Two Americans share Nobel Prize in medicine for controlling genes

By Matt Moore
ASSOCIATED PRESS

6:38 a.m. October 2, 2006

STOCKHOLM, Sweden – Americans Andrew Z. Fire and Craig C. Mello won the Nobel Prize in medicine Monday for discovering a powerful way to turn off the effect of specific genes, opening a potential new avenue for fighting diseases as diverse as cancer and AIDS. The process, called RNA interference, also is being studied for treating such conditions as hepatitis virus infection and heart disease. It already widely used in basic science as a method to study the function of genes.
Fire, 47, of Stanford University, and Mello, 45, of the University of Massachusetts Medical School in Worcester, published their seminal work in 1998.
RNA interference occurs naturally in plants, animals and humans. The Karolinska Institute in Stockholm, which awarded the $1.4 million prize, said it is important for regulating the activity of genes and helps defend against viral infection.
“This year's Nobel laureates have discovered a fundamental mechanism for controlling the flow of genetic information,” the institute said.
Erna Moller, a member of the Nobel committee, said their research helped shed new light on a complicated process that had confused researchers for years.
“It was like opening the blinds in the morning,” she said. “Suddenly you can see everything clearly.”
Genes produce their effect by sending molecules called messenger RNA to the protein-making machinery of a cell. In RNA interference, certain molecules trigger the destruction of RNA from a particular gene, so that no protein is produced. Thus the gene is effectively silenced.
For instance, a gene causing high blood cholesterol levels was recently shown to be silenced in animals through RNA interference.
The prize for Mello and Fire came remarkably quickly after they did the work. Nobels are generally given decades after the research they honor.
Mello, reached at his home in Shrewsbury, Mass., said the award came as a “big surprise.”
“I knew it was a possibility, but I didn't really expect it for perhaps a few more years. Both Andrew and I are fairly young, 40 or so, and it's only been about eight years since the discovery.”
He said he would try to get to work Monday but expected to accomplish “not a lot.”
Fire, reached in California, said he was awakened by a call from the Nobel committee.
'At first I was very excited.... Then I thought I must be dreaming or maybe it was the wrong number,” he said. But then he confirmed the good news by checking the Nobel Web site.
“It makes me feel great. It makes me feel incredibly indebted at the same time,” he said. “You realize how many other people have been major parts of our efforts.”
Fire conducted his research while at the Washington-based Carnegie Institution.
The announcement opened this year's series of prize announcements. It will be followed by Nobel prizes for physics, chemistry, literature, peace and economics.
Last year's medicine prize went to Australians Barry J. Marshall and Robin Warren for discovering that bacteria, not stress, causes ulcers.
Alfred Nobel, the Swedish inventor of dynamite, established the prizes in his will in the categories of literature, peace, medicine, physics and chemistry. The economics prize is technically not a Nobel but a 1968 creation of Sweden's central bank.
Winners receive a check, handshakes with Scandinavian royalty, and a banquet on Dec. 10 – the anniversary of Nobel's death in 1896. All prizes are handed out in Stockholm except for the peace prize, which is presented in Oslo.

Associated Press Writer Brooke Donald in Los Angeles contributed to this report.

On the Net:
Nobel Foundation: nobelprize.org/

I've been optimistic about RNAi and hope the clinical applications don't take too darn long. The process can be controlled, maybe easier than ES cells.


Human Molecular Genetics 2004 13(Review Issue 2):R275-R288; doi:10.1093/hmg/ddh224

RNA interference: from model organisms towards therapy for neural and neuromuscular disorders

From the article:

RNA interference (RNAi) is a powerful new gene knockdown technique that permits tissue-specific, temporally controlled suppression of gene expression.......

Gene knockdown by RNAi is temporary, but can be rendered stable by transfecting target tissues or cell lines so that they express dsRNA autonomously. Such expression can be constitutive or under the control of an inducible promoter, allowing the experimenter to induce knockdown at a specified time.

Some non-specific RNAi effects have been reported (5), but with appropriate controls and physiological follow-up experiments RNAi has quickly become one of the most potent tools of modern reverse genetics. The versatility of the technique has led to a number of exciting applications. For instance, RNAi can be used in drug/chemical target validation. RNAi can target specific spliced exons, enabling the investigation of the functional roles of alternatively spliced forms of a gene. Furthermore, one of the most exciting opportunities offered by RNAi is the ability to identify all candidate genes required for certain physiological processes using genome-wide RNAi screens.....

PARKINSON'S DISEASE

Where a disorder results from a reduction in gene expression, RNAi can be used to mimic gene function loss. Parkinson's disease, for example, is associated with loss of dopaminergic neurons, and as with SMA, RNAi will be an important approach for exploring the molecular mechanisms underlying Parkinson's disease.

Recently, this approach has been used in combination with overexpression studies to explore the role of Parkin, an E3 ubiquitin ligase, in dopamine neuron degeneration in Drosophila.

Overexpression of Parkin was shown to degrade its substrate (Pael-R) and suppress its toxicity, whereas interfering with endogenous Parkin promoted substrate accumulation and augmented its neurotoxicity (111).

Viral-mediated RNAi has been used (112) to block dopamine synthesis in mid-brain neurons of adult mice. This study used an adeno-associated virus vector in which a U6 promoter drove the expression of shRNA directed against tyrosine hydroxylase, an enzyme required for the production of dopamine.

This was injected stereotactically into the substantia nigra of one side of the brain and a similar vector promoting the expression of a randomized shRNA injected into the other side.

GFP expression was observed in both halves of the brain, but dopamine staining was reduced only in the side of the brain into which the anti-tyrosine hydroxylase shRNA had been injected.

The resultant behavioural deficits included loss of motor performance: bilateral shRNA knockdown of dopamine synthesis resulted in reduced motor activity in response to amphetamine (a well-established dopamine-dependent behaviour) and poorer performance in the rotarod test.

Although only 30–40% protein knockdown was reported, these results are similar to previously established toxin-induced models of dopaminergic neuron loss, suggesting that RNAi-induced knockdown of dopamine synthesis furnishes a reasonably faithful model of Parkinson's disease.

http://hmg.oxfordjournals.org/cgi/co...3/suppl_2/R275