Saez-Rodriguez J, Alexopoulos LG, Epperlein J, Samaga R, Lauffenburger DA, Klamt S, Sorger PK. (2009) Mol Syst Biol 5: 331.
Large-scale protein signalling networks are useful for exploring complex biochemical pathways but do not reveal how pathways respond to specific stimuli. Such specificity is critical for understanding disease and designing drugs. Here we describe a computational approach–implemented in the free CNO software–for turning signalling networks into logical models and calibrating the models against experimental data. When a literature-derived network of 82 proteins covering the immediate-early responses of human cells to seven cytokines was modelled, we found that training against experimental data dramatically increased predictive power, despite the crudeness of Boolean approximations, while significantly reducing the number of interactions. Thus, many interactions in literature-derived networks do not appear to be functional in the liver cells from which we collected our data. At the same time, CNO identified several new interactions that improved the match of model to data. Although missing from the starting network, these interactions have literature support. Our approach, therefore, represents a means to generate predictive, cell-type-specific models of mammalian signalling from generic protein signalling networks.
I just came on this paper today, very interesting and parallels my thinking and future activities.
An initial implementation using discrete, boolean logic is what I proposed, and have in place, in my poster I presented at CCC2010. Having started from a simple cell implementation following Robert Weinbereg’s 2000 depiction of a cell, my approach is to elaborate it with information curated from papers on the experimental information of the different forms of treatment for Waldenstrom’s macroglobulinemia. The goal, as the road offered by specialists in WM at DFCI is to combine different forms of treatment to achieve disease control, is to have a “Virtual WM B-Cell” that can be used by researchers to help guide future efforts.
Your thoughts and reply would be greatly welcomed. Maybe we could sit and have a cup of coffee sometime and you could offer some guidance.
John…