APPLICATIONS

Scientists at the University of Chicago and Argonne National Laboratory have constructed a computer simulation that allows them to study the relationship between biochemical fluctuations within a single cell and the cell’s behavior as it interacts with other cells and its environment. The simulation, called AgentCell, has possible applications in cancer research, drug development and combating bioterrorism. Other simulations of biological systems are limited to the molecular level, the single-cell level or the level of bacterial populations. AgentCell can simultaneously simulate activity on all three scales, something its creators believe no other software can do. “With AgentCell we can simulate the behavior of entire populations of cells as they sense their environment, respond to stimuli and move in a three-dimensional world,” said Thierry Emonet, a Research Scientist in Philippe Cluzel’s laboratory at the University of Chicago’s Institute for Biophysical Dynamics. Emonet and his colleagues have verified the accuracy of AgentCell in biological experiments. AgentCell now enables scientists rapidly to run test experiments on the computer, saving them valuable time in the laboratory later. Emonet is the lead author of a paper announcing the development of AgentCell that was published in the June 1 issue of the semimonthly journal Bioinformatics. His co-authors are Argonne’s Charles Macal and Michael North, and the University of Chicago’s Charles Wickersham and Philippe Cluzel. The work was funded by the U.S. Department of Energy and the University of Chicago/Argonne National Laboratory Seed Grant Program. AgentCell will be used to tackle a major goal in single-cell biology today: to document the connection between internal biochemical fluctuations and cellular behavior. “The belief is that these fluctuations are going to be reflected in the behavior of the cell as shown experimentally by John Spudich and Daniel Koshland in 1976,” Emonet said. They may even reveal why cells sometimes act as individuals and sometimes as part of a community. AgentCell was made possible by agent-based software, which researchers developed to simulate stock markets, social behavior and warfare. Argonne’s Macal and North contributed their agent-based software expertise to the project. Macal and North operate Argonne’s Center for Adaptive Systems Simulation. Cluzel’s laboratory began its collaboration with Macal and North following a suggestion by Robert Rosner, Argonne’s Director and the William Wrather Distinguished Service Professor in Astronomy & Astrophysics at the University of Chicago. Before shifting to Cluzel’s lab, Emonet worked with Rosner in devising simulations to understand how the sun reverses its magnetic field every 11 years. Each digital cell in AgentCell is a virtual Escherichia coli, a single-celled bacterium, which is equipped with all the virtual components necessary to search for food. These digital E. coli contain their own chemotaxis system, which transmits the biochemical signals responsible for cellular locomotion. They also have flagella, the whiplike appendages that cells use for propulsion, and the motors to drive them. Emonet and his associates have designed their digital bacterial system in modules, so that additional components may be added later. “Right now it’s a very simple model,” Emonet said. “Basically the only thing those cells have is a sensory system.” But additional components that simulate other biological processes—cell division, for example—can also be introduced. And the software is available to other members of the research community for the asking. “The hope is that people will modify the code or add some new capabilities. The code will soon be available for download from our Web site, http://www.agentcell.org,” Emonet said. AgentCell has already yielded benefits in Cluzel’s laboratory, even in its current rather simple configuration. In his simulations, Emonet discovered that one type of protein controlled the sensitivity of E. coli’s chemotaxis system, which helps the bacteria find food. "When you changed the level of that protein, it would change the sensitivity of the cell,” Emonet said. Subsequent laboratory experiments came out exactly the same way. Sometimes, though, conducting the actual experiment would be undesirable. Preparing for a bioterrorism attack is one example. “You can actually try to simulate dangerous experiments,” said Cluzel, an Assistant Professor in Physics. “For instance, if you mix a pathogenic strain with a friendly strain, which one is going to win, and with what kind of speed?”