Systems biology towards life in silico: mathematics of the control of living cells.

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 is much more Mathematical Biology to be discovered in the area between molecules and Life.

1,25-dihydroxyvitamin D(3)-independent stimulatory effect of estrogen on the expression of ECaC1 in the kidney.

Estrogen deficiency results in a negative Ca(2+) balance and bone loss in postmenopausal women. In addition to bone, the intestine and kidney are potential sites for estrogen action and are involved in Ca(2+) handling and regulation. The epithelial Ca(2+) channel ECaC1 (or TRPV5) is the entry channel involved in active Ca(2+) transport. Ca(2+) entry is followed by cytosolic diffusion, facilitated by calbindin-D(28K) and/or calbindin-D(9k), and active extrusion across the basolateral membrane by the Na(+)/Ca(2+)-exchanger (NCX1) and plasma membrane Ca(2+)-ATPase (PMCA1b). In this transcellular Ca(2+) transport, ECaC1 probably represents the final regulatory target for hormonal control. The aim of this study was to determine whether 17beta-estradiol (17beta-E(2)) is involved in Ca(2+) reabsorption via regulation of the expression of ECaC1. The ovariectomized rat model was used to investigate the regulation of ECaC1, at the mRNA and protein levels, by 17beta-E(2) replacement therapy. Using real-time quantitative PCR and immunohistochemical analyses, this study demonstrated that 17beta-E(2) treatment at pharmacologic doses increased renal mRNA levels of ECaC1, calbindin-D(28K), NCX1, and PMCA1b and increased the protein abundance of ECaC1. Furthermore, the involvement of 1,25-dihydroxyvitamin D(3) in the effects of 17beta-E(2) was examined in 25-hydroxyvitamin D(3)-1alpha-hydroxylase-knockout mice. Renal mRNA expression of calbindin-D(9K), calbindin-D(28K), NCX1, and PMCA1b was not significantly altered after 17beta-E(2) treatment. In contrast, ECaC1 mRNA and protein levels were both significantly upregulated. Moreover, 17beta-E(2) treatment partially restored serum Ca(2+) levels, from 1.63 +/- 0.06 to 2.03 +/- 0.12 mM. In conclusion, this study suggests that 17beta-E(2) is positively involved in renal Ca(2+) reabsorption via the upregulation of ECaC1, an effect independent of 1,25-dihydroxyvitamin D(3).