A computer for living cells

In a boost to the field of linkurl:synthetic biology,;http://www.the-scientist.com/article/display/18854/ researchers have created an RNA-based device that can control gene expression of target genes, thus regulating molecular processes in living cells, a linkurl:paper;http://www.sciencemag.org/cgi/content/abstract/322/5900/456 in this week's Science reports. The paper "shows this design approach for the first time in a biological system," linkurl:Christina Smolke;http://www.che.caltech.edu/groups/cds/index.htm of the California Institute of Technology, the main author on the study, told The Scientist. For the past decade or so, researchers applying engineering principles to biology have been working to construct molecular machines that can be inserted into live cells to act as biosensors, drug delivery vehicles, or protein factories for biofuel or medicine production, among other functions. Recently, for example, researchers at Harvard University linkurl:inserted;http://www.nature.com/nbt/journal/v25/n7/abs/nbt1307.html a DNA plasmid into a living cell that could perform a simple operation -- regulating the level of linkurl:GFP;http://www.the-scientist.com/blog/display/55080/ expression. That device, however, could not receive signals from the cell into which it was encoded, explained linkurl:Ehud Shapiro,;http://www.wisdom.weizmann.ac.il/~udi/ an expert in biomolecular computing at the Weizmann Institute in Israel, who cowrote the accompanying commentary to this week's Science paper. It could merely perform its one operation, completely autonomous from the cell's normal processes. "The advance in this work is that they show their computation can actually sense molecules in the cell." Smolke and graduate student Maung Nyan Win constructed a three-part device. One part, the "sensor," consisted of an RNA aptamer, or stretch of RNA selected to bind to a specific molecular target. Another part, the "actuator," was made of a linkurl:ribozyme,;http://www.the-scientist.com/article/display/53763/ or catalytic RNA which cleaves itself upon a specific signal from the sensor. The third part, a "transmitter," links the other two together. The self-cleaving of the ribozyme switches off gene expression of a specified gene -- in this case, again, GFP. What makes the system especially powerful is that the three components are modular, which creates numerous possibilities for signal integration. For example, the same sensor could be attached to two different actuators, coupling two different responses to a single signal. Alternatively, two different sensors could be attached to a single actuator, such that the device would regulate gene expression only if both signals were present. The researchers created several such combinations, using the molecules theophylline and tetracycline as the signals, and were able to regulate levels of GFP expression. "They basically achieved a sophisticated control of the fluorescence molecule, depending on whether or not the aptamer was able to sense" the input molecule, Shapiro explained. Most previous cell engineering attempts have relied on DNA computing or protein systems, but this is the first demonstration of relatively complex functions being built into an RNA device. "The nice thing about RNA is that this is one molecule we've learned to engineer to a certain extent," said Shapiro. Using RNA has several advantages, Smolke explained. First, it's a relatively simple molecule, composed of just four building blocks, compared with proteins' 20 amino acids. Also, researchers have a better understanding of how structure relates to function in RNA than in proteins, where structure plays a more complex role. Since RNA primarily folds into a 2-dimensional structure, a few clicks of a computer mouse can accurately predict how the RNA molecule will interact with other components of the cell. "That gives me a very powerful design capability," said Smolke. "It's something you can't do with proteins." But the real advances in the field are yet to come, said Shapiro, noting that researchers have been able to create much more sophisticated devices than Smolke's in vitro. His own group, for example, created a linkurl:DNA computer;http://www.nature.com/nature/journal/v429/n6990/abs/nature02551.html that could deliver a drug molecule upon sensing and diagnosing a disease symptom. "Just by comparing what has already been accomplished in vitro, you can see there is more work to do in vivo," he said. "Every year or two there is an advance in this field -- they're all exciting, but there's still a long road."

A computer for living cells

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