1. Mathematical Models for Systems Biology and How to Construct Them

Chris P. Barnes, Maxime Huvet, Nathan Harmston and Michael P.H. Stumpf

Modelling methodologies in the life- and biomedical sciences are hampered by the complexity of the processes and systems at work. Modelling studies into prokaryotic systems require the elucidation of the mechanistic model. In this chapter we introduction modelling methodologies and discuss the problem of model (and parameter) inference. We comment on state-of-the-art research questions and provide a general discussion on how models can and should be used in order to better understand the structure, function and dynamics of biological systems. The aim is not to provide an introduction to modelling per se, but to provide readers with an overview on the available methodologies. The modelling approach chosen depends on the biological question at hand as well as a range of social factors.

2. Dynamics and Robustness of Metabolic Networks: a Systems Biology Review of Escherichia coli Metabolism

Eivind Almaas, Per Bruheim, Rahmi Lale and Svein Valla

The functional repertoire of an organism's metabolic network is closely linked to its phenotype and potential for utility in metabolic engineering applications. In this chapter, we discuss a systems biology view of Escherichia coli metabolism by integrating current genome-scale computational modelling approaches with available molecular genetics tools, as well as the experimental framework for metabolite and metabolic flux determination.

3. Bacterial Chemotaxis: Rising Complexity

Diana Clausznitzer, Judith P. Armitage and Robert G. Endres

Bacterial chemotaxis is a paradigm for biological sensing and information transmission. The chemotaxis signal-transduction pathway allows cells to sense chemicals in their surroundings in order to regulate flagellated rotary motors, thus allowing them to swim towards nutrients and away from toxins. Importantly, cells are able to sense with remarkably high sensitivity over a wide range of chemical background concentrations. To make this possible, chemoreceptors do not signal independently but form clusters for amplification and integration of signals, as well as for adaptation to persistent stimulation. While chemotaxis in Escherichia coli has been exceptionally well characterised, new experimental facts still require revisions of existing models and thus further increase our understanding of sensing and signalling in bacteria. Additionally, experiments on other bacterial species such as Bacillus subtilis and Rhodobacter sphaeroides indicate that bacteria other than E. coli can have substantially different and more complex chemotaxis pathways, which provides renewed challenges for experimentalists and modellers alike. Here we discuss our current understanding as well as the frontiers of bacterial chemotaxis research.

4. Systems Biology of Infection: the Pathogen Perspective

Dirk Bumann

Microbial infections still cause around one quarter of all deaths globally, despite the advances that have been made in the treatment of infectious disease. The increasing occurrence of drug resistant pathogens, both old and new, coupled with an increasingly mobile human population has creatd many novel opportunities for potential pathogens to meet new human hosts. All of this requires new prevention and control strategies but progress has been slow, despite recent technological advances and increased investment. The rapid increase in data proved difficult to translate into practical applications for human health care, and new approaches and analyses are needed to make the most of new opportunities. One of these is the use of the new tools of systems biology and this chapter will review the application of these to microbial pathogens.

5. Manipulating the Fight Between Human Host Cells and Intracellular Pathogens

Rico Barsacchi, Varadharajan Sundaramurthy, Kees Korbee, Jacques Neefjes, Tom Ottenhoff, Tiziana Scanu and Marino Zerial

Host-microbe interactions are complex phenomena spanning multiple levels of complexity, from environmental and ecological factors up to the cellular and genetic levels of host responses. At each of these levels a relationship is established between one or more microorganisms and the host, resulting in formation of various forms of associations ranging from symbiosis to parasitism. Pathogens have the potential to cause disease in their hosts through host-pathogen interactions in which host defences are challenged by the invasive capacities of the pathogen. The aim of this chapter is to give an outline of attempts made to unravel the components of host-pathogen interactions at the cellular and molecular levels and to discuss strategies to skew the balance in favour of the host, focusing our attention on crucial intracellular pathogens causing globally relevant diseases such as tuberculosis, gastroenteritis, influenza and malaria.

