Stephen Quake

The forces of physics move oceans, mountains and galaxies. But applied physicist Stephen Quake uses them to manipulate things on a vastly reduced scale: tiny volumes of fluids thousands of times smaller than a dewdrop. Microfluidics, as Quake’s field is called, is a promising new branch of biotechnology. The idea is that once you master fluids at the microscale, you can automate key experiments for genomics and pharmaceutical development, perform instant diagnostic tests, even build implantable drug-delivery devices-all on mass-produced chips. It’s a vision so compelling that many industry observers predict microfluidics will do for biotech what the transistor did for electronics.

Quake’s 11-person lab at Caltech is not the only outfit bent on realizing this vision. Over the past decade or so, scores of researchers have set out to build microscale devices for many of the basic processes of biological research, from sample mixing to DNA sequencing. But many of those groups have run into roadblocks in developing technology that can be generalized to a broad range of applications and would allow several functions–such as sample preparation, DNA extraction and detection of a gene mutation-to be integrated on a single chip. Moreover, some of the manufacturing approaches involved, particularly silicon micromachining, are so expensive that experts in the field question whether products relying on these techniques could ever be economical to manufacture.

Quake’s group is one of several now working their way around these obstacles. Last spring, the team unveiled a set of microfabricated valves and pumps–a critical first step in developing technology general enough to work for any microfluidics application. And to make microfluidic devices cheaper, Quake and others are casting them out of soft silicone rubber in reusable molds, using a technique called “soft lithography.” The potential payoff of these advances is huge: mass-produced, disposable microfluidic chips that make possible everything from drug discovery on a massive scale to at-home tests for common infections.

Because microfluidics is so promising and yet so technically frustrating, expectation and hype have sometimes outpaced the development of viable technology. Yet Quake and his group have consistently turned out elegant devices that actually work. First was a microscale DNA analyzer that operates faster and on different principles than the conventional, full-sized version, then a miniature cell sorter and most recently, those valves and pumps, described last April in the journal Science. All this while regularly publishing important findings on the basic physics of biological molecules.

If Quake seems adept at straddling fields-in this case science and technology-perhaps it’s because that’s exactly the sort of challenge he has long craved. Even as an undergraduate at Stanford University, where he earned bachelor’s and master’s degrees simultaneously in only four years, Quake worried that physics was “somewhat finished” as an experimental science, that it was hard to find the field’s frontiers. A pioneer at heart, Quake started looking to tackle questions that lay at the boundaries between disciplines. As he recalls: “It was completely obvious, even to an outsider, that biology was going through this period of incredible growth and intellectual excitement, and there were going to be big questions asked and answered, and the frontiers were advancing at a tremendous rate in all directions.”

After Quake finished his doctorate in theoretical physics at Oxford University, he went back to Stanford as a fellow working on the physics of DNA. When Caltech’s applied physics department hired him in 1996, Quake says, “it was an experiment for them”-he was the first faculty member in the department with a biological bent. So far, the experiment seems to be going smoothly; this past summer, at only 31, Quake got tenure.

Quake’s inventions are also thriving in industry, through a startup called Mycometrix. Founded in 1999 by Quake, two of his college classmates and a consultant, the South San Francisco-based company has licensed all of Quake’s microfluidics patents from Caltech. When TR went to press, the company was planning to deliver its first microfluidic devices to selected university researchers and industry partners by the end of 2000, and was hoping for a commercial release by the end of this year or early 2002. The competition will be intense. Several startups and even electronics giants like Hewlett-Packard and Motorola are getting in on the game. But to date, only one of Mycometrix’s competitors has brought a microfluidic product to market.

Although Quake’s work is rapidly flowing into the commercial marketplace, it’s still the very early stages of science and technology development that interest him the most. And though he has built quite a reputation as a technologist, he hopes soon to focus more of his attention on some of the most pressing questions in basic biology: How do the proteins that control gene expression work? How can you do studies that cut across the entire genome? “Now that we’ve got some pretty neat tools,” Quake says, “we’re going to try and do some science with them.” Quake’s ability to work in areas from basic research to hot commercial markets make him a prototypical innovator. And the same versatility makes microfluidics a field to pay close attention to in the next few years.

Others in Microfluidics

Organization	Project
Aclara BioSciences (Mountain View, Calif.)	Genomics and drug screening
Caliper Technologies (Mountain View, Calif.)	DNA, RNA and protein assays
Cepheid (Sunnyvale, Calif.)	DNA analysis
Micronics (Redmond, Wash.)	Diagnostics and chemical analysis
TECAN (Hombrechtikon, Switz.)	Drug discovery