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Fat Attackers (video)
April 01, 2003

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Interviewees: Eric Schadt, Rosetta Inpharmatics; Stephen Friend, Rosetta Inpharmatics.

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Produced by Joyce Gramza

Copyright © ScienCentral, Inc., with additional footage courtesy Merck & Co., and UCLA.

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Elsewhere on the web

Some Cases of Obesity Caused by a Single Gene - Reuters

CDC Overview of Obesity

Human Genome Research

It’s not just one gene, but many genes that can cause obesity.

As this ScienCentral News video reports, genetics researchers are studying obesity, and the results may help drug designers create more effective treatments.

Divide and Conquer

Some diseases are caused by one gene. But more common are "complex" diseases—like cancer, heart disease, diabetes, and obesity—that are caused by many genes or sets of genes. Now geneticists have demonstrated that they can subdivide obesity into different genetic causes. The study was published in the journal Nature.

Researchers at Rosetta Inpharmatics, a subsidiary of the pharmaceutical company Merck collaborated with university scientists to combine clinical and gene sequence information with new gene chip experiments to find different groups of genes that underly obesity.

"What we want to be able to do is subtype individuals who have a particular disease," says Eric Schadt, Director of Research Genetics at Rosetta, "because these different subtypes may require different treatments to be effective."

Rosetta collaborated with UCLA geneticists Jake Lusis and Thomas Drake. They bred mice so that the geneticists knew details about their genetic inheritance. They fed the mice a high-fat diet, "a Western diet that was meant to simulate the type of diet that a lot of people [in] the United States and Europe are eating these days—high in fat, high in cholesterol," explains Schadt. They examined them clinically over time for obesity traits such as weight, length and amount of fat.
Then they tested tissue samples from both mice that stayed lean and those that got obese using high-tech “gene chips,” or microarrays. Gene chips gather information about gene activity or “gene expression”—in other words, which genes are turned on or off.

By studying the patterns of gene expression in the mice, Schadt and his team were able to see differences in the genes of the obese and lean mice, and identify genes that were associated with either obesity or leanness. Then they found they could also separate the obese mice into two groups based on their distinct patterns of gene expression.

Schadt explains, “They looked the same, clinically they were obese, but their gene expression patterns said something differently, and that was that they were being controlled by different genes. Their obesity was a result of different causes.”
It might be revealed that some people are obese because their genes are affecting the rate at which they metabolize food, and others because their genes are affecting their perception of hunger, explains Schadt.

Treating the Cause

These discoveries are leading to a different way to treat many diseases, which some call “personalized medicine.”
“Up until now, diseases such as depression and obesity have been assumed to be similar for everyone,” says Stephen Friend, president of Rosetta and a senior vice president at Merck. “Once we know that it is a particular type of obesity that a patient has, it becomes possible to identify the target that allows one to make a drug against that component of that disease.

"More importantly," says Friend, "the chance that you could discover a drug that would work in an individual, work in an actual patient, and have a higher probability of working, is much higher once you’ve broken down a broad disease into the real diseases that were inappropriately clustered as one before.”

Zeroing in on the genes that cause obesity will enable patients to be treated based on the cause of their disease, not the symptom. Clinical trials can be done more quickly and safely, because every person in a trial won’t be given the same treatment. Patients can be assigned to treatment groups and given drugs that are likely to be effective for them and won’t cause adverse reactions.

Further studies into the possible roles these obesity genes play in the formation of fat are underway at UCLA. According to the American Obesity Association, approximately 60 million adults in the U.S. are obese, and 9 million are severely obese.

by Karen Lurie

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