Vicki Chandler: Quiet Down Over There! The New Science of Silencing Genes

From grade school, we learned in biology how we inherit blue or brown eyes. Simple as A B C. It's that blue or brown-eyes gene, part of a recipe called DNA in our cells.

Now it turns out, it's not so simple. And what's really going on is much more dramatic.

Revolutionary is a label often applied to epigenetics, a relatively new science that studies patterns of gene regulation beyond the DNA. 'Downright exciting' is the phrase used by Vicki Chandler, BIO5 director and a plant geneticist in the Department of Plant Sciences, College of Agriculture and Life Sciences.

Part of the thrill, she says, is working on a frontier of basic science, getting to contribute to shaping some surprising elements of genetics theory. She also relishes her chance to take a risk that few scientists enjoy: doing experiments beyond the safe zone of most grant funding. She's using an outside-the-box research grant to extend her celebrated work in plant genetics to all living things.

At one end of her lab in BIO5's Thomas W. Keating Bioresearch Building, researchers work on human tissue. At the other end they work on maize and other plants, as models of genetic effects.

'You wouldn't know from the lab work whether they were working on plants or animals,' said Chandler, who is a University of Arizona (UA) Regents' Professor of Plant Sciences and Molecular and Cellular Biology. 'The same elements are in play: DNA, RNA, proteins. Very similar genetic pathways operate.'

What ties together her plant and animal studies, Chandler says, is a single theme, what she calls 'miss regulation of gene expression.' That bulky phrase explains what happens when cells go off in an odd direction, say, as coat color changes in mammals or when a plant alters its color.

Back to that basic biology. Those school biology classes told us our cells contain genes that hold the recipe for us, as for any organism. The recipe is passed to RNA, which works like an obedient waiter, delivering whatever the DNA orders. But there were always exceptions that scientists couldn't quite explain.

Now, experiments like Chandler's are showing how RNA is not simply an obedient waiter, but can direct changes by itself in determining what information in addition to DNA gets passed along to offspring. That's at the core of the fast-evolving field of epigenetics, in which Chandler has been a pioneer for two decades.

Chandler's newest work, bridging plant and animal gene expression, is funded by a National Institutes of Health Director's Pioneer Award, aimed at providing the freedom to explore risky, outside-the-box experiments.

A host of DNA and RNA mysteries are far from solved, but the old theory is looking a bit out of date in the Chandler lab.

'There were these things we've known about for decades, but couldn't explain, until now,' she says. 'One of my students likes to joke that we are doing the quantum mechanics of epigenetics.'

In any case, she says, 'This research blows the textbook paradigm. We are uncovering the unseen. It was always there but now we are learning how it works.'

Discover magazine cited Chandler's RNA experiments with corn, or maize, as among the top six scientific discoveries in 2006. It said her work was helping solve a perplexing phenomenon in genetics. Specifically, she found that a trait, a light-purple corn stalk instead of a dark purple corn stalk, was passed on to offspring but the gene sequence was the same in light and dark colored plants, and Chandler's work showed the change is mediated by RNA. The new trait can be passed down through many generations.

Just how RNA passes on those changes is still unexplained, but the findings may open new avenues for research applying epigenetics to many diseases, like cancer, diabetes, and certain neurological diseases.

For Chandler, her work with mammalian cells is a return to her roots. Chandler, who is a member of the National Academy of Sciences, began her career on the animal side, working on gene activation of mouse mammary tumor virus by steroid hormones. She was then working on her PhD in biochemistry at the University of California, San Francisco. Later at Stanford as a postdoctoral fellow, she was drawn to a new project in plant genetics, and worked on gene silencing through 12 years at the University of Oregon. She came to the UA in 1997 and became director of BIO5 in 2004.

At UA, on a recent day in her lab, graduate students were studying variation in the quantity of RNA and other proteins in corn. A rocking machine mixed a DNA solution on a bench near a polymerase chain reaction machine. A gel electrophoresis machine awaited it chance to reveal the RNA and DNA in tissue. Another graduate student stared at a computer screen. 'He's working on hypotheses to explain what he's observed, across several generations,' Chandler explained.

Chandler also collaborates with labs in three institutions in Mexico and with researchers in China and in the Netherlands.

She has used the pigment pathway in maize, Chandler says, because it offers a dramatic display of the RNA influence on the phenotype, or the feature observed in an actual organism. Her approach to molecular genetics is the standard one: first, prevent a gene from expressing itself, then examine the organism and learn what trait it controls. 'You silence it,' she says. 'Then you get a phenotype and you can deduce the function.' In nature, that 'on and off' function is critical, she says. 'Cancer can be caused by the ON state, or the OFF state of particular genes. This has always been going on, but now, at last, we are beginning to understand the diverse ways that gene expression can be altered.'

From blue or brown eyes to white tails on mice to shifting colors of corn stalks, the Chandler lab in helping explain the complex mosaic of epigenetic activity that makes us who we, and all creatures, really are.

Accomplishments

Since 2004, Vicki Chandler has been director of BIO5, an interdisciplinary research arm of the UA with more than 150 faculty members from agriculture, medicine, pharmacy, basic science and engineering.

As a researcher, she was selected in 2002 as a member of the National Academy of Sciences, the most prestigious scientific body in the U.S. Her selection recognized her work in gene regulation in plants and animals. In 2005, she became the first UA researcher to win the NIH Director's Pioneer Award. She has also won the Presidential Young Investigator Searle Scholar award.

She was named Arizona's 2007 Ed Denison Business Leader of the Award for leading partnership efforts by BIO5, faculty and industry.

Chandler is a Regents Professor in the UA departments of Plant Sciences and Molecular and Cellular Biology, and holds the Weiler Endowed Chair for Excellence in Agriculture and Life Sciences.