- The Washington Times - Wednesday, January 15, 2003

In the unabating battle of the bulge, geneticists using a cutting-edge screening technique said Wednesday they have gotten the skinny on hundreds of fat regulators in an animal model for human obesity.

The genetic weight watchers came to light in the first comprehensive survey to sift through an organism's entire set of genes in search of all those involved in determining the body's fat content.

The identification of more than 400 suspects in the tiny roundworm Caenorhabditis elegans, which shares a substantial number of genes with humans and other mammals, has important implications for understanding — and treating — obesity, a potentially life-threatening condition affecting more than 300 million people worldwide, scientists said.

The landmark results, reported in the Jan. 16 issue of the British journal Nature — which need to be corroborated by further tests — point to tantalizing treatment targets for pharmaceutical companies developing drugs for obesity, diabetes and other related diseases, researchers told United Press International.

The analysis was made possible by, and bespoke the power of, a system pioneered on the new frontier of functional genomics, said study leader Gary Ruvkun, professor of genetics at Harvard Medical School and Massachusetts General Hospital in Boston.

The technique enabled one scientist, Harvard University postgraduate fellow Kaveh Ashrafi, to accomplish in two years what would have taken 200 researchers two decades to complete with classical genetics methods, Ruvkun said in a telephone interview.

Having deciphered the cryptic codes of man, mouse, worm, fly and other organisms in recent years, scientists now face an even greater, and more important, challenge: figuring out what all those newly identified genes do.

"Understanding what every gene does will help us to develop more specific therapeutics," cellular biochemist Thomas Tuschl told UPI. This month, Tuschl transfers from the Max Planck Institute for Biophysical Chemistry in Germany to The Rockefeller University in New York City.

In pursuit of that goal, researchers have devised a system — reported in Nature in a second paper by many of the same authors — that takes advantage of the roundworm's unusual eating habits, and a technique called RNA interference, to provide each gene with a job description.

In a painstakingly executed investigative tour de force, the researchers designed a library of more than 16,000 bacteria strains, each of which can turn off, or "silence," a specific gene. They fed the microbe meals to the worms and observed any changes ensuing from the corresponding gene's shutdown.

"The worms eat the bacteria … silencing the gene in the worm and her progeny," Julie Ahringer, of the Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology at the University of Cambridge in England, told UPI. "We optimized this … technique and then worked out methods to efficiently engineer the large number of bacterial strains needed (one for each gene)."

Ahringer's group used the method to render inactive 16,757 — or 85 percent — of the worm's predicted 19,757 genes. From their observations of the results, the investigators gauged the roles of 1,722 of the genes. Two-thirds of these functions previously were unknown.

The technique provides a much faster, less laborious and more practical alternative to the traditional method of analyzing gene function, which involves examining the development of animals with a mutated gene. This agonizingly arduous and time-consuming process is not feasible on a global scale, Ahringer noted.

"One way of finding out what genes do is to inactivate them, and to study the effects, in 'model' organisms," said Tuschl, who analyzed the findings. "That has now been done for many thousands of worm genes in two large-scale analyses."

By scrutinizing the effects of turning off, one by one, nearly 17,000 roundworm genes, Ashrafi and colleagues identified 417 that seem to determine how fat is stored and used in C. elegans, the first animal to have its inheritance instructions interpreted. They found 305 genes that reduce body fat and 112 that increase it.

"We identified a number of worm genes that are related to mammalian genes that had already been shown to be important in body weight regulation," Ashrafi said. "But more important, we identified many new worm fat regulatory genes whose human counterparts we believe will play key roles in human fat regulation as well."

The discovery slims down significantly the list of weight-stimulating suspects in the human gene set, investigators asserted.

"This study is a major step in pinpointing fat regulators in the human genome," Ruvkun said. "Of the estimated 30,000 human genes, our study highlights about 200 genes as likely to play key roles in regulation of fat levels. For now at least, we can ignore the other 29,800 genes and look at the 200 to see whether there's a gold nugget or two," he told UPI. "I think there will actually turn out to be around 10 among them."

If so, the "nuggets" could serve as targets in efforts to trim the world's expanding waistline, researchers said.

The number of cases of obesity — a complex condition with severe, even fatal, health consequences — has ballooned since the 1960s, with no signs of abating. In the United States, substantially overweight adults number some 60 million men and women, exacting a heavy cost in lives — 300,000 each year — and expenditures — some $100 billion in health care annually, the American Obesity Association reports.

More than 127 million Americans fall into the overweight or obese category. The former is defined as having a Body Mass Index — a weight-height ratio — of between 25 and 29.9, while the latter exceeds 30 on the BMI scale.

With the worm fat regulators identified, researchers now can zero in on the human versions. Of the 200 human counterparts revealed by the study, some produce proteins already used in drug formulations, making them particularly appealing to a high-risk, high-cost industry that favors the tried and true, scientists said.

In further tests, the researchers homed in on 70 core fat regulators that, when inactivated, reduced fat levels dramatically in the worms without affecting their health. The scientists hope these encouraging findings hold up in humans.

The researchers also found some of the genes regulating fat levels in all strains of C. elegans and others could only affect fat in certain worm obesity syndromes caused by brain defects. This is significant, they said, because even at this early stage of understanding, in the complex regulation of human fat, the brain's key role already is clear.

Studies indicate signals from fat cells, such as the much-publicized hormone leptin, are sensed by cerebral regions to control feeding — an ability that falls short in some obese people with a seemingly insatiable appetite. Even in the usual middle-age spread, the difference between staying slim or gaining 20 pounds over 20 years is a matter of a mere one part in 1,000 of the food intake-energy balance, scientists pointed out.

"A non-obese person eats exactly what he or she metabolizes whereas a run-of-the-mill obese person eats 0.1 percent too much," Ruvkun noted. "This highlights the fine tuning of our consumption of food to our energy balance. Subtle defects in the control of feeding by our brains and the complex interplay between our brain and our fat are the root cause of most obesity."

With the majority of worm genes now tested and classified, the new screening method offers a more systematic way of discovering fat regulatory genes, researchers said. The new approach beats the traditional, cumbersome and less comprehensive method that relies on genetic mapping of individuals and their families.

Now, any researcher can use this bacterial library to carry out new screens to study specific biological questions.

Scientists already have availed themselves to the quick reference source in studies of aging, just as Ruvkun's group relied on the information to screen for genes involved in fat metabolism.

The new data and associated library will accelerate progress in understanding a wide range of biological processes, leading to insights into the genetic underpinnings of human disease, development and behavior, scientists said.

"Together, their work sets a new standard for systematic, genome-wide genetic studies," Tuschl said.


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