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Ever since biochips-such as DNA microarrays-came on the scene in 1996, researchers have raced to increase their diagnostic capability. Now, a research team at Yale University led by biology professor Ronald Breaker has produced a prototype for an RNA-based microarray that promises to put a powerful diagnostic lab on a dime-sized chip.

For years, Breaker has been tinkering with the theory that RNA, not DNA, was the fundamental component of life 3.5 billion years ago. Unlike DNA-the library containing our genetic code-RNA is dynamic, executing the instructions in DNA’s storehouse and orchestrating protein synthesis.

In 1995, Breaker and his team began to resurrect this extinct “RNA world” in a test tube and successfully engineered RNA-based molecular switches in the effort. (A molecular switch is a molecule that’s turned on or off by another molecule or compound.)

Array for RNA

With dozens of these switches on hand, Breaker thought, why not arrange them on a surface and create an array of biosensors that use RNA to measure or detect compounds? By engineering the RNA switches to detect many different kinds of compounds, Breaker knew that the potential of his array could surpass that of a DNA chip, which identifies specific DNA or RNA sequences and nothing else.

To create the prototype, Breaker placed the RNA switches on a gold-coated silicon surface and arranged them in clusters. Each switch was designed to bind only to a specific molecule-its “target”-and then to release a signal that identifies the target molecule. (In the prototype, the switches released a radioactive signal.)

As reported in April’s Nature Biotechnology, Breaker and his team tested the array of RNA switches on a variety of complex mixtures. In one experiment they successfully identified different strains of E. coli found in bacterial cultures.

The implications are enticing. The array’s ability to simultaneously identify a potentially large number of compounds, combined with the precise exclusivity of each switch, adds up to a recipe for a powerful and wide-ranging laboratory on a dime-sized slice of silicon.

RNA Superchip

Breaker’s invention opens the way for future RNA chips capable of revealing the molecular composition of complex mixtures-like blood serum and industrial waste-far more comprehensively than current biochips.

“Advanced versions of our RNA biochip could be used for many different targets like drugs, toxins and metabolites, as well as proteins and nucleic acids,” Breaker says. “They should be able to detect almost anything that RNA can be made to bind to.”

Furthermore, the preliminary success of Breaker’s work “ushers in a new era of what might be termed ‘active arrays,’” declares Gerald Joyce, a molecular biologist at the Scripps Research Institute in La Jolla, CA. Indeed, it should be possible to engineer RNA switches to do “far more extraordinary things” than target identification, Breaker says. Regulating gene expression is one example.

Another benefit of RNA switches is their ability to withstand the sometimes unpredictable and harsh environment outside the lab. Breaker compares them with a protein biochip and says that the latter, if accidentally heated, fries like an egg. The proteins unfold and “you can never put the complex structures back together again,” he says.

Breaker’s RNA switches have been engineered to refold back to their original form after heating. “This snap-back character will give RNA biochips a considerable advantage for use in more exotic test environments,” Breaker claims.

Getting There from Here

The next step for RNA switches is pretty clear, says Joyce. They must be engineered to release a fluorescent, rather than a radioactive, signal. This enhancement would enable labs to make use of already-existing equipment and bypass regulatory red tape, allowing quick development of an RNA chip containing up to 1,000 switches. And that’s the goal of biosensor arrays-massive parallel analysis on the smallest surface possible.

Breaker says his aim is to “put the capability of a thousand scientists into a dime-sized chip while generating the answers you want a thousand times faster.” In addition to biomedical research, he sees many uses for an RNA chip in diverse fields like chemical engineering, environmental science, and even biological and chemical warfare defense.

There are still some obstacles, however, particularly with manufacturing costs, the chemical stability of the switches and some of the finer points of molecular recognition.

“This technology is so new that it is unclear just how many different compounds it will prove possible to recognize,” says Andrew Ellington, a biochemist at the University of Texas. “For example, there are no published examples of protein recognition.” In addition, RNA is vulnerable to certain chemicals often found in test situations that can disintegrate a switch.

Breaker’s team is working on solutions to some of these snags, such as clearing any RNA-destroying compounds from test samples. They are also working to engineer DNA so that it can carry out certain RNA-like functions.

That could make those “thousand scientists on a chip” even smarter.

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