Chips Ahoy: Microchips Covered with DNA Emerge as Powerful Research Tools

Article excerpt

Good things often come in small packages. The latest proof of that familiar saying lies in the thumbnail-sized chips of glass or silicon that have recently become the talk of the molecular biology community.

Resembling the microprocessors that revolutionized the computer industry, the chips carry checkerboardlike arrays of DNA rather than intricate electronic circuits. These devices, often called DNA chips, promise their own revolution, biologists have been saying for a decade.

A surge of journal articles in the last few months may finally herald the realization of that promise. Academic investigators and a few companies are designing or have developed DNA chips that quickly screen tissue samples for disease-producing microorganisms or cancer-causing gene mutations.

Scientists already envision the day when they can use a small number of DNA chips, or perhaps just one, to examine the action of every human gene, all 100,000 or so, in a group of cells.

"The molecular biology of the '70s, '80s, and first part of the '90s has mostly focused on studying one gene or one protein at a time. Now, we're moving into systems analysis, where we can analyze entire genomes at a time," says Leroy Hood of the University of Washington in Seattle.

The key to DNA chips is a phenomenon known as hybridization, the zipperlike joining of two strands of genetic material. A gene normally exists as two strings of nucleotides entwined in a helical shape resembling a spiral staircase. There are four DNA nucleotides-A, C, G, and T-and the sequence of these nucleotides in a gene encodes the information a cell uses to build a specific protein.

In hybridization, one chain of nucleotides binds to another. Since A binds only to T and G only to C, the nucleotide sequence ATTCG will only hybridize to TAAGC, its complementary sequence. This specificity, which provides the foundation for DNA's ability to copy itself, is also the key to the DNA chip's effectiveness.

To create such a chip, researchers divide a surface, typically glass or silicon, into hundreds, thousands, or even millions of sites called features. At each feature, they firmly attach millions of copies of a single DNA segment, or probe, its length ranging from several nucleotides to millions.

They then label the genetic material to be tested with a fluorescent marker and apply this sample to the chip. The marked DNA will stick to the device only where it hybridizes to a DNA probe whose sequence is complementary to all or much of its own.

By carefully designing and arraying DNA probes, investigators can create chips that represent an entire gene's nucleotide sequence. Such chips can reveal visually-in a fluorescent glow, when viewed with a microscope-whether a tested sample's DNA differs by even a single nucleotide from the standard version. For example, a gene might normally contain the nucleotide A at one point in its lengthy sequence and so hybridize to a probe sequence with a T there. If the DNA being tested hybridizes instead to features where the DNA probes contain a G at that spot, it would signify that the tested sample had a C instead of an A there, representing a single mutation.

DNA chips vary greatly in how the probes are attached to a surface. Hood makes use of ink jet printer technology to shoot droplets containing the DNA probes onto a chip. Another strategy immobilizes the DNA probes in a gel.

"There are lots of approaches. Internally, we've used at least 10, I believe," says Stephen P.A. Fodor, president of Affymetrix, a firm in Santa Clara, Calif., that has been at the forefront of DNA chip manufacturing and research.

Affymetrix normally relies on photolithography, a manufacturing technique critical to the semiconductor industry. Photolithography uses ultraviolet light and stencil-like masks to activate microscopic regions of a glass surface. With photolithography, Affymetrix attaches selected nucleotide sequences to specific sites on the chip. …