Miniaturization, Parallel Processing Come To Lab Devices

The laboratory is shrinking. Scientists and engineers are borrowing miniaturization, integration, and parallel-processing techniques from the computer industry to develop laboratory devices and procedures that will fit on a wafer or microchip. A growing number of companies and investors are betting that the technology will revolutionize drug development, genomics, environmental monitoring, forensics, and clinical diagnostics, in much the same way the microprocessor transformed the computer industry. A few years hence, doctors may use biochips covered with DNA probes to determine-within minutes-a patient's ability to metabolize a given drug to determine the ideal course of therapy. Pharmaceutical companies will use arrays of microfabricated devices to synthesize and screen tens of thousands of drug candidates in a single day. Ultimately, people may wake up each morning and check their cholesterol levels on personal diagnostic devices. "The future is really small," says Ken Nussbacher, executive vice president of Santa Clara, Calif.-based Affymetrix Inc., makers of the GeneChip. GeneChips are dime-sized glass wafers covered with as many as 400,000 DNA probes, each 20 bases long. Photolithography, the same technique used to make microprocessors, allows Affymetrix to place DNA strands of known sequence in precise locations. Sample DNA is denatured, equipped with a fluorescent tag, and placed on the DNA array. Hybridized sequences are picked up by a specialized scanner, which, according to Nussbacher, can scan 400,000 probes in six minutes. Affymetrix recently introduced a chip to analyze the coding sequence of the human p53 tumor suppressor gene, mutated in greater than half of all human cancers. The company's HIV assay detects mutations in the viral genes for protease and reverse transcriptase. Affymetrix is working with the British company Glaxo Wellcome plc (which owns 34 percent of Affymetrix) to determine the correlation between treatment and response in HIV-infected patients with different mutations. Affymetrix Inc. 3380 Central Expressway Santa Clara Calif.95051 (408) 731-5000 tax: (408) 481-0422 http://www.affymetrix.com/ Aurora Biosciences Corp. 11149 N. Torrey Pines Rd. La Jolla, Calif.92037 (619) 452-5000 ~ Fax: (619) 452-5723 http://www.aurorabio.com/ Caliper Technologies Corp. 1275 California Ave. Palo Alto, Calif.94304 (415) 842-1960 Fax: (415) 842-1970 http://www.calipertech.com/ Cepheid 3410 Garrett Dr. Santa Clara, Calif. 95054 (408) 969-0770 Fax: (408) 969-0760 CuraGen Corp. 555 Long Wharf Dr. 11 th Floor New Haven, Conn.06511 (203) 401-3330 Fax: (203) 401-3331 "Miniaturization is still emerging as an important concept in the investment community," says Carl Gordon of Mehta and Isaly, a New York investment firm specializing in the biotechnology and pharmaceutical industries. (The firm is an investor in Caliper Technologies Corp., a Palo Alto, Calif.-based company that calls itself the "Lab on a Chip" company.) "I expect that in the future, these companies will capture a lot of interest in the investment community, just as currently genomics companies currently capture a great deal of interest from investors." Even at this early stage, the companies have received considerable support from venture capitalists, collaborative agreements with major diagnostic and pharmaceutical firms, and government grants. Nanogen, for example, has raised $39 million in venture financing since its inception in 1993; Caliper, incorporated in 1995, has raised $29 million in venture financing. The National Institute of Standards and Technology has given several competitive Advanced Technology Program grants to several of the companies, including Nanogen and CuraGen Corp., a genomics firm in New Haven, Conn. And, although many of these young companies remain privately held, Affymetrix raised $85 million from its initial public offering in June 1996. Caliper is one of several companies to create microchip-sized laboratories, complete with the functional equivalents of pumps, valves, reactors, extractors, and separation systems. Caliper's LabChip, which is slated to be available on the research market by 1998, is a kind of liquid integrated circuit. Just as computer chips use tiny wires to move electrons around the surface of a silicon chip, the LabChip uses microscopic channels etched into the surface of the chip that can move as little as 10 picoliters of fluid along a predetermined network. Based on a technique pioneered by J. Michael Ramsey (from Oak Ridge National Laboratory), Jed Harrison (from the University of Alberta), and Andreas Manz (then at Ciba-Geigy, now at Imperial College of Science, Technology and Medicine, London), the movement of the fluid is controlled by the application of voltage across various portions of the chip, effectively creating functional valves and pumps with no moving parts. According to Michael Knapp, vice president of science and technology at Caliper, the design of the network, coupled with the application of electric fields controlled by specialized software, makes it possible to carry out a variety of analytical tasks, including electrophoresis, molecular sieving, and chromatography. "Ours is kind of a Nintendo vision," says Knapp, "in which you have a generic chip 'player,' and you insert into it a disposable chip onto which you've placed the sample. It might be an enzymology chip, a molecular separations chip, even a flow cytometry chip." Caliper, along with competitor Soane BioSciences Inc. of Hayward, Calif., is developing a plastic version of the chip technology. Another player in the field is Cepheid in Santa Clara, Calif. Cepheid aims to combine its own integrated fluid microcircuits with polymerase chain reaction (PCR) analysis to produce devices that can be used to test for disease-causing microbes at the patient's bedside or in the environment. PCR can be done much more rapidly on a micro scale, say Cepheid officials, because it takes much less time to run through the heating and cooling cycles required for the analysis. MICROCHROMATOGRAPHY: Purdue's Fred Regnier, right, and student Bing Ho examine a silicon wafer containing a scaled-down version of the liquid chromatograph. While most companies producing miniaturized research or diagnostic and analytical devices are relatively young start-ups, some larger companies have entered the arena. PerSeptive Biosystems Inc., a publicly held Framingham, Mass., company that produces biomedical research