Molecular logic inches towards smart therapeutics for living cells

US scientists have assembled ribonucleic acids into an adaptable logic system that can be programmed to sense and respond to molecules inside living yeast cells. The work paves the way towards the dream of artificial computing devices that could monitor cell conditions and take appropriate action - such as sending out drugs to treat a diseased cell.

The biological computers, made entirely of RNA, control the translation of messenger RNA (mRNA) into proteins. So far they have only been embedded into the mRNA of green fluorescent protein (GFP), in order to make yeast cells glow green in response to the presence of particular molecules. But in theory the response could be any molecular function, says Christina Smolke, who led the study at the California Institute of Technology.

Though biological computing devices have been made before, Smolke stresses that her work describes a general framework for building RNA-based biocomputers. The system is easy to program, she says, because it is made of three separately adjustable components, analogous to the ’plug-and-play’ modules of electronic circuits. 

"It’s a step towards fulfilment of a very big dream where you would have complete artificial circuits making various decisions in the cell. In five or ten years the whole picture will come together" - Milan Stojanovic, Columbia University, New York

The sensor of each device is made from an RNA aptamer, a short sequence that binds specific target molecules. This is coupled, using another RNA strand, to a ribozyme, a final strand of RNA that can cleave mRNA. When an ’input’ molecule binds to the sensor, this causes a conformational change in the ribozyme - either causing it to cleave the mRNA, or shutting it down. 

’We group the components under three functional categories: sensor, transmitter, and actuator,’ says Smolke. ’So as long as a piece of RNA is a sensor, for example, you can pop it into this part of the device. And so you have this "plug-and-play ability" that allows you to assemble very diverse functions from a very small number of well defined components.’

Smolke and co-author Maung Nyan Win used their system to create biomolecular logic gates, mirroring those in electronic circuits. Their RNA devices are the first to make multi-input computations (reacting to two or more molecules at the same time). In a simple example - an AND gate - fluorescence in the yeast cells was detected only when two molecular inputs, theophylline and tetracycline, were both present.

’It’s a step in the right direction,’ says Milan Stojanovic, an experimental therapeutics expert studying biocomputation at Columbia University in New York. ’A step towards eventual fulfilment of some very big dream where you would have complete artificial circuits making various decisions in the cell. My expectation is that in five or ten years, the whole picture will come together.’

Friedrich Simmel, who studies biomolecular computing at the Technical University of Munich in Germany, says, ’It’s hard to say whether it will work in practice but in principle you can make incredibly complicated logical computations with the few functions that are demonstrated here.’

Hayley Birch

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