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Putting DNA to Work as a Biomedical Tool

Science: Caltech chemist's molecular machines might someday target viruses or cancer cells.

December 29, 1997|K.C. COLE | TIMES SCIENCE WRITER

Jacqueline Barton is on intimate terms with DNA, the master molecule of life. She knows its secret crevices, weird loops, strange digressions and switchbacks. When she talks about DNA, her hands trace its imaginary contours, lovingly, like a sculpture. They slice through the air, showing how the "steps" in the DNA ladder stack up on each other like a pile of coins.

She pokes at a huge plastic DNA model in her office to show how it jiggles, probes it like a doctor palpating a patient. Her fingers follow an imaginary electron moving through the strand.

She also gets her hands on the real thing, working amazing tricks on the spiraling double-helix that encodes all the genetic instructions for life.

The chemist churns it out in her Caltech lab, tailor-made, one link at a time. She fits it out with fancy metallic propeller blades that slide into its creases like tongues. She dresses it up in fluorescent lights, like a Christmas tree--each glow signaling a specific "word" in the genetic instructions. She attaches molecular-sized alligator clips to the ends of a DNA chain, moving electrons from one end to another like a current.

There's a purpose to this play. Barton wants to use her inventions for medicinal purposes, as made-to-order molecules that could kill viruses and perhaps someday prevent, or even cure, cancer.

"DNA-based pharmaceuticals," she calls them.

While other researchers manipulate DNA to alter genes or kill cancer, her pioneering approach relies on tiny metal-based molecular machines of her own design--machines that have the potential to change the way scientists approach this all-important molecule.

Radiation's Effect on DNA

Her most recent and controversial work has focused on trying to find out what happens when DNA gets damaged by radiation from the sun, or gamma rays from outer space--something that happens every day. Does the radiation do damage at the spot where it strikes, like lightning striking an open field? Or does the damage somehow travel down the DNA strand to a specific, most sensitive, site--like lightning traveling down a telephone pole and into a house?

Her tentative answer is yes, it can travel.

If she's right, the finding might lead to methods for targeting dangerous bits of dividing cancer cells for destruction.

"It would be like the remote control on your TV," she says. "You do something from a distance, but you still have a measure of control over what you're doing."

This concept has not been popular with many researchers who haven't traditionally believed that electrons could travel easily from one spot on DNA to another. What's more, they think Barton is stepping dangerously over disciplinary lines. After all, she's an inorganic chemist, a specialist in metals assumed to have little to do with life.

"I probably didn't realize what a crazy idea this was [to some other scientists]," she says.

It's a radically different way to think about DNA. As a chemist, Barton is interested in the architectural structure of the master molecule. She studies its properties--like electrical conductivity--as if it were an inorganic crystal, such as a piece of a rock or a semiconductor in a cell phone.

Like many scientists, she's taken some flak for going against the grain. But risks are part of the bargain, she says, and she takes criticism in stride.

"When you rattle the foundations, people get nervous," she says. "But at places like Caltech, it's OK to go out on a limb. It's OK to have an idea proved wrong. I'm supposed to be pushing the boundaries."

Her work has earned an impressive array of awards. She was the first woman to win the prestigious Nichols medal (14 winners have gone on to win the Nobel Prize), the first woman to win the National Science Foundation's Waterman Prize (known as the junior Nobel Prize), and the first woman given a chair--the Hanische Chair--at Caltech. She also has won a MacArthur Fellowship--the so-called "genius" award.

An Intricate 3-D Structure

Composed of billions of atoms, DNA looks something like a twisted ladder, with two outside rails connected by a series of molecular links. The various links are letters in the alphabet that spell out genetic instructions for a cell.

But unlike steps in a ladder, the links can slide around, like a "stack of copper pennies," as Barton calls them. The steps can twist up or down, instead of lying flat. The rails don't always run smoothly, but bulge and loop in shapes essential to correctly conveying instructions to other parts of the cell.

"These weird shapes in DNA . . . are places where things get turned on and off," she says. They are, in effect, bits of code that tell biological reactions to start and stop. Because of DNA's intricate three-dimensional structure, she designs three-dimensional tools to work with the molecule. "I'm always thinking about 3-D structure," she says.

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