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Nobel Prize in Medicine 2006
Nobel Prize in Medicine 2006
jointly to
mRNA
SM CYTOPLA
When a protein is to be formed, single-stranded messenger RNA is made as a copy of one of the strands of DNA (transcription). mRNA moves from the nucleus to the cytoplasm where the information is decoded (translation). Proteins are formed in ribosomes.
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mRNA
SM CYTOPLA
In RNA interference, RNA in doublestranded form breaks down the mRNA for a specific gene, thus stopping production of protein.
dsRNA
RISC
One of the RNA strands is eliminated, while the other serves as a search probe and links RISC to an mRNA molecule.
RISC
mRNA
The gene for which the mRNA is a messenger has been silenced and no protein is formed.
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cally modified to ripen more slowly than usual has been created in this manner. But attempts to use antisense RNA experimentally in animals have not been equally successful. Sometimes the method has worked, sometimes it has not, and it turned out to be difficult to get consistent results when experiments were repeated. Around 1990, a series of observations were obtained that were difficult to explain. The most puzzling findings were reported by plant scientists who were trying to intensify the hue of red petunias. They inserted a gene that controls formation of red pigment but in some Plant scientists wanted to make petunias cases the result was that the flowers lost their even more beautiful by enhancing the red color altogether! It turned out that the mRNA of the petals. But sometimes the flower lost for the pigment had disappeared. The cause of all its color! these unexpected effects remained enigmatic until the discoveries of Andrew Fire and Craig Mello solved the riddle.
C. elegans
In the 1990s, Andrew Fire and Craig Mello were studying how gene expression is regulated in C. elegans. Among other things, they were examining mRNA that encodes a protein involved in the nematodes ability to move. They injected the nematode gonads with sense RNA (a molecule identical to a segment of mRNA). This had no visible effect on the nematodes or on their offspring. Fire and Mello injected other nematodes with antisense RNA that could bind to the corresponding mRNA for the muscle protein, and again nothing happened. But when they injected a mixture of sense RNA and antisense RNA, the nematode offspring moved in an odd, twitching fashion. Similar movement patterns could be seen in nematodes with a defective muscle protein gene. What was the explanation for this surprising finding?
Sense RNA Antisense RNA Double-stranded RNA
Neither injection of sense RNA for the muscle protein nor of the corresponding antisense RNA had any effect. But after simultaneous injection of both sense and antisense RNA (which bind to each other and form double-stranded RNA) the nematode offspring showed the same twitching movements as nematodes whose muscle protein gene was defective.
Parent
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Dicer
MicroRNA gene
We have hundreds of different genes that encode small RNA (collectively, microRNA) whose precursors can form doublestranded RNA. These can activate the RNA interference process and thus switch off the activity of various genes with matching segments.
RISC
MicroRNA
RISC
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Dicer
dsRNA
RISC
Virus
Primitive organisms use RNA interference to protect themselves from virus infections. Double-stranded RNA from a virus activates the protein complexes Dicer and RISC and the infection is stopped.
RISC
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Dicer
dsRNA
RISC
Scientists can now tailor double-stranded RNA molecules to activate RNA interference. This makes it possible to turn off specific genes. In the future it may be possible to use this technique to treat diseases.
RISC
mRNA degraded
Medical applications?
The discovery of RNA interference raised hopes for improved treatment of many different disorders, including viral infections, cardiovascular diseases, cancer and metabolic disorders. In many diseases, certain genes are over-expressed (that is, overactive), and it might be possible to alleviate these disorders by suppressing the activity of specific genes. It is conceptually attractive to use RNA interference to treat diseases: RNA interference is a natural mechanism and double-stranded RNA is an endogenous substance. RNA interference unlike antisense techniques has also been shown to give reproducible results. In addition, double-stranded RNA molecules can easily be synthesized. So far no drugs based on RNA interference have been approved, but successful animal experiments have been performed and several substances are being tested in clinical trials in humans. For example, double-stranded RNA is being tested as a means to treat agerelated degeneration of the fovea (neovascular or wet macular degeneration). This condition is common among elderly people and can severely reduce the eyesight. Blood vessels grow into and damage the fovea, the part of the retina that gives the sharpest image. One important cause of vessel growth is a substance called VEGF (vascular endothelial growth factor). If double-stranded RNA corresponding to the mRNA for VEGF is injected into the eye, this can decrease the amount of the growth factor and prevent new vessels from invading the fovea.
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Promising experiments
RNA interference is also being tested as a method to combat RS virus, which can cause severe respiratory infections in small children. The principle behind the treatment is that when the child inhales double-stranded RNA, viruses in the lung will be inactivated and the infection will be terminated. To date, one study has been carried out on healthy human volunteers and the treatment did not have any serious side-effects. Many RNA interference studies on animals and in cell cultures are also currently ongoing. In a recent study on animals (rodents and monkeys), double-stranded RNA was successfully used to silence a gene that leads to high cholesterol levels. Experiments have also been performed, in human cells, where RNA interference has been found to reduce the activity of the AIDS virus HIV. Although many experiments with RNA interference have yielded promising results, quite a few problems remain to be solved to make this treatment work optimally. For example, we have to be able to get the double-stranded RNA molecules into the right type of cell and the right number of those cells. It must also be possible to control treatment so the double-stranded RNA is active for the appropriate length of time. Andrew Fire and Craig Mello have been awarded the Nobel Prize for their discovery of a central mechanism of gene regulation. The future will show whether their finding will contribute to the development of new treatment strategies it looks promising.
The Laureates
Andrew Fire, born in 1959, is a US citizen. Since 2003 he has been professor of Pathology and Genetics at Stanford University School of Medicine, Stanford, California, USA.
In 1983 he took his PhD in Biology at the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. He began his research on the nematode C. elegans during his time as visiting scientist in Cambridge, England, at the laboratory of Sydney Brenner (Nobel Laureate 2002). When Fire and Mello made their key discoveries about RNA interference, Fire was working at the Carnegie Institution of Washington.
Craig Mello, born in 1960, is a US citizen and a professor of Molecular Medicine. Since 1994 he has worked within the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. He is also a Howard Hughes Medical Institute Investigator. In 1990 he took his PhD in Cellular and Developmental Biology at Harvard University, Boston, Massachusetts. Before he moved to the University of Massachusetts Medical School in Worcester, he worked at the Fred Hutchinson Cancer Research Center.
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R.CARLIN/UMMAS
L. CICERO/STANFORD
For further reading A. Fire, S.Q. Xu, M.K. Montgomery, S.A. Kostas, S.E. Driver & C.C. Mello: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391:806-811. Information online: http://nobelprize.org The editorial committee for this years popular presentation of the Nobel Prize in Physiology or Medicine included the following, who are professors at Karolinska Institutet and members of the Nobel Assembly: Bertil Daneholt, Gran K. Hansson, Hans Jrnvall and Nils-Gran Larsson Text: Anders Nystrand, MD and medical writer Illustrations: Annika Rhl, graphic editor Translation: Janet Holmn, editor
2006 The Nobel Committee for Physiology or Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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