Dynamical pathway analysis

Although a great deal is known about one gene or protein and its functions under different environmental conditions, little information is available about the complex behaviour of biological networks subject to different environmental perturbations. Observing differential expressions of one or more genes between normal and abnormal cells has been a mainstream method of discovering pertinent genes in diseases and therefore valuable drug targets. However, to date, no such method exists for elucidating and quantifying the differential dynamical behaviour of genetic regulatory networks, which can have greater impact on phenotypes than individual genes.

We propose to redress the deficiency by formulating the functional study of biological networks as a control problem of dynamical systems. We developed mathematical methods to study the stability, the controllability, and the steady-state behaviour, as well as the transient responses of biological networks under different environmental perturbations. We applied our framework to three real-world datasets: the SOS DNA repair network in E. coli under different dosages of radiation, the GSH redox cycle in mice lung exposed to either poisonous air or normal air, and the MAPK pathway in mammalian cell lines exposed to three types of HIV type I Vpr, a wild type and two mutant types; and we found that the three genetic networks exhibited fundamentally different dynamical properties in normal and abnormal cells.

Difference in stability, relative stability, degrees of controllability, and transient responses between normal and abnormal cells means considerable difference in dynamical behaviours and different functioning of cells. Therefore differential dynamical properties can be a valuable tool in biomedical research.