A systems biology approach to the blood-aluminium problem: The application and testing of a computational model

Transport and distribution of systemic aluminium are influenced by its interaction with blood. Current understanding is centred upon the role played by the iron transport protein transferrin which has been shown to bind up to 90% of serum total aluminium. We have coined what we have called the blood-aluminium problem which states that the proportion of serum aluminium which, at any one moment in time, is bound by transferrin is more heavily influenced by kinetic constraints than thermodynamic equilibria with the result that the role played by transferrin in the transport and distribution of aluminium is likely to have been over estimated. To begin to solve the blood-aluminium problem and therewith provide a numerical solution to the aforementioned kinetic constraints we have applied and tested a simple computational model of the time-dependency of a putative transferrin ligand (L) binding aluminium to form an Al-L complex with a probability of existence, K-E, between 0% (no complex) and 100% (complex will not dissociate). The model is based upon the principles of a lattice-gas automaton which when ran for K-E in the range 0.1-98.0% demonstrated the emergence of complex behaviour which could be defined in the terms of a set of parameters (equilibrium value, E-V, equilibrium time, E-T, peak value, P-V, peak time, P-T, area under curve, AUC) the values of which varied in a predictable way with K-E. When K-E was set to 98% the model predicted that ca. 90% of the total aluminium would be bound by transferrin within ca. 350 simulation timesteps. We have used a systems biology approach to develop a simple model of the time-dependency of the binding of aluminium by transferrin. To use this approach to begin to solve the blood-aluminium problem we shall need to increase the complexity of the model to better reflect the heterogeneity of a biological system such as the blood. (c) 2007 Elsevier Inc. All rights reserved.