Leading Edge Review Measuring and Modeling Apoptosis in Single Cells Sabrina L. Spencer1,2 and Peter K. Sorger1,* 1Center for Cell Decision Processes, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA 2Present address: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA *Correspondence:
[email protected] DOI 10.1016/j.cell.2011.03.002 Cell death plays an essential role in the development of tissues and organisms, the etiology of disease, and the responses of cells to therapeutic drugs. Here we review progress made over the last decade in using mathematical models and quantitative, often single-cell, data to study apoptosis. We discuss the delay that follows exposure of cells to prodeath stimuli, control of mitochondrial outer membrane permeabilization, switch-like activation of effector caspases, and variability in the timing and probability of death from one cell to the next. Finally, we discuss challenges facing the fields of biochemical modeling and systems pharmacology. Introduction receptors, primarily members of the tumor necrosis factor Apoptosis is a form of programmed cell death involving receptor (TNFR) family (Kaufmann and Earnshaw, 2000). caspases, specialized cysteine proteases found in animal cells Receptor binding by TNF family ligands activates caspase- as inactive proenzymes (Fuentes-Prior and Salvesen, 2004). dependent pathways that are quite well understood in molecular Dramatic progress has been made in recent years in identifying terms. In general, extrinsic apoptosis has received more atten- and determining the biochemical activities and cellular functions tion than intrinsic apoptosis from investigators seeking to of biomolecules that regulate apoptosis and carry out its proteo- develop mathematical models, but extrinsic and intrinsic lytic program.