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FEATURE: Microfluidics Under the Microscope

SAN FRANCISCO, March 20 - Picture a room the size of a railroad boxcar filled with lab glass, electronics, and robotics. Now blink and replace the vision of the room, this time configured to do multi-step chemical and gene analysis and diagnostics on a chip the size of a matchbook.


That's what microfluidic researchers hope to see when they blink.


Today, the most sophisticated integrated and automated labs are still just "a bunch of robots and components made by different companies and put together," said Stephen Quake, associate professor of applied physics at the California Institute of Technology. "Microfluidics gives you the ability to do many different things in one package"--to take a population of cells, put them on a chip, sort them, break them open, assay them, remove RNA, conduct PCR and then begin cloning.


The complete process is simple enough: Everything would take place on a tiny chip embedded with channels as wide as a human hair. Inside these channels, samples and reagents would undergo chemical reactions in a directed flow and yield data along the way to be read by computers. Applications for the technology include genotyping, protein analysis, and biochemical assays.


"Smaller is better," declared Quake. "The mission is to take biologists from the microliter to nanoliter standard."


The reasoning is simple: Significantly smaller volumes of chemicals, often measured in nanoliters, will help researchers save on expensive reagents and limited samples. Also, the transportability of tiny, relatively low-cost chips opens up sampling and analysis to broader use, advocates contend.


And researchers studying microfluidics want all sorts of people to have access to the technology--pharma and biotech firms, diagnostics centers, primary-care physicians, and eventually anyone concerned about bacteria levels in their steak tartare. Scientists say they are on the cusp of delivering on that vision.


Catching up to the hype


"Microfluidics is about 10 years old," said Quake. But there was "too much promised out of the gate. Technology has [now] caught up."


Companies like South San Francisco-based Fluidigm, which Quake cofounded, Caliper Technologies, and Aclara Biosciences, both based in Mountain View, Calif., have chips in various stages of development and market release. Each company approaches in different ways the task of moving nanoliters of fluid through a chip.


Caliper makes many of its chips from glass. Aclara uses plastic and Fluidigm relies on rubber. These choices affect the chemical reactions taking place in the channels as certain chemicals may respond differently to the chip material. Additionally, different methods are used to move the liquid through the chips, with Caliper and Aclara using electrical current and pressure differentials for various applications, and Fluidigm using pumps and valves to move liquid though the channels.


Business models also differ. Caliper makes money by selling the chip-reading instruments and charging for the use of its chips which it sells at cost, said Daniel Kisner, CEO of Caliper. Aclara, which says its chips are compatible with readers and robotic systems already used by the life sciences industry, profits in chip and reagent sales, according to Antonio Ricco, the firm's senior director of microtechnologies and materials. Fluidigm, with chips currently undergoing in beta testing, plans to make money through chip sales, said CEO Gajus Worthington.


The market itself is set to explode: The microfluidics space is predicted to grow from an estimated $77 million in 2001 to $395 million in 2004, according to a report release last year by market research firm Frost & Sullivan.


Additionally, a variety of technologies and applications, while fostering competition, may also serve to expand the market and create bigger slices of pie for everybody.


"There was a view from a minority of microfluidic players in the early days that there was just room for one or two players," said Herbert Hooper, a cofounder of Aclara and currently a member of its board of directors. "Not true. By having a number of companies focusing on different areas, you hope the technology will be more broadly recognized, and this will be good for all."


The companies share the vision, after all, to create "incredibly shrinking scientists," as Caliper CEO Kisner put it.


"We want the [sample analysis] process to be simple," explained Michael Lucero, senior vice president of marketing at Fluidigm. "Sample in, result out. We're not saying we will do tomorrow, but we have the potential."


That potential, according to Richard Mathies, director of the Center for Analytical Biotechnology at Berkeley, is huge: "All areas of chemical analysis will be penetrated by these devices in 10 years. [But] no one has developed a complete chemical analysis at the nanoscale. Once that's done it revolutionizes everything."


The slow pace of genomic research, paradoxically, may hold back microfluidics advancement a bit.


"Genomics is turning out to be evolutionary and not revolutionary," said Winton Gibbons, an analyst at William Blair & Co. in Chicago. "Companies like Caliper are looking to create a high-throughput system that happens to use microfluidics. I think [acceptance of the technology] will be more incremental. It's not clear there will be some killer app."


Gibbons also sees reluctance on the part of pharmaceutical companies to make big purchases of new equipment.


"The market wants to leverage [the] investment [it has already made] and not start something new," he said. "If you had disposable or reagent technology that fits in with that, you have a shot. [Pharma] does not want wholesale equipment replacement."


"The real value of microfluidics is making a large number of assays in parallel," added Mathies. "Making one small transistor, who cares? Making a million together is a computer. I don't understand how computers work, but I can use it," he said.


Conceded Kisner: "Like any new and unconventional technology displacing old technology, it takes time."

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