QSB: Computing Life and the Kinetics of the Cell

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Arnold0425762The main goal of this research is to implement and validate a novel approach towards quantitative functional genomics, referred to as the computing life paradigm, which integrates state-of-the-art experimental probes of the time-dependent intra-cellular kinetics with a recently proposed ensemble-based kinetics modeling technique. Its starting point are quantitative RNA and protein profiling experiments to monitor the cell's responses to controlled external perturbations such as gene knock-outs, protein inhibition and various time-dependent schedules of external food sources and starvation. The ensemble modeling technique then utilizes such time-dependent experimental data to not only constrain the topology and the parameter space of the genetic network model(s) under study; but also to make quantitative predictions and, most importantly, to provide quantitative criteria for the rational design of a "maximally informative next experiment". The full implementation of the computing life paradigm thus results in a workflow cycle wherein rationally designed new experiments further constrain the "ensemble of models" while the model ensemble becomes more and more refined and discriminating in its predictive capabilities. The initial applications of this approach will focus on two previously well explored genetic model systems in fungal organisms, specifically in Neurospora crassa, exhibiting widely different dynamical behavior: the quinic acid (qa) gene cluster, involved in transient responses of the cell's carbon metabolism; and the biological clock, the proto-type of an oscillatory system.