Researchers have been experimenting for some time with the idea that biology can be harnessed to perform computations. Biological systems can amplify and sample a large collection of molecules simultaneously, and they can register states that are far more subtle and complex than the binary ones handled by standard computers. Although there are no clear cases where a biological computer will outperform standard silicon, a biological computer may be useful for detecting the state of other biological systems, and it may find uses in diagnostics or environmental sensing. A potential step forward for biological computing was just reported in Science, where researchers describe logic gates built from RNA, a chemical the helps run the basic metabolism of the cell.

RNA is a close cousin to the more famous DNA, differing only by the presence of one oxygen atom in its component sugars. Although it acts much like DNA and undergoes base pairing, that oxygen atom makes it significantly more reactive. RNA molecules can twist to form elaborate structures that can catalyze chemical reactions, including those that rearrange RNA molecules (either themselves or others). In the new experiment, researchers built their logic gates using a type of catalytic RNA called a "hammerhead ribozyme."





Image: UCSB chemistry.

As seen here, the hammerhead RNA undergoes base pairing with itself to form a complex, three-dimensional structure. Place the hammerhead sequence within any RNA molecule and it will break up the RNA to cut itself neatly out, leaving the RNA molecule in pieces.

The ribozyme is flexible enough that extra RNA can be inserted into one or both of the two lobes of the structure shown above without destroying its function. The researchers inserted RNA sequences that also formed base paired structures. With the additional sequences in place, the entire molecule acted like a switch: if it base pairs one way, a normal, functional hammerhead ribozyme was formed. If it pairs up using different stretches of RNA, parts of the ribozyme are pulled open, destroying its function.

The authors arranged it so that they could control this switch. Several RNA sequences have been identified that bind small molecules, like the drug tetracycline. The authors inserted these into the extended lobes, such that the drug controlled the folding of the RNA. When tetracycline is present, the RNA would fold so that there was no active ribozyme. Remove the tetracycline, and the molecule would reshuffle so that the ribozyme became active.

The end result is that the drug acts as a switch, turning the ribozyme on and off. Making each of the two lobes sensitive to a different drug even created a biological AND switch; both drugs need to be present for an active ribozyme. But a ribozyme isn't necessarily easy to detect, so the authors made it obvious: they inserted their logic gates into a gene that encodes a messenger RNA that produces the Green Fluorescent protein (the protein that recently won folks a Nobel Prize). Now, when the ribozyme is active, the messenger RNA gets broken up and no GFP is made; otherwise, the cells glow green.

This setup allowed the creation of an OR logic system as well. Simply placing two ribozymes in the same message, each sensitive to a different drug, ensured that no GFP was made if either drug was present. By combining different versions of these structures in a gene encoding a single messenger RNA, all sorts of basic logical operations were possible, and their state was easy to read out based on whether the yeast cells carrying these genes glowed green or not.

Detecting tetracycline isn't especially interesting, but RNA that binds to specific small molecules is actually relatively easy to make; repeated rounds of amplification and selection for binding can evolve these RNAs in a couple of days. This means that, in a matter of days, researchers can grow yeast colonies that glow in response to a variety of chemicals, or even to combinations of chemicals.

More complicated circuits should be possible if the ribozymes are inserted into messenger RNAs that encode transcription factors, which could, in turn, regulate genes that encode yet other ribozymes. It's possible that the first biological calculations using this system are already under way in the lab responsible for this publication.

Science, 2008. DOI: 10.1126/science.1160311