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Bioengineers Develop First Genome-Scale Computational Model of Gene Regulation

It has taken more than half a century to accumulate the current body of knowledge on Escherichia coli, a bacterium which is one of the best studied organisms in biology. Now Jacobs School bioengineers have integrated this knowledge into the first genome-scale model of the gene regulatory system in E.coli.

"This research is evidence of how much more quickly biological discovery is going to progress now, given that we have high-throughput experimental tools for gathering large volumes of data, and the use of these tools can be guided by computer models," said Bernhard Palsson, professor of bioengineering at the Jacobs School. Palsson co-authored the study, published in the May 6, 2004 issue of Nature, with his UCSD bioengineering student Markus Covert, who is now a post-doctoral researcher at the California Institute of Technology.

In 2000, Palsson completed an in silico (computational) model of E.coli metabolism that is being used by scientists worldwide to design and interpret laboratory experiments as well as engineer strains for industrial purposes. In this more recent work, Covert modeled the regulatory network in E.coli representing how the cell responds to environmental cues and expresses genes involved in cellular metabolism. He scoured the scientific literature to reconstruct an E.coli model incorporating all known data about regulatory network components, their functions and their actions.

The UCSD model now includes a network for 1,010 genes, including 104 regulatory genes, whose products together with other molecules regulate the expression of 479 of the 906 genes known to be involved in metabolism.

"UCSD recognized the importance of this embryonic field of systems biology ahead of many others. We have quietly been implementing plans - hiring faculty and developing core curriculum at the graduate and more recently\ the undergraduate level." -Bernhard Palsson
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. The team found 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.

Palsson is one of a dozen bioengineering and computer science faculty at the Jacobs School who are focusing on the emerging fields of systems biology and bioinformatics. Their holy grail is to understand how living systems are "engineered," and to develop predictive models of biological function based on a global understanding of how genes and molecules relate to one another in health and disease.

"This work could revolutionize biomedicine and drug discovery," said bioengineering professor Shankar Subramaniam, who is leveraging the computing power of the San Diego Supercomputer Center to lead the data integration efforts for two of the nation's largest bioinformatics initiatives - the $50 million Alliance for Cellular Signaling and the $35 million Lipid MAPS Consortium.

Educating the Next Generation
While systems biology and bioinformatics hold great promise for advancing medicine, Subramaniam says it requires a new breed of scientists cross-trained in both computational analysis and the latest technologies for systematic biological experimentation.

Subramaniam led the development of the UCSD graduate program in bioinformatics, which was established as one of the first of its kind in 2001 and has been heralded by the NIH as a model program in the country. The program has also been extended to undergraduates and there are now 27 Ph.D. candidates and 30 undergraduate students pursuing degrees in bioinformatics at UCSD.

In his commentary for the April issue of Nature Biotechnology, Jacobs School bioengineering professor Trey Ideker reported that at least 17 universities worldwide have begun offering courses in systems biology within the past two years. At UCSD, the Jacobs School Department of Bioengineering introduced a sequence of three graduate-level courses in systems biology this year, including such topics as biological components, network reconstruction, and building and simulating largescale in silico models.

Of mice, men... and rats
Bioinformatics expert Pavel Pevzner (CSE) and two co-authors depict the course of evolution for the X chromosome in humans, rats and mice from a common ancestor over 80 million years ago (Genome Research May 2004, cover image). Pevzner also coauthored a consortium’s official publication of the rat genome in the journal Nature.