Advance may put gene chip technology on scientists’ desktops

The most insightful technology in modern genetics, the gene chip, which permits scientists to analyze thousands of genes at once, may soon come within easy reach of most biologists.

Writing in the October issue of the journal Nature Biotechnology, a group of scientists from UW–Madison describe a new way to cheaply and simply manufacture the customized chips capable of deconstructing long segments of DNA. The technique enables biologists to scour huge chunks of animal and plant genomes in search of the genes that promote disease, the genetic switches that govern such biological phenomena as aging, and the DNA codes that permit microorganisms to make antibiotics.

At present, such chips are available only from a single company, Affymetrix of Santa Clara, Calif. Off the shelf versions of Affymetrix chips, known as GeneChips, cost $2,500. Customized chips containing DNA from specific organisms or tissues can take months to make and cost as much as $12,000 each.

“Now, the chips are expensive. You use it one time and throw it away,” said Roland Green, a UW–Madison post-doctoral fellow and a lead author of the Nature Biotechnology paper.

The new technique, according to Michael Sussman, a UW–Madison professor of horticulture and genetics, and a co-author of the paper, is known as MAS for Maskless Array Synthesizer. It promises to take the technology and put it in the laboratory of virtually any research biologist.

“This technology could sit on anyone’s bench top,” said Sussman. “It will give people the ability to make any array of synthetic compounds, any time.”

Gene chip technology now depends on photolithography, a process that requires shining ultraviolet light through a series of stencil-like masks onto a glass chip resulting in the synthesis of tens of thousands of DNA molecules of interest. Each DNA molecule synthesized on such a chip, said Sussman, is like a window to a wealth of genetic information, providing a glimpse of the workings of tens of thousands of genes found in the cells of living organisms.

A recent example of gene chip technology at work was the report of another group of Wisconsin scientists who used a gene chip to discover the genes involved in the process of aging in mice.

But making those chips and their masks, each customized to dissect a specific problem in genomic analysis, is a clumsy, time-consuming and expensive process. Sometimes, as many as 100 masks are required to make a single chip that has as many as 500,000 tiny, DNA-laden compartments.

The new technology reported by the Wisconsin team capitalizes on an off-the-shelf Texas Instruments technology used in overhead projection known as Digital Light Processors. At the heart of the technology is an array of 480,000 tiny aluminum mirrors arranged on a computer chip.

By manipulating the mirrors, the Wisconsin team, an unusual mix of molecular biologists and semiconductor engineers, found that they could shine light in very specific patterns, eliminating entirely the need for the delicate and expensive masks used in traditional DNA chip technology.

The MAS process for making customized DNA chips, according to UW–Madison professor of electrical and computer engineering Franco Cerrina, can be likened to desktop publishing: “Instead of several weeks, it takes eight hours to make a chip,” he said, and the cost of producing such chips is reduced significantly.

Moreover, MAS has the potential to be used to clinically diagnose genetic disease in humans, and holds great promise for various drug discovery schemes, and the testing of other biological building blocks such as proteins and carbohydrates.

The Wisconsin group has applied for a patent for the new technology through the Wisconsin Alumni Research Foundation, a not-for-profit corporation that manages intellectual property on behalf of UW–Madison scientists. Rights to the technology have been licensed to a Madison-based company known as NimbleGen Systems.

NimbleGen, founded by three of the paper’s authors, will focus on development and commercialization of the new technology.

The Wisconsin team includes Green of the UW–Madison Environmental Toxicology Program; physicist Sangeet Singh-Gasson, now of the University of Illinois at Chicago; Yongjian Yue of the UW–Madison department of electrical and computer engineering; Clark Nelson of the UW–Madison Biotechnology Center; Fred Blattner, UW–Madison professor of genetics; Sussman; and Cerrina.