6. How One Cell Eats Another: Principles of Phagocytosis

Sylvain Tollis, Navin Gopaldass, Thierry Soldati and Robert G. Endres

Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by deforming their plasma membrane. Particle engulfment involves particle recognition by cell-surface receptors, signalling, and remodelling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. The signalling complexity is daunting, involving hundreds of different molecular species during the initial stages of engulfment. For instance, the well-characterised immune Fcγ and the integrin CR3 receptors signal to tyrosine kinases and Rho GTPases, ultimately regulating a wide variety of proteins, which direct actin polymerization and myosin-motor proteins for force generation and contraction. Despite the signalling complexity, phagocytosis also depends strongly on simple biophysical parameters, such as shape and cell stiffness, or membrane biophysical properties that are independent of the type of cell or particle. We argue that these emergent, universal features are particularly important to address in order to explain this evolutionary well-conserved and robust mechanism. In this chapter we review these universal features to describe the principles of phagocytosis. Specifically, we use a recently published model of phagocytic engulfment as a guide. Finally, we discuss state-of-the-art live-cell fluorescence microscopy, recently used to elucidate the dynamics of phospholipids, actin polymerization and myosins in the particle-shape recognition by the amoeba Dictyostelium.

7. System-level Strategies for Studying the Metabolism of Mycobacterium tuberculosis

Dany J.V. Beste and Johnjoe McFadden

Despite decades of research many aspects of the biology of Mycobacterium tuberculosis remain unclear and this is reflected in the antiquated tools available to treat and prevent tuberculosis. Consequently, this disease remains a serious public health problem responsible for 2 to 3 million deaths each year. Important discoveries linking M. tuberculosis metabolism and pathogenesis have renewed interest in the metabolic underpinning of the interaction between the pathogen and its host. Whereas, previous experimental studies tended to focus on the role of single genes, antigens or enzymes the central paradigm of systems biology is that the role of any gene cannot be determined in isolation from its context. Therefore systems approaches examine the role of genes and proteins embedded within a network of interactions. We here examine the application of this approach to studying metabolism of M. tuberculosis. Recent advances in high throughput experimental technologies, such as functional genomics and metabolomics, provide datasets that can be analysed with computational tools such as flux balance analysis. These new approaches allow metabolism to be studied on a genome scale and have already been applied to gain insights into the metabolic pathways utilized by M. tuberculosis in vitro and identify potential drug targets. The information from these studies will fundamentally change our approach to tuberculosis research and lead to new targets for therapeutic drugs and vaccines.

8. Sulfolobus Systems Biology: Cool Hot Design for Metabolic Pathways

Theresa Kouril, Alexey Kolodkin, Melanie Zaparty, Ralf Steuer, Peter Ruoff, Hans V. Westerhoff, Jacky Snoep, Bettina Siebers and the SulfoSYS consortium

Life at high temperature challenges the stability of macromolecules and cellular components, but also the stability of metabolites, which has received little attention. For the cell, the thermal instability of metabolites means it has to deal with the loss of free energy and carbon, or in more extremes, it might result in the accumulation of dead-end compounds. In order to elucidate the requirements and principles of metabolism at high temperature, we used a comparative blueprint modelling approach of the lower part of the glycolysis cycle. The conversion of glyceraldehyde 3-phosphate to pyruvate from the thermoacidophilic Crenarchaeon Sulfolobus solfataricus P2 (optimal growth-temperature 80ºC) was modelled based on the available blueprint model of the eukaryotic model organism Saccharomyces cerevisiae (optimal growth-temperature of 30ºC). In S. solfataricus only one reaction is different, namely glyceraldehyde-3-phosphate is directly converted into 3-phosphoglycerate by the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, omitting the extremely heat-instable 1,3-bisphosphoglycerate. By taking the temperature dependent non-enzymatic (spontaneous) degradation of 1,3-bisphosphoglycerate in account, modelling reveals that a hot lifestyle requires a cool design.