Worm created to be thin may hold genetic key to obesity
Published: Thursday, January 16, 2003 at 6:01 a.m.
Last Modified: Wednesday, January 15, 2003 at 9:41 p.m.
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 to identify about 400 genes in the roundworm's genetic code related to fat production and storage.
His team then deactivated 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.
"If someone told me we'd be using this kind of protocol even three years ago, I'd have said that's crazy," 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 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 will 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.
"The worm studies will allow the identification of many more genes much more rapidly. It'll also speed up the process of figuring out how they work," said Leon Avery of the University of Texas Southwestern Medical Center in Dallas, which is conducting its own fat gene experiments with roundworms. "For the drug companies, this means a much longer list of 'targets' that they can try to find drugs for."
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 foreign and destroyed that sequence in their own genetic coding. In doing so, the worms rapidly turned themselves into knockout versions.
The technique takes advantage of the roundworm's natural defenses against viruses.
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."
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