May 29, 2003 

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Worm Fat (video)
January 15, 2003

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Interviewee: Kaveh Ashrafi, Massachusetts General Hospital.

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Produced by Joyce Gramza

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What can fat worms tell us about why people get fat? Plenty.

As this ScienCentral News video explains, geneticists writing in the journal Nature report they've identified hundreds of genes that appear to make worms either fat or slim. And this may lead to big new anti-fat drugs.


Genome-wide search

Geneticists work with model animals like the nematode worm C. elegans because they are quicker to breed, their genes are easier to manipulate, and they are much less expensive than animals like mice. Still, finding even a single gene that may be important in human health can take years.

Now, researchers at Massachusetts General Hospital have identified hundreds of genes that regulate obesity in the microscopic worm, and found many human counterparts of those genes.

"A typical case is that you might spend about two years and you might identify one gene that got mutated and it results in the particular thing that you're interested in," says the report's lead author Kaveh Ashrafi, of the Ruvkun lab at MGH.

"I was able to go through an entire genome in about six months or so... and find hundreds of genes."

To accomplish this feat, the scientists combined some exciting new techniques. They used a hot new genetics trick called "RNA interference" or "RNAi," to turn off individual worm genes. While genes are encoded by sequences of DNA, they are expressed by being translated into corresponding sequences of RNA. Scientists can create specific sequences of RNA that they can introduce into cells to prevent the expression of specific genes. Since scientists have the worm genome sequence, they could create an RNAi for every worm gene.

"Our collaborators in England constructed, in a pretty heroic effort, a huge RNAi library that systematically contains almost every known or predicted gene that the worm's body encodes," Ashrafi says. "So one by one, I could go through 17,000 genes and try to knock out each one of them and see what happens to the body weight of the animal."

To get the RNAi's into worm cells, they put them into E. Coli bacteria, the normal diet of lab worms. "What works really beautifully is that these interfering RNA's, they are actually expressed in the E. Coli that are fed to the animals," Ashrafi says. "And amazingly, that works well enough to inactivate the [worm’s] genes."

To see what happened to the worms' body fat as a result of inactivating a specific gene, the lab invented a new chemical trick—a fluorescent dye that makes fat glow under UV light. They just added the dye to the worms' food.

"So the animals are growing the way they normally do, genes are being inactivated, and I just have to take the animals under UV fluorescence and look at the amount of fat they have," explains Ashrafi.

They identified some 400 worm genes that seem to regulate body fat—about 300 genes that reduced body fat when they were turned off, and 100 that increased body fat when turned off. When they searched the human genome sequence, they found that more than half of these worm genes corresponded to human genes, many of which had never been linked to human obesity.

Gary Ruvkun, the lab's leader, says this information will make the jobs of drug developers and researchers who study human obesity much easier. "It's really setting up a hierarchy," says Ruvkun. "It says, OK, don't look at all 30,000 genes (in the human genome), look at these 100 genes."

Ruvkun says many of the genes seem to affect metabolism and fat storage, but many others appear to control communication signaling pathways in the worm. Those pathways may influence obesity and lifespan by affecting sensations like hunger, satiety, and even, Ruvkun says, happiness.

"The idea of being well-fed and satisfied with your place in the world is something that we are studying," he says. "And by identifying all these genes, we are identifying how it is that the periphery of our bodies communicates with our brains to actually tell our brains that we're doing a good job of feeding."

The research was funded by the National Institute on Aging and The Wellcome Trust.



by Joyce Gramza


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