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Two papers published in the 1st March issue of the journal Science describe Systems Biology studies of a bacterium Bacillus subtilis. Bacteria are among the simplest living organisms. Nevertheless many bacteria such as B. subtilis are versatile and able to survive and grow in diverse and changing environments. B. subtilis lives naturally in the soil, but it is widely used as a laboratory organism for basic research and it is commercially important. B. subtilis is used in the food industry for the production of vitamins and in the biotechnology industry for the production of enzymes such as those used in washing powders.
To survive in its changing natural as well as laboratory and industrial environments, B. subtilis adapts to the diverse conditions. A consortium of researchers from eight European countries and Australia has collaborated on an EC funded project BaSysBio which sought to understand these adaptations. The emphasis was on understanding the cell as a system of interacting molecular components and on defining the strategies used in adaptation. This level of understanding requires the acquisition and analysis of large experimental data sets and their combination with mathematical models in the developing field of Systems Biology.
Models are necessary to capture the complexity the cellular system. The B. subtilis genome carries about 4200 genes that can be transcribed (expressed) into messenger RNA molecules from which proteins are then made. These proteins catalyze the chemistry of life including energy generating reactions and biosynthesis. The amount and activity for each of these cellular components may be adjusted by the cell during its adaptation to a new environment. This generates a system of enormous complexity.
The repertoire of genes expressed under more than a hundred different conditions, which mimic the natural, laboratory and industrial environments of B. subtilis, was determined [link to Nicolas et al in Science, Link to]. Through this study of unprecedented scope, we have been able to infer how the B. subtilis transcription network is regulated during adaptation to nutritional changes and physical and chemical stresses [Link to]. The study identified 512 new potential genes and abundant antisense RNAs. It also identified over 3000 promoters which were classified according to their activity profiles by a newly developed statistical approach. Groups of genes with similar profiles were associated with various types of the gene expression machinery (RNA polymerase sigma factors), allowing for the first time to quantify the contribution of the sigma factors in the variation of gene expression. We discovered that switching between sigma factors accounts for two thirds of the variance in promoter activity. This is therefore the major mechanism by which cells trigger a new genetic program. Moreover, we analysed quantitatively the origins of antisense transcription, and found that the majority of antisense RNAs arise from spurious initiation and/or imperfect termination. This suggests that not all antisense RNAs have biological functions.

Bacillus subtilis grows equally well when consuming the sugars glucose or malate. We investigate the seemingly simply adaptation of B. subtilis from growth on a single nutrient to a situation when additionally one other nutrient is available [link to Buescher et al in Science, Link to]. If one was to design a cell to achieve this task, only a handful of changes would be necessary. By using a novel combination of computational methods, we were able to show that adaptation to malate addition is almost instantaneous and primarily controlled by changes in the activities of enzymes already present. Surprisingly, the adaptation to glucose addition is much slower with huge changes that involve almost half of the 4200 genes of this organism. Why do cells launch such a major reorganization when few simple changes would have been enough? Based on a computational model, we show that under certain environmental conditions, evolution favors complex rather than simple regulation programs that enable cells to optimize their performance. Since many cells feature such complex regulation, our results are of general significance.

The two studies are relevant far beyond the model bacterium B. subtilis because they represent a blueprint for bacterial systems biology. Indeed, interdisciplinary experimental and computational methodologies are developed to unravel how cellular adaptation is coordinated and what the key events are. This systems biology approach lays a foundation for applications in biotechnology and medicine. Indeed, application of our approach to poorly studied bacteria of medical or biotechnological relevance could be a very powerful means of global functional characterization. For example, understanding how pathogenic bacteria adapt during the infection process will help develop strategies to combat them.