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Duke study may push research past gene mutations

By Jim Shamp, Herald-Sun

31 July 2003: DURHAM -- Common nutritional supplements given to mice at the Duke Comprehensive Cancer Center may be feeding a whole new understanding of what triggers disease and disability.

Duke scientist Randy Jirtle and research fellow Rob Waterland report in today's issue of Molecular and Cellular Biology that feeding the supplements to female mice not only changed the color of their mouse offspring's coat, but also protected them from obesity and related disorders such as diabetes and cancer.

It challenges scientists to broaden the way they've been searching for the origins of disease over the past couple of decades, beyond a focus on gene mutations. Instead of searching for "the obesity gene" or "the diabetes gene," researchers might be finding new answers in patterns of DNA-related activity, beginning with the first few cells after conception, Waterland said.

He and Jirtle gave mice dietary supplements -- vitamin B12, folic acid, choline and betaine -- before pregnancy and through lactation. The supplemented mice had babies predominantly with brown coats. Mice that didn't get the supplements mostly had babies with yellow coats, even though the mothers technically weren't deficient in the supplemented nutrients.

The health differences between the different-colored mice, however, were striking. The scientists found that cellular differences between the groups of baby mice created the change in coat color, all because the extra nutrients reduced the expression of a specific gene, called Agouti, which regulates yellow coat color and obesity. But the gene itself wasn't changed.

"To me, this is really amazing," said Jirtle, professor of radiation oncology at Duke and the study's senior investigator. "If your mother says eat your vegetables, do it. This is starting to show that we not only are what we eat, but we're also what our parents and grandparents ate."

Jirtle said even though it's no surprise that maternal nutrition and other environmental factors affect babies' health, this study explains for the first time how they can affect the way genes are expressed, or do their business, even if those genes remain unchanged.

The color changes in the mouse babies' coats were the result of a process called "DNA methylation," said Waterland, lead author of the study. That's the process that appears to involve many other genes that wreak such havoc as obesity, out-of-control cell growth in cancer, diabetes and possibly even autism, he said.

During DNA methylation, four atoms -- called a methyl group -- attach themselves to a gene to alter its function within a cell.

In the treated mice, the researchers said, one or more of the nutritional supplements caused the Agouti gene to become methylated, changing its ability to function. It all happened early in the development of the mouse embryos, Jirtle said, even before pregnancy was apparent.

Nutritional or other environmental effects that early in development can produce lifelong changes, he said -- including some that can be passed to future generations. Some of them may be beneficial, he said, like the obesity protection conferred to the brown mice. Others can be detrimental, such as the change in the Agouti gene in the yellow mice, which left them unable to understand when they'd eaten enough. It disabled their internal "satiety switch," Jirtle said.

"One of the things we need to do now is refine this model and see how generalizable it is," Waterland said. He noted that he and Jirtle still don't know which one or combination of the nutritional supplements created the changes in the experimental mice. They also want to know if other genes might be involved, and if the supplements caused any negative effects.

"You're going to see more of this kind of work," Jirtle said, "not just from our group, but from all over."

"At one time, this pursuit, called epigenetic, meaning before genetic, was put in the same category as metaphysics and pseudoscience by some researchers. But not anymore. It's real, and it's exciting."