobel Prize in Physiology or Medicine 2006

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Press Release
2 October 2006
The Nobel Assembly at Karolinska Institutet has today decided to award
The Nobel Prize in Physiology or Medicine for 2006
jointly to
Andrew Z. Fire and Craig C. Mello
for their discovery of
"RNA interference – gene silencing by double-stranded RNA"

Summary

This year's Nobel Laureates have discovered a fundamental mechanism for contr
olling the flow of genetic information. Our genome operates by sending instru
ctions 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 Fir
e and Craig Mello published their discovery of a mechanism that can degrade m
RNA from a specific gene. This mechanism, RNA interference, is activated when
RNA molecules occur as double-stranded pairs in the cell. Double-stranded RN
A activates biochemical machinery which degrades those mRNA molecules that ca
rry a genetic code identical to that of the double-stranded RNA. When such mR
NA 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 import
ance for the regulation of gene expression, participates in defense against v
iral infections, and keeps jumping genes under control. RNA interference is a
lready being widely used in basic science as a method to study the function o
f genes and it may lead to novel therapies in the future.

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 c
ontained in the DNA are copied to mRNA and subsequently used to synthesize pr
oteins (Fig 1). This flow of genetic information from DNA via mRNA to protein
has been termed the central dogma of molecular biology by the British Nobel
Laureate Francis Crick. Proteins are involved in all processes of life, for i
nstance as enzymes digesting our food, receptors receiving signals in the bra
in, and as antibodies defending us against bacteria.
Our genome consists of approximately 30,000 genes. However, only a fraction o
f them are used in each cell. Which genes are expressed (i.e. govern the synt
hesis of new proteins) is controlled by the machinery that copies DNA to mRNA
in a process called transcription. It, in turn, can be modulated by various
factors. The fundamental principles for the regulation of gene expression wer
e identified more than 40 years ago by the French Nobel Laureates a target=_b
lank href=" http://nobelprize.org/nobel_prizes/medicine/laureates/1965/index.h
tml">François Jacob and Jacques Monod. Today, we know that similar pri
nciples operate throughout evolution, from bacteria to humans. They also form
the basis for gene technology, in which a DNA sequence is introduced into a
cell to produce new protein.
Around 1990, molecular biologists obtained a number of unexpected results tha
t were difficult to explain. The most striking 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 comp
lete 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 receive this year's Nobel Prize.

The discovery of RNA interference
Andrew Fire and Craig Mello were investigating how gene expression is regulat
ed in the nematode worm Caenorhabditis elegans (Fig. 2). Injecting mRNA molec
ules encoding a muscle protein led to no changes in the behaviour of the worm
s. The genetic code in mRNA is described as being the 'sense' sequence, and i
njecting 'antisense' RNA, which can pair with the mRNA, also had no effect. B
ut when Fire and Mello injected sense and antisense RNA together, they observ
ed that the worms displayed peculiar, twitching movements. Similar movements
were seen in worms that completely lacked a functioning gene for the muscle p
rotein. 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 si
lences 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, inje
ction 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 specifi
c 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 enou
gh to inject tiny amounts of double-stranded RNA to achieve an effect, and Fi
re and Mello therefore proposed that RNA interference (now commonly abbreviat
ed 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 experimenta
l observations and revealed a natural mechanism for controlling the flow of g
enetic information. This heralded the start of a new research field.

The RNA interference machinery is unraveled
The components of the RNAi machinery were identified during the following yea
rs (Fig 3). Double-stranded RNA binds to a protein complex, Dicer, which clea
ves it 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, cle
aved and degraded. The gene served by this particular mRNA has been silenced.


RNA interference – a defense against viruses and jumping genes
RNA interference is important in the defense against viruses, particularly in
lower organisms. Many viruses have a genetic code that contains double-stran
ded RNA. When such a virus infects a cell, it injects its RNA molecule, which
immediately binds to Dicer (Fig 4A). The RISC complex is activated, viral RN
A is degraded, and the cell survives the infection. In addition to this defen
se, higher organisms such as man have developed an efficient immune defense i
nvolving antibodies, killer cells, and interferons.
Jumping genes, also known as transposons, are DNA sequences that can move aro
und 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 anothe
r 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 t
he genome against transposons.

RNA interference regulates gene expression
RNA interference is used to regulate gene expression in the cells of humans a
s well as worms (Fig 4B). Hundreds of genes in our genome encode small RNA mo
lecules called microRNAs. They contain pieces of the code of other genes. Suc
h a microRNA molecule can form a double-stranded structure and activate the R
NA interference machinery to block protein synthesis. The expression of that
particular gene is silenced. We now understand that genetic regulation by mic
roRNAs plays an important role in the development of the organism and the con
trol 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 activate the silencing of
specific genes in humans, animals or plants (Fig 4C). Such silencing RNA mol
ecules are introduced into the cell and activate the RNA interference machine
ry to break down mRNA with an identical code.
This method has already become an important research tool in biology and biom
edicine. In the future, it is hoped that it will be used in many disciplines
including clinical medicine and agriculture. Several recent publications show
successful gene silencing in human cells and experimental animals. For insta
nce, a gene causing high blood cholesterol levels was recently shown to be si
lenced by treating animals with silencing RNA. Plans are underway to develop
silencing RNA as a treatment for virus infections, cardiovascular diseases, c
ancer, endocrine disorders and several other conditions.

Reference:
Fire A., Xu S.Q., Montgomery M.K., Kostas S.A., Driver S.E., Mello C.C. Poten
t and specific genetic interference by double-stranded RNA in Caenorhabditis
elegans. Nature 1998; 391:806-811.

Andrew Z. Fire, born 1959, US citizen, PhD in Biology 1983, Massachusetts Ins
titute of Technology, Cambridge, MA, USA. Professor of Pathology and Genetics
, Stanford University School of Medicine, Stanford, CA, USA.
Craig C. Mello, born 1960, US citizen, PhD in Biology 1990, Harvard Universit
y, Boston, MA, USA. Professor of Molecular Medicine and Howard Hughes Medical
Institute Investigator, Program in Molecular Medicine, University of Massach
usetts Medical School, Worcester, MA, USA.