TY - JOUR

T1 - Systems biology towards life in silico

T2 - Mathematics of the control of living cells

AU - Westerhoff, Hans V.

AU - Kolodkin, Alexey

AU - Conradie, Riaan

AU - Wilkinson, Stephen J.

AU - Bruggeman, Frank J.

AU - Krab, Klaas

AU - van Schuppen, Jan H.

AU - Hardin, Hanna

AU - Bakker, Barbara M.

AU - Moné, Martijn J.

AU - Rybakova, Katja N.

AU - Eijken, Marco

AU - van Leeuwen, Hans J.P.

AU - Snoep, Jacky L.

PY - 2009/1

Y1 - 2009/1

N2 - Systems Biology is the science that aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their system. Dedicated to the memory of Reinhart Heinrich, this paper discusses the origin and evolution of the new part of systems biology that relates to metabolic and signal-transduction pathways and extends mathematical biology so as to address postgenomic experimental reality. Various approaches to modeling the dynamics generated by metabolic and signal-transduction pathways are compared. The silicon cell approach aims to describe the intracellular network of interest precisely, by numerically integrating the precise rate equations that characterize the ways macromolecules' interact with each other. The non-equilibrium thermodynamic or 'lin-log' approach approximates the enzyme rate equations in terms of linear functions of the logarithms of the concentrations. Biochemical Systems Analysis approximates in terms of power laws. Importantly all these approaches link system behavior to molecular interaction properties. The latter two do this less precisely but enable analytical solutions. By limiting the questions asked, to optimal flux patterns, or to control of fluxes and concentrations around the (patho)physiological state, Flux Balance Analysis and Metabolic/Hierarchical Control Analysis again enable analytical solutions. Both the silicon cell approach and Metabolic/Hierarchical Control Analysis are able to highlight where and how system function derives from molecular interactions. The latter approach has also discovered a set of fundamental principles underlying the control of biological systems. The new law that relates concentration control to control by time is illustrated for an important signal transduction pathway, i.e. nuclear hormone receptor signaling such as relevant to bone formation. It is envisaged that there ismuch more Mathematical Biology to be discovered in the area between molecules and Life.

AB - Systems Biology is the science that aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their system. Dedicated to the memory of Reinhart Heinrich, this paper discusses the origin and evolution of the new part of systems biology that relates to metabolic and signal-transduction pathways and extends mathematical biology so as to address postgenomic experimental reality. Various approaches to modeling the dynamics generated by metabolic and signal-transduction pathways are compared. The silicon cell approach aims to describe the intracellular network of interest precisely, by numerically integrating the precise rate equations that characterize the ways macromolecules' interact with each other. The non-equilibrium thermodynamic or 'lin-log' approach approximates the enzyme rate equations in terms of linear functions of the logarithms of the concentrations. Biochemical Systems Analysis approximates in terms of power laws. Importantly all these approaches link system behavior to molecular interaction properties. The latter two do this less precisely but enable analytical solutions. By limiting the questions asked, to optimal flux patterns, or to control of fluxes and concentrations around the (patho)physiological state, Flux Balance Analysis and Metabolic/Hierarchical Control Analysis again enable analytical solutions. Both the silicon cell approach and Metabolic/Hierarchical Control Analysis are able to highlight where and how system function derives from molecular interactions. The latter approach has also discovered a set of fundamental principles underlying the control of biological systems. The new law that relates concentration control to control by time is illustrated for an important signal transduction pathway, i.e. nuclear hormone receptor signaling such as relevant to bone formation. It is envisaged that there ismuch more Mathematical Biology to be discovered in the area between molecules and Life.

KW - Flux balance analysis

KW - Glucocorticoid receptors

KW - Metabolic control analysis

KW - Modeling

KW - Signal transduction

KW - Silicon cell

KW - Systems behaviour

KW - Systems biology

UR - http://www.scopus.com/inward/record.url?scp=62049085905&partnerID=8YFLogxK

U2 - 10.1007/s00285-008-0160-8

DO - 10.1007/s00285-008-0160-8

M3 - Article

C2 - 18278498

AN - SCOPUS:62049085905

VL - 58

SP - 7

EP - 34

JO - Journal of Mathematical Biology

JF - Journal of Mathematical Biology

SN - 0303-6812

IS - 1-2

ER -