Drs. Naren Ramakrishnan, a Virginia Tech computer scientist, and Upinder S. Bhalla at the National Centre for Biological Sciences in India, have developed a computer method to identify signaling biochemical switches within cells that are responsible for all the communications happening inside.
The National Science Foundation explains:
In the July 2008 edition of PLoS Computational Biology, they detail how they used the System X supercomputer at Virginia Tech to search for “switch-like” combinations within a cell’s store of possible chemical reactions. They programmed the computer to look for combinations that formed what are known as bistable circuits, that is, groups of chemical reactions that can be switched back and forth into two separate but stable states. This allows a cell to use chemical compounds to model state, much like a transistor switch that can be set to a steady ‘one’ or ‘zero.’
Finding these potential switches among all the hundreds of thousands of reaction combinations in a cell is no easy task. Ramakrishnan and Bhalla estimate that it would take a standard computer approximately one hundred years of continual computations to test them all. But using the System X supercomputer, the researchers were able to identify thousands of switches in a relatively short period of time. They produced a catalogue of all the switch combinations they discovered, providing an invaluable guide to future research.
The System X supercomputer also enabled the researchers to map out a ‘family tree’ of the switches, which led to another intriguing discovery–although the switches are different, they are related to each other. According to Bhalla, this discovery may offer an insight into how switch designs evolved within cells.
Now other scientists trying to understand how cells function and how cells can be manipulated to correct abnormalities caused by disease or genetic mutations can utilize this catalogue of switches in their own research. But Ramakrishnan and Bhalla want to continue to use the same viewpoint of an electrical engineer to study cells.
From the study abstract:
Just as complex electronic circuits are built from simple Boolean gates, diverse biological functions, including signal transduction, differentiation, and stress response, frequently use biochemical switches as a functional module. A relatively small number of such switches have been described in the literature, and these exhibit considerable diversity in chemical topology. We asked if biochemical switches are indeed rare and if there are common chemical motifs and family relationships among such switches. We performed a systematic exploration of chemical reaction space by generating all possible stoichiometrically valid chemical configurations up to 3 molecules and 6 reactions and up to 4 molecules and 3 reactions. We used Monte Carlo sampling of parameter space for each such configuration to generate specific models and checked each model for switching properties. We found nearly 4,500 reaction topologies, or about 10% of our tested configurations, that demonstrate switching behavior. Commonly accepted topological features such as feedback were poor predictors of bistability, and we identified new reaction motifs that were likely to be found in switches. Furthermore, the discovered switches were related in that most of the larger configurations were derived from smaller ones by addition of one or more reactions. To explore even larger configurations, we developed two tools: the “bistabilizer,” which converts almost-bistable systems into bistable ones, and frequent motif mining, which helps rank untested configurations. Both of these tools increased the coverage of our library of bistable systems. Thus, our systematic exploration of chemical reaction space has produced a valuable resource for investigating the key signaling motif of bistability.
NSF press release: Finding the Switches to Our Cells’ ‘Computer’
Abstract: Memory Switches in Chemical Reaction Space; PLoS Computational Biology 4(7): e1000122 doi:10.1371/journal.pcbi.1000122
Image: This computer-generated image shows the “family” of switches and how they are related