System biology shows how bacteria adapt to changing circumstances

How can a soil bacterium like Bacillus subtilis stay alive in constantly changing circumstances (dry, warm, hot and cold)? Scientists from seven European countries and Australia have exposed Bacillus subtilis to 104 different conditions, and charted how the organism reacts with gene regulation, protein production and conversion products. For the first time, all the levels of regulation in a bacterium have been studied together. The researchers have published their results today in two articles in the leading scientific journal Science.

This approach to the entire system has resulted in computer models that can predict the functioning of a bacterium. ‘These insights into the complex regulation mechanisms of a relatively simple bacterium will be used to investigate how bacteria common in humans can cause diseases when circumstances are different’, states one of the researchers, Prof. Jan Maarten van Dijl of the department of Medical Microbiology of the University Medical Center Groningen (UMCG).

What is innovative in this research is the level of detail used to chart the regulation mechanisms. Usually only one level in the bacterium is examined, whereas here all levels have been studied as well as how they are related to one another. Intensive cooperation between biologists, bioinformatics scientists and mathematicians was needed for this system biological research. The articles in Science concern a description of the models used to describe how the bacterium works, and how they are used to better predict and test two important living conditions of the bacterium.

Stress conditions

Using 104 different stress conditions, the researchers replicated the situations Bacillus subtilis can be confronted with, and then used analyses to measure the physiological effects in living bacteria. To this end, about 3000 locations in the DNA were marked where gene reading begins. A complete series of new gene functions has also been clarified. Because data were gathered over time at all regulatory levels, i.e. the genome, the proteome and the metabolome, models able to predict which genes would become active under which conditions could be designed. Among other things, the researchers have been able to demonstrate that 96% of the genes of Bacillus subtilis play a role in physiological regulation.

Adaptation

With the help of the models developed, the researchers then studied how exactly Bacillus subtilis adapts itself to changing conditions. Two important living conditions for the bacterium were taken as a starting point. The living conditions differed in the range of nutrients/energy sources that the bacterium absorbs and processes. It could be ascertained how the bacterium switches between the uptake of one to another nutrient/energy source, and which parts of the regulatory mechanism were being used. The regulatory models developed appear to be able to predict the functioning of the bacterium well.

Evolutionary significance

The researchers asked themselves what from an evolutionary point of view could be the significance of the ability to take in and process different nutrients/energy sources. They calculated that from an energy point of view, the bacterium can live most frugally if in most instances it has one substance, namely malic acid. The findings are very plausible because Bacillus subtilis has a strong preference for the roots of plants that excrete exactly this organic compound. The researchers conclude that their findings can act as a model for the physiological regulation of bacteria that live in complex environments in which they are constantly challenged and constantly have to adapt.

New developments

Research on Bacillus subtilis is relevant because this soil bacterium is physiologically related to the common hospital bacterium Staphylococcus aureus. The insights from this research may also lead to a better understanding of the functioning of Staphylococcus aureus, which can cause serious illnesses. This may lay the basis for the development of a new generation of antibiotics that act on the regulatory mechanisms that the newly acquired system-wide insights relate to.

International cooperation

The research being reported on in Science was a four-year cooperation between 14 groups in 7 European countries and one group in Australia. Research funding to a total of 20 million Euro was acquired from the 7^th Framework Programme of the European Union and from SysMO, a European transnational research initiative in the field of Systems Biology of Microorganisms. The department of Medical Microbiology of the UMCG has contributed to the research by developing and standardizing methods for transcription analyses. What is innovative about it is that the transcription experiments could be performed in living cells and growing colonies and followed over time. In addition, tools were developed so that similar experiments could be conducted in various laboratories and the data be combined in a reliable way.