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Tiny Couch Potatoes

– Christopher O’Carroll

Deborah Good’s mice are fat, lazy and undersexed (photo by Ben Barnhart) DEBORAH GOOD'S PARENTS HELPED HER set up a lab bench in the basement of her childhood home in upstate New York. “It was basically two sawhorses and a piece of plywood,” Good says of that early shrine to her passion for science. “It held my microscope and my encyclopedia set. I was a bit of a geek, I think. I had my microscope, I had a slide set, I had test tubes. I liked to read about science and think about science even when I was really young.” Nowadays, she works with a somewhat more sophisticated array of lab equipment. Breeding and studying generation after generation of genetically engineered mice, she zeroes in on the biochemical activity of genes that influence such fundamental body functions as diet, exercise and sexual behavior. She holds a patent on one chemical compound with anti-cancer potential and she has another patent pending. Since she joined the UMass department of veterinary and animal sciences in 1997, her genetics research has attracted more than a million dollars in grant support from the National Institutes of Health. When Good first contemplated a career in science, she did not picture herself operating at this high level – earning a Ph.D. and directing her own laboratory team at a major research university. “My parents didn’t go to college,” she explains. “My grandparents never went to college. I didn’t know anybody who was a professor.” She thought maybe she’d get a bachelor’s degree, then find a job as a medical technologist in a hospital lab. But the more she learned in her college science classes at SUNY Fredonia, the more her curiosity drove her to pursue studies at higher levels. She was intrigued by the new frontiers in genetics that were opening up when she was an undergraduate in the 1980’s, especially the “gene splicing” or recombinant DNA technology that made it possible to alter an organism by adding or subtracting specific genetic traits. In high school she had been interested in science across the board – biology, chemistry and physics – but by the time she graduated from college, she knew that she wanted to focus on cellular and molecular biology. As a graduate student at Northwestern, she got involved in a genetic study of tumor growth. The goal was to pinpoint the genes that control the growth of new blood vessels at tumor sites and to identify the factors involved in the expression of those genes. (A gene is said to “express itself” when it causes the body to manufacture a particular biochemical – a protein or enzyme, for example.) It was this research that led Good to her first patent, for a protein that suppresses blood vessel growth and thus helps starve tumors. “I loved what I was doing,” she says of that graduate school experience. “I wanted to continue in the field of cancer research.” So after completing her Ph.D., she took a position at the National Cancer Institute in Bethesda, Maryland. It was there that she first began working with genetically altered mice. Up to that point, her laboratory animal experience had mostly been limited to hamsters. “I liked hamsters as pets,” she says, “but I hated them as research animals. They bite. And they will hold on and clamp down. You have to wear metal mesh gloves to work with them.” Mice were a happy alternative. The genetically engineered animals Good uses in her research are known as knockout mice, because they’ve had a particular gene removed, or knocked out, from their DNA. By comparing a knockout mouse to an animal with a full set of genes, scientists can spot the missing traits and thus identify the function of the absent gene. The gene that Good has deleted from her mice goes by the catchy name Neural helix-loop-helix 2, Nhlh2 for short. (She has also done studies of the closely related Nhlh1 gene.) One of the most noticeable differences in mice born without Nhlh2 is that the males are endowed with such small penises that they look at first glance like females. In addition, the testicles of the males and the ovaries of the females are abnormally small. When the knockout mice reach breeding age, they show little interest in mating. “All sorts of fertility problems,” Good says. As if these reproductive issues weren’t burden enough for any rodent to bear, the knockout mice are also prone to obesity. They overeat, and they shun the exercise wheel, with the result that they balloon up to four times normal adult weight. Good is especially interested in the brain chemistry behind these physical abnormalities. She and her research team have traced Nhlh2’s activity to one small portion of the brain known as the hypothalamus. In this sliver of tissue located just above the pituitary gland, specialized brain cells express the Nhlh2 gene by manufacturing minuscule quantities of a surprisingly powerful protein known to scientists as a transcription factor. This protein stimulates other genes to express themselves in other regions of the brain, producing chemicals that activate the nervous system and send signals to various parts of the body. The brain signals governed by Nhlh2 appear to play a role in telling the reproductive system how to develop, and also in monitoring energy levels and alerting the body when it’s time to stop eating or start exercising. By studying how a single gene reaches out to touch such diverse biological functions, Good hopes to learn more about the details of gene expression, nervous system activity, and the complex ways in which groups of genes interact with one another. It is that basic research goal, a more complete understanding of how genes operate in the body, that motivates Good’s work. She plays down any suggestion that her work is about to produce, for example, a magic-bullet drug to combat obesity. Any such application of her work will come many years in the future, if it comes at all, she says. In the meantime, the best weight-control advice she can offer has nothing to do with esoteric laboratory research. “Eat less and exercise more,” she says with a broad grin. “When I do that, I lose weight.”

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Tiny Couch Potatoes

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