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Tiny Bubbles

Microfluidics Is Revolutionizing Biology by Shrinking Test Devices to Lilliputian Dimensions. Leading the Charge Is Caltech Physicist Stephen Quake.

March 07, 2004|Linda Marsa | Linda Marsa is a regular contributor to The Times' Health section.

Stephen Quake has the full lips and startling blue eyes of a cherub in a Renaissance painting, and the only sign that he is old enough to teach at a top academic institution is his corona of thinning curls. Wearing an olive-green golf shirt, loosely fitting khaki pants and sandals--the equivalent of formal attire among Caltech's lab rats--he ushers his visitor into an office where papers are stacked precariously high. The 34-year-old physicist exudes the restless energy of a teenager, and hardly looks like a man at the center--make that epicenter--of a revolution.

Quake whizzed through a bachelor's in physics and a master's in math in four years at Stanford University before arriving at Caltech at a mere 27. He was focusing on DNA research but was frustrated by the time-consuming laboratory processes in which huge, expensive machines were required to separate cells for study.

He had a feeling that a new technology called microfluidics might help. Microfluidics can process a sample of liquid thousands of times smaller than a drop of water through minuscule laboratory plumbing composed of hundreds of channels--each about the width of a strand of hair--and mixing chambers the size of a few cells. This mini experiment all takes place on a rubbery chip as small as a pat of butter. Like computer microprocessors, the ultimate goal is to perform hundreds, even thousands, of experiments at the same time on one tiny chip, and thereby accelerate the pace of medical research and testing.

But when it came time to have a company involved in microfluidics actually produce the equipment for Quake's Caltech operation, "we realized the field wasn't as far advanced as we thought, and we ended up having to go back and invent a whole new set of technology," he says, fidgeting in his chair.

So they did. For more than a decade, scientists had been trying to use glass and silicon, the brittle crystal used in computers, to shrink cumbersome laboratory equipment down to one-inch-square chips and perform relatively simple functions, such as snipping strands of DNA. But Quake and his research team found these materials were difficult to work with, expensive and slowly produced. The costly silicon, which needs to be used in a sterile room, was too stiff for making tiny devices, and the valves that controlled the fluid flow had to be sealed with rubber so they wouldn't leak.

After some trial and error, Quake's group in 1997 found a refreshingly easy solution. Inspired by Harvard chemist George Whitesides' soft lithography, a technique used to mold and stamp tiny structures on pliable materials such as silicone, they hit upon the idea of using a piece of silicone--the same inexpensive rubber used to caulk bathtubs and augment breasts--to fashion their own microchips.

For the chips, silicone was poured onto a mold that formed channels in the material, a sort of lab "piping," and another sheet of silicone was put on top to create an enclosed device. But there were problems. "We really couldn't use it because it didn't have any valves, so there was no capacity to turn things on and off," recalls chemist Marc A. Unger, one of Quake's first postdoctoral researchers at Caltech. "It's like having all the showers and faucets in your house running all the time."

Still, Quake felt he was on to something. In 1999 he co-founded a company, now called Fluidigm, a South San Francisco biotech, to commercialize his microfluidic systems.

Shortly after, Unger and his team came up with an ingenious solution to the valves problem. They made a two-level structure where the channels crossed at right angles, and pumped pressurized water or air through the top layer and fluids through the bottom. When the water on the top pushes down on the lower channels, it closes them, like stepping on a garden hose.

"We slapped the two pieces together and it worked better than I had any right to expect," Unger says. "Now we had a method of controlling the fluids."

Quake was doubtful, though, whether the larger scientific community would recognize the significance of this elegantly simple breakthrough. He bet Unger $20 that their paper outlining the discovery wouldn't be published by the prestigious journal Science. "Sometimes you're ahead of the curve and sometimes you're behind it," Quake says. "I thought we were ahead of the curve."

Science accepted the paper. Once the daunting technical problems were resolved, he says, "the technology really took off."

As a child, Stephen Quake witnessed a similar breakthrough in scientific technology, one he thinks will be mirrored by microfluidics. The son of an early software pioneer, Quake grew up in New Canaan, Conn., a bucolic enclave of Yankee affluence, immersed in computer technology. He wrote his first program using a stack of punch cards at age 11, and he earned extra money in high school running a computer programming camp at his parents' home for the neighborhood kids.

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