products, first ventured into the miniaturization arena in 1993, when PerSeptive scientists showed that they could perform immunoassays in etched channels on chips. PerSeptive recently added a new tool to its miniaturized repertoire with a microfabricated chromatography column. "A standard liquid pumping system and column may cost $15,000, but a chip can be fabricated for $400, and we can line up 10 to 100 mini-laboratories on a single chip," states Fred Regnier, a Purdue University chemist and chief technical officer of PerSeptive. The company hopes to bring the first column on a chip products out in about two years. CuraGen recently announced plans to develop a nanoscale engine on a chip capable of pumping DNA-or charged molecules of any type-from one point to the next. "We're confident of the ability of the device [called an IDEA chip] to perform size-based DNA separations," says Joel Bader, group leader at CuraGen. "Right now we're investigating the resolution-with a few bases of resolution, we can do genotyping, and if we can get down to single base resolution, we can use it for sequencing also." The IDEA chip would allow researchers to take DNA separations out of the research lab and into the clinical lab or even doctor's office, according to Bader. Several companies have signed collaborative agreements with major diagnostic firms. The market for these diagnostic devices is small now, according to Gordon, but "will almost certainly become big as the molecular diagnosis of diseases becomes more important in the future." Regulatory hurdles will no doubt slow down commercialization of diagnostic devices, which have to undergo Food and Drug Administration (FDA) scrutiny. The process could take as little as a few months and up to a year and a half, according to Knapp, if the product is judged to be substantially equivalent to one already approved by FDA. Approval of products that aren't judged to be substantially equivalent to previously approved devices could take much longer. But many regard drug development as the "killer application" for these technologies. Thanks to genomics, scientists now have the know-how to identify thousands of potential drug targets, both human and microbial. Combinatorial chemistry has made it possibly for pharmaceutical firms to expand their libraries from 10,000 or 20,000 to 1 million compounds. "We were set up to solve this problem," says Gordon Foulkes, chief technical officer of Aurora Biosciences Corp., a publicly held firm based in La Jolla, Calif. "There's no way to test millions of compounds against thousands of genes. Conventional technology can't do that." Aurora is developing a miniaturized system for ultra-high-throughput screening that uses fluorescent probes for cellular analysis and cell signaling, making it possible to assay molecular events in real time within a single cell or small population of cells. The company hopes to eventually make it possible to screen for 500,000 discrete compounds every day. Orchid Biocomputer Inc., a Princeton, N.J., company cofounded by the Sarnoff Corp., is collaborating with Philadelphia-based SmithKline Beecham to produce a device that uses combinatorial chemistry methods to synthesize and then screen up to 10,000 compounds on a single chip. The three-dimensional device consists of massively parallel arrays of reactors, fed by rows and columns of reagent delivery channels, according to Dale Pfost, Orchid's chairman and CEO. Orchid's vision, Pfost says, is to use informatics to tie together high-throughput chemical synthesis and screening systems with genomics-all in one closed loop. "Where [these companies] can use their technology for pharmaceutical development, the market becomes very, very large," says Gordon. "I think that these companies will make a lot of money in high-throughput screening, and they've already begun to do that." Hoffmann-LaRoche Inc. of Nutley, N.J.; New York-based Bristol-Myers Squibb Co.; Johnson and Johnson of New Brunswick, N.J.; and Indianapolis-based Eli Lilly and Co. are just a few of the big-name pharmaceutical firms that have signed collaborative agreements with the smaller companies to develop high-throughput screening devices. FAST TRACK: Howard Birndorf of Nanogen notes that his company's APEX chip "can drive the hybridization rate to seconds." The companies are growing fast, and with them, career opportunities. "We've almost doubled already this year," says Birndorf. "We're at 70-some people now, and we've got about 25 job openings. I think this whole area is going to open up a tremendous amount of jobs." Pfost agrees, adding that Orchid is looking for people who enjoy being at the edges of two disciplines. "We like to have chemists who don't mind learning about engineering, and we like to hire engineers who don't mind learning about chemistry. The pharmaceutical industry is one of the last industries on the planet to industrialize its fundamental processes, and I think that's because it requires combinations of engineering, chemistry, biochemistry, and molecular biology in all their forms." In fact, more than half the employees at the rapidly expanding Aurora-which went from seven to 80 employees in less than two years-are engineers. Although Foulkes agrees that the trend toward miniaturization bodes well for the job market, he advises a cautious approach to selecting an employer. "There are so many companies out there, and it can be hard for people on the outside to pick a good company," he explains. "You've got to look at the technology, but you've also got to see who they've already recruited, what the management structure is like, and the finances of the company. Look at the strength of the deals they've got, and how many years those deals have been in existence." It's no coincidence that many of the firms developing miniaturized systems for lab research and analysis are located in or near California's Silicon Valley. And now, many feel, the Valley may be the cradle of yet another revolutionary industry. "Experimentation really hasn't changed in hundreds of years," says Knapp. "You look in a Fisher [Scientific] catalog and there are still pages and pages of test tubes and pipettes, which remarkably most people use by putting them in their mouths on sucking on them, and holding their finger over the end. We're really doing experiments in a completely new way." Sara Latta is a science writer based in Champaign, Ill.

Miniaturization, Parallel Processing Come To Lab Devices

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