From Worm Genes, Human Obesity Clues
By NICHOLAS WADE
Published: 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 roundworm.
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 method.
''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.
Chart/Diagram: ''Switching Off Fat Genes (in Worms)'' Scientists have found that strands of RNA, delivered via bacteria to the tiny soil roundworm C. elegans, can be used to suppress genes functions, including fat storage. It may provide clues to obesity in humans. From Worm Genes, Human Obesity Clues GENE SPLICE -- A section of the worm gene is inserted into a plasmid, a structure for carrying genes into bacteria. DELIVERY -- Inside the bacteria, the plasmid makes a double-stranded RNA version of the gene. The bacteria are fed to the worm. GENE TURNED OFF -- The double strands of RNA provoke the cell to attack RNA of the same sequence, which inactivates the target gene. 17,000 bacteria types were made, one for each gene. C. elegans is favored for study because it is fast growing and translucent, which makes its development easy to observe. Diagram of worm gene highlighting the following: GENE (DNA) PLASMID dsRNA BACTERIA APPROX. ACTUAL LENGTH: 1 MILLIMETER