NYTimes.com Article: From Worm Genes, Human Obesity Clues

khare@alumni.caltech.edu khare@alumni.caltech.edu
Thu, 16 Jan 2003 19:51:32 -0500 (EST)

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has been sent to you by khare@alumni.caltech.edu.

Fascinating... in DNA as in software, the oldest features are the most critical and fragile; the newest ones are the flakiest and optional. 

The double-strand RNA hack could stand to be better explained... anyone? 



>From Worm Genes, Human Obesity Clues

January 16, 2003


Biologists have laid a new basis for studying human obesity
by identifying almost all the genes that regulate fat
storage and metabolism in a small animal, the laboratory

The finding should provide leads to the many unknown genes
that regulate fat storage in people and to the defects in
the genes that underlie many obesity cases. 

It is also a landmark in studying genomes, because this is
apparently the first time that almost all of an animal's
genes have been inactivated in a single experiment. The
technique for creating "knockout" mice, strains missing a
single gene, is invaluable in biomedical research, but it
takes months to generate each strain. 

The fat genes were identified by feeding the roundworms
17,000 strains of bacteria, their favorite food. Each
strain contained a chemical that inactivated a different
gene. The researchers at the Massachusetts General
Hospital, Dr. Kaveh Ashrafi, Dr. Gary Ruvkun and
colleagues, monitored changes in fat storage as each gene's
activity was suppressed. They found 305 genes whose
inactivation reduced body fat and 112 genes whose loss led
to extra fat, they report today in Nature. 

A library of gene-inactivating bacteria was painstakingly
constructed over two years by Dr. Julie Ahringer, an
American biologist working at the University of Cambridge
in England. The library, which she said would be made
freely available to academic researchers, can be used to
screen the worm's genome for any quality of interest. 

Although roundworms, not related to earthworms, and people
are different, they shared a common ancestor just 600
million years ago, and many genes in the two species have a
similar sequence of DNA units and similar function. The
researchers say 100 fat-regulating genes in worms have
counterpart genes in people. 

"We would certainly be looking very interestedly at these
genes as human candidate genes for obesity," said Dr.
Steven O'Rahilly, an expert on obesity genetics at
Addenbrookes Hospital in Cambridge. 

Dr. Jeffrey Friedman of Rockefeller University, who
discovered the gene for leptin, a central player in human
fat metabolism, described the report as "a lovely piece of
work" and said there would be "a tremendous opportunity in
following up the genes they identify." 

As it happens, the roundworm does not have a gene for
leptin or the specialized fat cells, known as adipocytes,
in which human lard is stored. But Dr. Friedman said that
did not diminish its relevance as a model of human fat
storage, because adipocytes, and probably leptin, too, were
an evolutionarily recent invention that came in with
backboned animals. 

Though the epidemic of obesity in the United States is of
recent origin, and so might seem to have a nongenetic
cause, Dr. O'Rahilly noted that the average weight gain has
been merely 10 pounds. Although that makes millions more
people qualify as obese, it is a very small shift compared
with the 50- to 400-plus-pound human weight range allowed
by the genes. 

"You have to conclude that internal biological determinants
are greater than social and environmental factors," he
said, meaning that he expects genes will turn out to have a
decisive role in human obesity. 

The technique for inactivating the worm's genes one by one
builds on the recent discovery that animal and human cells
will destroy RNA, a close chemical cousin of DNA, when they
encounter it in the form of a double strand. That is a
defense against certain viruses that store their genetic
information as double-strand RNA. So if a cell is exposed
to double-strand RNA with the same sequence of units as one
of its genes, that gene will be suppressed. 

Dr. Andrew Z. Fire of the Carnegie Institution of
Washington recently found that double-strand RNA could
simply be fed to roundworms and that it would somehow
escape digestion and suppress their genes. Learning of the
discovery, Dr. Ahringer decided to build a library of
bacterial strains, each of which carried double-strand RNA
to inactivate a different gene in the worm's genome. 

"A lot of people tried to talk us out of doing it," she
said. But the Wellcome Trust of London put up the money.
She and colleagues copied short DNA segments from each of
the worm's 19,000 genes. They then inserted each DNA
segment into bacteria along with genetic signals that made
the bacteria synthesize a double-strand RNA version of the
inserted gene. About 17,000 bacterial strains repressed the
target genes. 

Dr. Ahringer and colleagues used the library to see which
genes could be inactivated without doing much harm to the
worm and which were so vital that they killed or deformed
it. In her article, also published today in Nature, she
reported that the very ancient genes, which the worm shares
with plants and fungi, are also the most essential. Their
loss is lethal. The more recently acquired genes, which
confer animal functions like moving, are less critical and
the worm can in many cases survive without them. 

RNA inactivation is a new tool that scientists are learning
how to use. Double-strand RNA can be injected in mice and
will directly suppress target genes. No one knows whether
RNA could be used directly as a drug to suppress errant
genes in people. There may be other and better drugs to
affect the fat storage genes now identified by the RNA

"It's a long step to a therapeutic target," Dr. O'Rahilly
said. But the Massachusetts experiment "provides us with a
set of new molecules to look at, one of which might turn
out to be exciting." 

In another paper, Dr. Ruvkun and Dr. Ahringer have used the
RNA method to screen the worm's genome for genes that
increase longevity. With two of the six chromosomes tested,
they have found that genes in the mitochondria, the
energy-producing structure, are particularly important in
determining life span.


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