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Online ISSN 1751-8857 Print ISSN 1751-8849

IET Systems Biology

Volume 5, Issue 4, July 2011

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Volume 5, Issue 4

July 2011

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    • Validation and invalidation of systems biology models using robustness analysis
      • Author(s): D.G. Bates  and  C. Cosentino
      • Source: IET Systems Biology, Volume 5, Issue 4, p. 229 –244
      • DOI:  10.1049/iet-syb.2010.0072
      • Type: Article
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      • p. 229 –244 (16)
        Robustness, the ability of a system to function correctly in the presence of both internal and external uncertainty, has emerged as a key organising principle in many biological systems. Biological robustness has thus become a major focus of research in Systems Biology, particularly on the engineering–biology interface, since the concept of robustness was first rigorously defined in the context of engineering control systems. This review focuses on one particularly important aspect of robustness in Systems Biology, that is, the use of robustness analysis methods for the validation or invalidation of models of biological systems. With the explosive growth in quantitative modelling brought about by Systems Biology, the problem of validating, invalidating and discriminating between competing models of a biological system has become an increasingly important one. In this review, the authors provide a comprehensive overview of the tools and methods that are available for this task, and illustrate the wide range of biological systems to which this approach has been successfully applied.
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      Flux balance analysis for ethylene formation in genetically engineered Saccharomyces cerevisiae
      • Author(s): C. Larsson ; J.L. Snoep ; J. Norbeck ; E. Albers
      • Source: IET Systems Biology, Volume 5, Issue 4, p. 245 –251
      • DOI:  10.1049/iet-syb.2010.0027
      • Type: Article
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      • p. 245 –251 (7)
        Biosynthesis of ethylene (ethene) is mainly performed by plants and some bacteria and fungi, via two distinct metabolic routes. Plants use two steps, starting with S-adenosylmethionine, while the ethylene-forming microbes perform an oxygen dependent reaction using 2-oxoglutarate and arginine. Introduction of these systems into Saccharomyces cerevisiae was studied in silico. The reactions were added to a metabolic network of yeast and flux over the two networks was optimised for maximal ethylene formation. The maximal ethylene yields obtained for the two systems were similar in the range of 7–8 mol ethylene/10 mol glucose. The microbial metabolic network was used for testing different strategies to increase the ethylene formation. It was suggested that supplementation of exogenous proline, using a solely NAD-coupled glutamate dehydrogenase, and using glutamate as the nitrogen source, could increase the ethylene formation. Comparison of these in silico results with published experimental data for yeast expressing the microbial system confirmed an increased ethylene formation when changing nitrogen source from ammonium to glutamate. The theoretical analysis methods indicated a much higher maximal yield per glucose for ethylene than was experimentally observed. However, such high ethylene yields could only be obtained with a concomitant very high respiration (per glucose). Accordingly, when ethylene production was optimised under the additional constraint of restricted respiratory capacity (i.e. limited to experimentally measured values) the theoretical maximal ethylene yield was much lower at 0.2/10 mol glucose, and closer to the experimentally observed values.
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      Biomolecular implementation of linear I/O systems
      • Author(s): K. Oishi  and  E. Klavins
      • Source: IET Systems Biology, Volume 5, Issue 4, p. 252 –260
      • DOI:  10.1049/iet-syb.2010.0056
      • Type: Article
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      • p. 252 –260 (9)
        Linear I/O systems are a fundamental tool in systems theory, and have been used to design complex circuits and control systems in a variety of settings. Here we present a principled design method for implementing arbitrary linear I/O systems with biochemical reactions. This method relies on two levels of abstraction: first, an implementation of linear I/O systems using idealised chemical reactions, and second, an approximate implementation of the ideal chemical reactions with enzyme-free, entropy-driven DNA reactions. The ideal linear dynamics are shown to be closely approximated by the chemical reactions model and the DNA implementation. We illustrate the approach with integration, gain and summation as well as with the ubiquitous robust proportional-integral controller. [Includes supplementary material]
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      Integrated analysis of the gene neighbouring impact on bacterial metabolic networks
      • Author(s): P. Bordron ; D. Eveillard ; I. Rusu
      • Source: IET Systems Biology, Volume 5, Issue 4, p. 261 –268
      • DOI:  10.1049/iet-syb.2010.0070
      • Type: Article
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      • p. 261 –268 (8)
        Different levels of abstraction are needed to represent a living system. Unfortunately information of different nature is not superposable in an obvious way, but requires a dedicated framework. Because biological abstractions, i.e., genomic or metabolic information, can be easily respresented as graphs, it is intuitive to integrate them into a unique graph, in which one can perform graph analysis for investigating a given biological assumption. This study follows such a philosophy and completes a genome and metabolome combination. In a such integrated framework and as illustration, we applied a graph analysis that automatically investigates impacts of the gene adjacency to predict functional relationships between genes and reactions. Our approach, called SIPPER, creates a weighted graph, in which the weights rely on the given relationship between genes, and computes (alternative) chains of reactions catalysed by genes. This method, as a generalisation of methods already published, can be easily adapted to several biological assumptions, properties or measures. This paper evaluates SIPPER on Escherichia coli. We automatically extract subgraphs, called k-SIPs, and quantify their interest in both genomic and metabolic contexts by showing functional compounds like operons or functional modules. [Includes supplementary material]
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      Adaptation as a genome-wide autoregulatory principle in the stress response of yeast
      • Author(s): G. De Palo ; F. Eduati ; M. Zampieri ; B. Di Camillo ; G. Toffolo ; C. Altafini
      • Source: IET Systems Biology, Volume 5, Issue 4, p. 269 –279
      • DOI:  10.1049/iet-syb.2009.0050
      • Type: Article
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      • p. 269 –279 (11)
        The gene expression response of yeast to various types of stresses/perturbations shows a common functional and dynamical pattern for the vast majority of genes, characterised by a quick transient peak (affecting primarily short genes) followed by a return to the pre-stimulus level. Kinetically, this process of adaptation following the transient excursion can be modelled using a genome-wide autoregulatory mechanism by means of which yeast aims at maintaining a preferential concentration in its mRNA levels. The resulting feedback system explains well the different time constants observable in the transient response, while being in agreement with all the known experimental dynamical features. For example, it suggests that a very rapid transient can be induced also by a slowly varying concentration of the gene products. [Includes supplementary material]
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