Using a combination of computational and experimental approaches we study the processes that determine whether mammalian cells live or die. Our lab is particularly interested in apoptosis triggered by extracellular ligands such as TRAIL, Fas and TNF and opposing pro-survival signals generated by receptors of the insulin and epidermal growth factor familes. We apply a combination of single-cell and intravital imaging, genetic and chemical perturbation and high-throughput biochemistry, to collect the data necessary to construct and calibrate mathematical models of mammalian signal transduction. These models range from data-driven statistical descriptions of interacting pro-growth and pro-death pathways to detailed physico-chemical models of individual steps in ligand-induced apoptosis. In all cases, our goal is to study biochemical mechanism within a cellular context and to probe the origins of genetic and non-genetic variation among individual cells of the same type and between cells of different types.

We also seek to understand oncogenic mutations that disrupt death and survival pathways and the drugs that target them. Determinants of drug sensitivity and resistance are being probed in tumor cell-lines, knock-in/knock-out primary cells and increasingly, in living animals, using a range of experimental and mathematical methods. We hope to determine why many therapeutics work in some patients and not others and to explore the use of biomarkers and poly-pharmacology to maximize therapeutic response. We envision a new “systems pharmacology” as a complement to pharmaco-genomics based on quantitative modelling of oncogenic pathways and precise description of the mechanisms of action on patient specificity of targeted therapies for breast, lung and live cancer.

Mitotic processes that maintain genomic integrity are a final area of research in our laboratory, particularly with respect to links between chromosome instability, apoptosis and oncogenic transformation. In cancer cells, the normal fidelity of chromosome transmission is lost and genomic instability is common, leading to the accumulation of mutations that drive tumor development. To better elucidate this poorly understand process we study mitotic checkpoint signaling and the consequences of checkpoint disruption on tumor development in the mouse.

Our laboratory comprises students and postdocs trained in cell biology, mouse genetics, biological engineering, chemical physics and applied mathematics. We emphasize interdisciplinary approaches combining cell biology, biochemistry and genetics and many lab members undertake projects that have both experimental and computational components. Knowledge of systems and quantitative biology is not a requirement for joining the lab, but interest in precise, mechanistic description of cell and tissue physiology is important. Former members of our lab most commonly hold academic positions, but many also have leadership roles in industry and several have started their own companies. Our lab is also a member of several multi-investigator research projects and we maintain close links with colleagues at MIT, other US universities and several laboratories in Europe.