Scientists have manipulated hundreds of genes to create roundworms that are sleek and trim -- a feat that could someday lead to new obesity treatments for people.

Harvard biologist Gary Ruvkun used a promising new technique (RNA interference [RNAi] - gene knockouts) to identify 305 genes (body fat) and 112 genes (fat storage) in the roundworm's genetic code related to fat production and storage.

His team deactivated, or turned off, about 300 of the genes in experiments, and now ''the worms are thin and happy,'' Ruvkun said. When they knocked out the activity of the remaining 100 genes, worms grew fatter.

Details of the roundworm experiments and the new genetic technique appear in today's issue of the journal Nature.
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''If someone told me we'd be using this knockout gene protocol even three years ago, I'd have said that's crazy -- don't even think about it,'' Ruvkun said.

Scientists frequently conduct basic experiments with roundworms -- known by their scientific name as C. elegans -- because they are inexpensive and simple. Scientists can fit 100,000 on a lab dish, and they reproduce within four days. In October, British and American researchers shared the Nobel Prize in medicine for experiments using roundworms to study organ growth and cell death. Roundworms are about a millimeter long, with smooth, cylinder-shaped bodies tapered at both ends. In nature, they live in the soil and feed on bacteria.

The Harvard scientists disabled genes so that the bioengineered roundworms would have much lower fat levels than normal.

Humans share about half of the roundworm's 19,000 genes, including 200 of the fat-storage genes. Whether the same gene knockout technique would work in humans is unclear, but obesity drugs might be developed based on the basic understanding of the genes, Ruvkun said.

Other biologists cautioned that drug companies would need at least a decade to safely develop a genetic therapy for obesity. One in five Americans is obese, and obesity contributes to heart disease, diabetes and other illnesses.

Ruvkun used a novel gene identification method developed at the Wellcome Trust/Cancer Research UK Institute in England. Scientists study a gene by deactivating it and examining how the organism behaves. But creating that version of an organism is not always easy; scientists often need up to six weeks to create a knockout roundworm.

In the new method, British researchers added genetic material from a roundworm to bacteria. Then they fed the bioengineered bacteria to the worms. The worms' immune systems recognized the genetic material carried by bacteria as a foreign antigen and destroyed that sequence in their own genetic coding. In doing so, the worms rapidly turned themselves into knockout versions, where specific genes had been "knocked-out".

The technique takes advantage of the roundworm's natural immune defenses against viruses.  "The discovery that double-stranded RNA can trigger sequence-specific gene silencing  has led to the development of a powerful screening technique for functional analysis of the genome. Using this technique, called RNA interference [RNAi], loss-of function mutants have been prepared for about 86% of the predicted genes of the nematode Caenorhabditis elegans, a model system in which more than half of the genes have human homologues. A systematic survey of the C. elegans genome for the regulation of fat storage has identified 305 genes that cause reduced body fat and 112 that increase fat storage. Many of these genes encode proteins related to known receptors, transport channels and kinases that are good candidates for drug development." (Nature: 16 January 2003 Volume 421 No. 6920 pgs 193 - 294)

The method can be used for many genetic experiments beyond obesity. ''We can inactivate hundreds of worm genes in a day,'' said Julie Ahringer, a Wellcome Trust researcher. ``It's amazing.''