Toward Automated Cell Model Development through Information Theory^†

The objective of this paper is to present a methodology for developing and calibrating models of complex reaction/transport systems. In particular, the complex network of biochemical reaction/transport processes and their spatial organization make the development of a predictive model of a living cell a grand challenge for the 21st century. However, advances in reaction/transport modeling and the exponentially growing databases of genomic, proteomic, metabolic, and bioelectric data make cell modeling feasible, if these two elements can be automatically integrated in an unbiased fashion. In this paper, we present a procedure to integrate data with a new cell model, Karyote, that accounts for many of the physical processes needed to attain the goal of predictive modeling. Our integration methodology is based on the use of information theory. The model is integrated with a variety of types and qualities of experimental data using an objective error assessment approach. Data that can be used in this approach include NMR, spectroscopy, microscopy, and electric potentiometry. The approach is demonstrated on the well-studied Trypanosoma brucei system. A major obstacle for the development of a predictive cell model is that the complexity of these systems makes it unlikely that any model presently available will soon be complete in terms of the set of processes accounted for. Thus, one is faced with the challenge of calibrating and running an incomplete model. We present a probability functional method that allows the integration of experimental data and soft information such as choice of error measure, a priori information, and physically motivated regularization to address the incompleteness challenge.