"CONTROL AND SYSTEMS THEORY - We are primarily concerned on the one hand with the development of effective control techniques, with application to complex industrial processes; we are also concerned on the other hand with understanding biological control systems-the means by which mammalian organisms maintain stable, efficient and "near-optimal" performance and homeostasis in the face of external and internal perturbations. In each case we apply principles of systems theory and develop appropriate analysis tools as needed. Our research program in engineering control systems has recently led to the development (and patenting) of a next generation regulatory controller as an alternative to the ubiquitous, but difficult to tune PID controller. This novel controller's tuning parameters are related directly and explicitly to the controller performance attributes of robustness, set-point tracking, and disturbance rejection (and also overall controller aggressiveness); they are also all naturally scaled between 0 and 1, leading to a controller that can be designed and implemented much more directly and transparently. We have validated the controller experimentally on several processes including a thin-film physical vapor deposition (PVD) process for manufacturing thin-film solar cells. The counterpart program in biological control systems has led to the recent elucidation of the control mechanism for DNA damage repair with the p53-Mdm2 system, enabling us to resolve the experimentally observed dilemma of "analog" damped oscillatory responses at the ensemble level but "digital" pulse-like responses at the single cell level. Obtaining these results required a combination of systems engineering, probabilistic and deterministic modeling and control theory. We are currently using similar tools to study the platelet signaling, activation, and aggregation control system for controlling blood loss following vascular injury. SYSTEMS BIOLOGY - An organism's objectives of viability, growth, and reproduction are realized via a carefully orchestrated cooperation among various cell types. Maintaining normal function involves individual cell decisions about growth, proliferation, differentiation, migration and death, mediated by cell-to-cell communications, and coordinated by regulatory systems in a manner far too complex to be understood by qualitative reasoning alone. Our research efforts bring quantitative modeling and engineering systems theory to bear specifically on signal transduction-the early signal propagation events occurring through the interactions of specialized proteins in the cell membrane and the cytoplasm-and also on the subsequent events occurring in the nucleus through the interactions of proteins with DNA, leading to changes in gene expression. In addition to explaining observed phenomena through signal transduction modeling, we continue to focus on some key fundamental challenges to effective signal transduction modeling such as combinatorial complexity, parameter identifiability, and experimental design for parameter estimation. We are also concerned with the problems associated with modeling and identification of gene regulatory networks in general, with particular application to the development and manifestation of such neurophysiological diseases as hypertension and alcohol withdrawal. As a general aid to our systems biology efforts, we are developing novel statistical techniques for analyzing cellular data, especially gene expression data from microarrays, and single-cell flow cytometry measurements for characterizing cell population heterogeneity."
Selected PublicationsSelected Awards
