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.
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
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.
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 [wormâ€™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.
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
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