The team conducted a series of experiments focused on E. coli's response to oxygen deprivation. They made predictions of cellular behavior through simulations with the in silico model. These predictions guided high-throughput data-gathering experiments using gene chip technology. In the laboratory, the team created strains of E. coli in which genes involved in oxygen regulation were deleted, and then subjected the strains to experiments both with and without oxygen. When the predicted outcomes did not match the experimental outcomes, the experimental data was used to update the in silico model.

Through this process, the team uncovered surprising new details about how E. coli responds to oxygen deprivation.

"We went into the experiments thinking that oxygen regulation is fairly well understood. But in one fell swoop, we identified 115 previously unknown regulatory mechanisms," said Covert. "For example, one interesting finding was that in several cases when a protein that transcribes a gene is active, the expression level of that gene is actually reduced. We also identified new regulatory interactions for genes that no one previously had described, basically opening up a whole new research frontier in terms of characterizing regulatory networks in E. coli."

Another observation by the team was that E. coli's regulatory network is much more complex than might be expected for such a relatively simple single-cell microbe. And that, Covert says, means that lessons learned through the E. coli modeling process will help scientists model much more advanced organisms such as mice and even humans.

UCSD has filed a patent on the model and is negotiating a license agreement. Palsson's group at UCSD will continue to develop the E. coli model, and is al
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Contact: Denine Hagen
dhagen@ucsd.edu
858-534-2920
University of California - San Diego
5-May-2004