Test-Tube Logic

Computers and liquids don’t mix, as many a careless coffee drinker has discovered. But a breakthrough by Caltech researchers could result in logic circuits that literally work in a test tube—or even in the human body. Made of DNA, these circuits work in salt water—an environment similar to that within living cells—which could lead to a biochemical microcontroller, of sorts, for cells and other complex chemical systems. The lead author of the paper describing this work, which appeared in the December 8 issue of Science, is Georg Seelig, a postdoctoral scholar in Erik Winfree’s lab. “Digital logic and water usually don’t mix, but these circuits work in water because they are based on chemistry, not electronics,” explains Winfree (PhD ’98), an associate professor of computer science and computation and neural systems and recipient of a MacArthur genius grant.

Rather than encoding signals in high and low voltages, the circuits encode signals in high and low concentrations of short DNA molecules. The logic gates that process the information are carefully folded complexes of two or more additional short DNA strands. When a gate encounters the right input molecules, it releases its output molecule. This output molecule in turn can help trigger a downstream gate, so the circuit operates like a cascade of dominoes in which each falling domino topples the next one. But unlike dominoes and transistors, these components have no fixed positions and cannot simply be connected by wires. Instead, the molecules bump into each other at random, relying on the specificity of their designed interactions to ensure that only the right signals trigger the right gates.

“We were able to construct gates to perform all the fundamental binary logic operations—AND, OR, and NOT,” explains Seelig. “These are the building blocks for constructing arbitrarily complex logic circuits.” The largest circuit the group has made so far processes six inputs with 12 gates in a cascade five layers deep. While this is not large by Silicon Valley standards, Winfree says that it demonstrates several important design principles. “Biochemical circuits have been built previously, both in test tubes and in cells,” Winfree says. “But these circuits rely solely on the properties of DNA base-pairing. No enzymes are required to make them work.”

“The idea is not to replace electronic computers for solving math problems,” Winfree says. “Compared to modern electronic circuits, these are painstakingly slow and exceedingly simple. But they could be useful for the fast-growing discipline of synthetic biology, and could help enable a new generation of technologies for embedding ‘intelligence’ in chemical systems for biomedical applications and bionanotechnology.” Such circuits could be used, for example, to detect specific cellular abnormalities.

The other authors of the paper are David Soloveichik and Dave Zhang, both grad students in computation and neural systems. —RT