HEALTH

BLACKSBURG, VA -- Understanding the genes and proteins that underlie the behavior of cells is similar to trying to figure out how a VCR works without an instruction manual, said John Tyson, University Distinguished professor of biology at Virginia Tech. Faculty members in Virginia Tech’s Departments of Biology and Computer Science are working together to take part in a new $50-million multidisciplinary, multi-university program called BioSPICE: Simulation Program for Intracellular Evaluation. Sponsored by the Defense Advanced Research Projects Agency (DARPA), the program is intended to create computer software for modeling the genes and proteins that underlie cellular behavior. The eventual goal is to understand the molecular mechanisms underlying such processes as bacterial contamination, jet lag, and wound healing. DARPA is supporting approximately 15 groups around the country working toward that goal in four basic areas: model kernel, experimental evaluation, software development, and software integration. The Virginia Tech Consortium has been awarded $1.65 million for three years to study cell-cycle regulation by mathematical modeling, experimental analysis, and computer simulation. The modeling group is trying to create accurate, reliable mathematical representations of the molecular mechanisms controlling DNA replication and cell division. The team includes Tyson and Kathy Chen at Virginia Tech, Bela Novak at the Budapest University of Technology and Economics, and several students. The experimental group, which is testing and refining the models in the laboratory, is directed by Virginia Tech’s Jill Sible, a biologist who studies frog eggs, and by yeast geneticist Fred Cross (Rockefeller University) and biochemist Michael Mendenhall (University of Kentucky Medical School). The software-development group consists of Virginia Tech computer scientists, led by Layne Watson, Cliff Shaffer, and Naren Ramakrishnan, who are creating software tools to assist modelers and experimentalists. "To understand how cells respond to their environments, we must understand the molecular machinery that lies inside," Tyson said. "Geneticists can open the cell and identify the relevant genes and proteins and how they connect to each other. From this information, we have to reconstruct the ‘wiring diagram’ of the cell’s control circuits—something like the wiring diagram for a VCR, only much more complicated. The challenge is to figure out how the cell works, so we can control it to our advantage or fix it when it’s broken. The problem is, cells don’t come with instruction manuals, or even with certified wiring diagrams. We have to guess the wiring diagram from the clues supplied by geneticists and biochemists, and then figure out how the contraption works." To do this, modelers convert their hypothetical wiring diagram into precise mathematical equations and use computers to predict the behavior of the model. They then compare the behavior of the model with the observed behavior of cells to see if the hypothesis and reality agree, Tyson said. "If they do, then we can have some confidence that the wiring diagram is correct, and we can use it to predict new experiments. From beginning to end, we need to collaborate closely with experimentalists to give us specific information about the mechanism itself and the idiosyncratic behavior of real, living cells." For many years, theoretical biologists have been building small models with restricted sets of experiments, but the goal of BioSPICE is to create software to facilitate simulation of complex, realistic molecular control systems—simulations that can be truly useful in solving military and health-related problems, Tyson said. He likened this to the change in the electronics industry: "When people were designing toasters and crystal radios," Tyson said, "they could do it without a fancy computer. Now, however, electrical circuits are so complicated, you can’t guess how they’ll work; you can’t even write down the governing equations by hand. Electrical engineers have programs to assist in the design of integrated circuits. BioSPICE will do the same for genetic engineers who want to understand the integrated molecular circuits within cells. Without these software tools, it will be impossible for scientists to take the next step in understanding the molecular basis of life." Understanding cell behavior can help in many situations. The Department of Defense (DOD), for example, is interested in how bacteria multiply, contaminate things, and survive adverse conditions. "All these processes have molecular bases," Tyson said. "If you want to get rid of harmful bacteria or re-engineer helpful ones, you must understand how the underlying molecular machinery works. To do this, we need the kind of simulation environment promised by BioSPICE." The DOD also is interested in the daily rhythms that control sleep and wakefulness. "There’s a molecular basis for our circadian rhythm, and it seriously impairs effectiveness when people cross time zones, do night work, or stay up for long periods of time," Tyson said. "The DOD is interested in improving human performance under such adverse conditions." The DOD is also interested, for obvious reasons, in the molecular mechanisms behind wound healing and the regeneration of nerve tissue, he said. About 15 other universities, including the University of California at Berkeley, Caltech, Harvard, the University of Pennsylvania, and Boston University, plus private companies, are involved in the program. The teams will collaborate to build software tools and models that will be useful because they are developed in the context of real research problems. SRI of Stanford, Cal., will carry out the project’s fourth phase, systems integration. "Their job is to pull together the models and software developed by other teams and put them into a computational environment where everything can work together," Tyson said. When finished, BioSPICE will be an open-source program, meaning that anyone can use the problem-solving software to approach his or her own problems in cell physiology. Any improvements made by those using the software will, in turn, be brought back into the central repository. "It will grow and get better as people use it," Tyson said.