RNA Trades Bit Part for
Starring Role in the Cell
 
by Andrew Pollack
The New York Times

In the family of genetic material, RNA has long been the poor cousin of DNA. DNA makes up the genes, the master instructions of life, while RNA merely conveys those instructions to other parts of the cell.

But surprising new discoveries are showing that cells contain an army of RNA snippets that do much more than act as DNA's messenger. The discoveries are helping to refine the prevailing theories of genetics or even upend them.

"It's like discovering the neutrino or something," said Dr. Gary Ruvkun, a professor of genetics at Harvard Medical School. "These things were all around us for many years," and no one was aware of them. "Now we're discovering they are all over the place," he added. "Genomes are full of them."

The discoveries are having practical applications. Scientists have found that tiny snippets of RNA with two strands instead of the usual one can be used to shut off specific genes. The technique, known as RNA interference, is being widely used to discover the functions of genes by turning them off and seeing what happens to the plant or animal.

In a paper published in Nature on Thursday, Dr. Ruvkun and his colleagues at Harvard and Massachusetts General Hospital used RNA interference to turn off almost all of a worm's genes, one at a time, to discover those linked to obesity. Doctors hope that RNA interference will one day be used for medicine, inactivating genes, say, in tumors or viruses.

"This is a gift from heaven," said Dr. Phillip A. Sharp, a Nobel laureate and a professor of biology at the Massachusetts Institute of Technology. He is also a founder of Alnylam Pharmaceuticals, one of several companies started to exploit RNA interference. Many other companies are trying to develop drugs based on other aspects of RNA.

Dr. Stuart Peltz, chief executive of PTC Therapeutics in South Plainfield, N.J., said RNA had become "sort of a huge discovery zone." PTC is developing drugs that influence the way RNA works.

Scientists have recently reported that Prader-Willi and Fragile X syndromes, each leading to mental retardation, and chronic lymphocytic leukemia may be linked to RNA defects. Biologists studying other species are also looking to RNA for answers to unsolved mysteries.

"Everybody wants to look in their favorite organism or favorite system and see if there's an RNA lurking there," said Dr. Susan Gottesman, chief of biochemical genetics at the National Cancer Institute, who studies E. coli bacteria. "A lot of the regulatory puzzles in E. coli are explained by small RNA's we didn't think were there."

Dr. Larry Gold

Qu3-D RNA Folds and Molds Like a Key for a Specialized Work By ANDREW POLLACK New York Times RNA is not only a tape, but a shape. Most scientists view RNA as a tape, a string of letters of the genetic code. The important thing is the information it holds. But it turns out that RNA can also fold into three-dimensional shapes that can bind to something like a protein by shape, as a key fits in a lock. That is important because proteins in a cell bind to one another by shape, and drugs often work by fitting into their target by shape. For instance, a popular area of biotechnology now is monoclonal antibodies, which can be made to order to fit a particular shape of a target. So several companies have sprung up trying to develop products that either bind to RNA by shape, or to use shaped RNA to bind to proteins. These shapely RNA's are called aptamers. "Whatever you can do with an antibody you can do with an aptamer," said Dr. Larry Gold, a discoverer of aptamers, who has long spoken of tape versus shape. It is possible using gene synthesis machines to make trillions of random RNA segments and let them fold into their natural shapes. Then, the target can be mixed in to see which pieces of RNA stick. While aptamers were discovered more than a decade ago, progress has been slow, in part, Dr. Gold conceded, because he did not license his patents out to enough scientists and companies. But that could be changing. A company called Archemix was formed in 2001 in Cambridge, Mass., to develop aptamers as drugs. Dr. Gold runs SomaLogic, a company in Boulder, Colo., that is trying to make diagnostic devices using aptamers to detect specific proteins. So far, the only aptamer drug to reach clinical trials has shown the ability to improve vision in some patients with macular degeneration, the leading cause of blindness in the elderly. The aptamer binds to and neutralizes a protein that promotes the growth of the leaky blood vessels in the eye that cause the disease. Pfizer Inc. recently agreed to pay Eyetech Pharmaceuticals of New York as much as $745 million for rights to the drug. And now, nature too has been found to exploit RNA shapes. Dr. Ronald R. Breaker, a biochemist at Yale, recently found that certain RNA, by virtue of shape, binds to vitamins B12, B1 and riboflavin in bacteria and other organisms. Folded bits of RNA appear to be used to regulate the levels of the vitamins in the organism. Dr. Breaker thinks such "ribo-switches," as he calls them, exist in all organisms, including humans. "People don't give RNA enough credit," Dr. Breaker said. "It was supposed to be incapable of doing these exotic functions. Proteins are supposed to be the complex molecules, not RNA." ."

RNA and DNA are strings of chemical units called bases that embody the genetic code. The bases are represented by the letters A, C, G and either T in DNA or U in RNA. The C base always binds to G. A binds only to T or U. So a single strand of DNA or RNA can bind to another strand that has the complementary bases.

Under what is known as the central dogma of genetics, genes, which are the recipes for making proteins, are part of the DNA of the chromosomes. When a protein is to be made, the DNA is copied onto a corresponding piece of single-stranded RNA, known as messenger RNA, that delivers the recipe to the cell's protein-making machinery. Proteins make up most of a cell and perform most of its functions, including turning genes on and off.

But new evidence suggests that some RNA is not merely the intermediary between DNA and protein, but the end product. Some huge stretches of DNA that do not contain protein-coding genes and have been considered "junk" actually hold the code for some of this RNA.

A study published in May by scientists at Affymetrix of Santa Clara, Calif., a maker of gene chips, reported that in addition to the DNA's containing the recipes for proteins, a lot more DNA was being copied into RNA.

The recently deciphered mouse genome was found to have about twice as much in common with the human genome as could be accounted for by protein-coding genes. Areas of the genome that are similar are thought to have important functions, explaining why they have not mutated as species evolved. At least part of this overlap appears to be genes that produce RNA as their end product.

What all of this RNA is doing is not clear, and much of it may have no function. Dr. Sean Eddy, a researcher at Howard Hughes Medical Institute at Washington University, said cells might just be sloppy, turning far more DNA into RNA than they needed. But mounting evidence suggests that at least some RNA is involved in regulating the way genes are turned on or off.

Dr. John S. Mattick, a molecular biologist at the University of Queensland in Australia, holds the most radical view: that RNA provides the command and control of cells.

Proteins, Dr. Mattick said, are like bricks and beams. But the RNA determines whether those bricks and beams become office buildings or houses. This RNA network, he said, provides the complexity that separates higher life forms from simpler ones.

"People have totally misunderstood the nature of genetic systems in higher organisms," he said. "This will probably turn out to be the greatest failure in the history of molecular biology."

Most scientists say Dr. Mattick's views, although intriguing, are not backed by much evidence. Rather than upending the central dogma, they say, the new findings just add some tenets.

It has long been known that RNA is more than a messenger. The ribosome, which makes proteins, is made partly of RNA. Another type of RNA, called transfer RNA, aids in protein production. Some scientists say it is not surprising that RNA has multiple roles, because it is generally believed that RNA had the role of both proteins and DNA in the early days of life on earth.

"We still have a lot of remnants from that," said Dr. Stephen R. Holbrook, a scientist at the Lawrence Berkeley Laboratory.

The recent excitement has been generated by two discoveries related to small RNA snippets and their ability to turn off genes.

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