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For the last five years, DNA chips have been a powerful research tool, holding much promise for future use in clinical settings. These tiny silicon or glass surfaces, covered with thousands of DNA fragments, are used by researchers to discover genes in DNA samples. But still elusive is the holy grail of this technology-a single, fully automated handheld device, or “lab on a chip,” that can instantly analyze DNA from a single strand of hair or drop of blood.

One company that has taken a big step in that direction is San Diego-based Nanogen. Its NanoChip is currently the only DNA chip on the market using microfluidics-the channeling of fluids on a chip surface-and electronic signaling to more precisely identify gene variants and mutations. This can lead to more accurate detection of pathogens, microorganisms or subtypes of genetic-based diseases.

Meet and Match

All DNA chips are based on an inherent property of DNA: when the familiar double helix is split in half, each piece of DNA will try to reconnect with another, complementary piece-a process called hybridization.

The surface of conventional DNA chips, like those produced by biochip giant Affymetrix, is usually covered with tens of thousands of DNA strands, called probes. In a typical application, genes from, say, a cancer tumor are tagged with a fluorescent dye and applied to the chip surface. Those that match bind to the probes, and the rest are washed off. The fluorescent markers, read with a scanner, allow researchers to identify the DNA sequences making up the bound genes. This process can take up to three hours.

In many cases, however, the binding of the sample gene and its matching probe can conceal a mismatch of one or two base letters (the building blocks of DNA). For most purposes, this degree of precision is adequate, since it allows researchers to identify genes, or gene families, with confidence.

But when researchers need to identify the exact gene variant-in order to distinguish, for example, between different subtypes of a disease-one or two letters can spell all the difference.

Electric Flow

Nanogen hopes the NanoChip will meet this need. More specialized than conventional DNA chips, it uses microfluidics, electronics and a clever piece of reverse engineering to arrive at a perfect match.

Within the chip, a series of microfluidic channels leads to a central core containing 99 test sites, each of which can be independently controlled with an electrical charge. While standard DNA chips come equipped with probes, the NanoChip cartridge arrives blank and must be customized. To prepare the chip, DNA probes are placed in the microfluidic channels, and an electrical charge is applied to the test sites that will hold the probes. Since DNA contains an inherent negative charge, the probes are drawn down the channels to the desired locations.

An electrical charge also speeds the hybridization process, drawing gene samples down to the probes. After hybridization, the electrical charge is reversed. Only perfectly matched samples remain, and the output is then read on a customized desktop workstation. The whole process takes about 15 minutes.

“So far, it’s yielded 100 percent accuracy,” says Paolo Fortina, a researcher at Children’s Hospital in Philadelphia, who has been using the NanoChip for nearly a year, primarily to validate results from a DNA sequencer. Recently, he used the NanoChip in a study of gene variants and cardiovascular disease.

Other Platforms

In a field rich with experimentation, other biotech companies are also courting success with their own approaches to DNA-chip construction.

Motorola’s eSensor group-with which Nanogen recently settled a patent dispute over molecular detection methods-plans to hit the market with its own DNA chip this fall. Motorola’s chip uses electronics not to increase speed and precision but to identify hybridized DNA without fluorescence. The eSensor chip contains probes labeled with an electronic tag. Once hybridization occurs, a voltage is applied to the chip, causing the hybridized probes to release a signal.

HandyLab, a University of Michigan spinoff, is working on a microfluidic-based DNA chip, which they hope will be approved for clinical use. Like Nanogen, HandyLab uses electronic signaling to manipulate the fluids. But rather than exploiting the inherent negative charge within DNA itself, HandyLab is experimenting with thermal pneumatics-electrically heating up small pockets of air to propel the fluid, then chemically controlling the flow. HandyLab predicts clinical trials of its product in 2003.

Princeton, NJ-based Orchid Biosciences is developing a biochip platform consisting of a multi-tiered microfluidic circuit, for detecting gene variants and mutations. Orchid hopes to incorporate this highly parallel platform into their product line by 2003.

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