MOSES - MicroOrganism Systems Biology: Energy and Saccharomyces cerevisiae: Coordination plus WPs 1 and 7 and contributions to 5 and 6

To complement existing top-down and bottom-up SB strategies, here a domino, problem oriented SB approach is developed, which follows the lines of regulation, pertinent to a selected highly connected molecule property. The selected property is ATP ('energy'). The approach is developed in the most suitable, well-defined, industrially most relevant organism, baker's yeast. The MOSES program connects yeast Systems Biology nuclei in SYSMO countries and is associated with the Yeast Systems Biology Network and HepatoSys. It will be open to new groups. Yeast helps us produce bread, wine and beer. It is also one of the fastest growing organisms: When provided with an excess of food it utilizes this as quickly as it can. Under such conditions of 'feast', the organism uses the energy very inefficiently. Under conditions of 'famine' yeast changes its strategy. It reduces the rate at which it grows and produces alcohol, tries to switch to producing carbon dioxide (the greenhouse gas) only. It then resumes growth but much more efficiently and more slowly. All of this involves subtle regulation of many processes at the same time. It was previously thought that regulation of this type is achieved by single 'key' molecules that would either be in an 'on' state or in an 'off' state. Recently, it has become clear that in living organisms, regulation tends to involve networks of many molecules. This makes biological regulation much more difficult to understand and may be one reason why the sciences still have a hard time to find effective treatments for the complex diseases that plague us, such as cancer, diabetes and arthritis. A new type of science is being developed that focuses on this network aspect of living organisms. It is called 'Systems Biology'. Until now most Systems Biology has either begun by looking at all of the many, many molecules of living organisms at the same time, or by looking at just a very few of them. The former approach tends to be so complex that it leads to confusion more than understanding. The latter may lead to understanding that may not be relevant to the living organism as a whole. Here we propose to develop a new type of Systems Biology, called domino systems biology. It begins by assessing what are the strongest regulatory routes and molecules in the network and then studies these first. It then has a mechanism to move to the next important regulatory routes and molecules, etc. The energy state of the cell may be read from the intracellular concentration of the molecule ATP. This molecules ATP is known to provide many important intracellular processes with the energy they require. We here propose to develop domino systems biology for yeast starting with the regulatory routes that involve ATP. The project is a collaboration between the most appropriate groups of five European countries. It is likely to result in understanding of how yeast can be made to do the things it does for us more efficiently. The domino systems biology developed should be an invaluable tool also for the analysis of diseased cells and the discovery of better drug targets.

This project develops 'domino systems biology'. It first focuses on a major process of the living cell and implements hierarchical regulation analysis to quantify whether gene-expression, signal-transduction, or metabolic regulation is the strongest. It then identifies which molecules are most strongly and directly regulating and determines by control analysis to what extents the concentrations of these molecules are controlled by the main processes in the cell. The results then quantify the strengths of the strongest regulatory loops. These regulatory loops are then further analyzed in terms of the strengths of the regulatory links within them. Subsequently, the weaker regulatory loops are analyzed. The approach will be developed for the regulation of the functioning of S. cerevisiae through central energy metabolism (e.g. ATP), first at low resolution, decomposing it system into catabolism, anabolism and maintenance. It will determine quantitatively how much regulation involves ATP and is metabolic, through gene expression, and through signal transduction modifying the covalent modification of enzymes. The biological functions studied include growth rate and yield, the rate of extrusion of toxins by P-glycoproteins and DNA repair. The study will focus on the regulation that occurs in response to starvation, osmotic shock and temperature changes. Important to the project is the standardization of the experiments, of the modelling, of the data handling, and of the way the systems biology is managed as a programme involving multiple groups in five different European countries. The experiments done by the various partners are planned together (Platform 1) and the analysis of the experimental results is again framed in mathematical models by all partners together (Platform 2). The two BBSRC projects in this transnational SYSMO program focus on the coordination and analysis (Westerhoff) and on the metabolomics and kinetics (Kell), respectively.