Synergistic control of oscillations in the NF-kappaB signalling pathway

In previous work, we studied the behaviour of a model of part of the NF-kappaB signalling pathway. The model displayed oscillations that varied both in number, amplitude and frequency when its parameters were varied. Sensitivity analysis showed that just nine of the 64 reaction parameters were mainly responsible for the control of the oscillations when these parameters were varied individually. However, the control of the properties of any complex system is distributed, and, as many of these reactions are highly non-linear, we expect that their interactions will be too. Pairwise modulation of these nine parameters gives a search space some 50 times smaller (81 against 4096) than that required for the pairwise modulation of all 64 reactions, and this permitted their study (which would otherwise have been effectively intractable). Strikingly synergistic effects were observed, in which the effect of one of the parameters was strongly (and even qualitatively) dependent on the values of another parameter. Regions of parameter space could be found in which the amplitude, but not the frequency (timing), of oscillations varied, and vice versa. Such modelling will permit the design and performance of experiments aimed at disentangling the role of the dynamics of oscillations, rather than simply their amplitude, in determining cell fate. Overall, the analyses reveal a level of complexity in these dynamic models that is not apparent from study of their individual parameters alone and point to the value of manipulating multiple elements of complex networks to achieve desired physiological effects.