A model predicts that just a little active death receptor is enough to activate caspases for cell death if FLIP is absent (right).

On page 839, Bentele et al. use a mathematical model to simplify a complex biological problem—programmed cell death.

Models are mostly used to study relatively simple and well-understood biological systems. Complex systems, in contrast, have so many unknowns that an overwhelming amount of data is needed to complete a model.

But Bentele et al. show that CD95-induced cell death can be simplified. The authors found that the activity or concentration of many molecules involved in this death pathway (such as caspases and Bcl family proteins) are unaffected by large changes in most parameters (including binding kinetics and reaction speeds). So they broke down their original model into modules—groups of molecules that change in response to changes in the same set of parameters. As a result, only a subset of molecules needs to be examined when certain parameters are changed in simulations.

Using these simulations, the group identified the pathway's most critical molecules as those that reacted strongly to parameter changes. The concentrations of these critical molecules were measured in lab experiments over time following CD95 activation to estimate some of the remaining unknown parameters and thus refine the model.

Both the refined model and lab experiments predicted that a threshold concentration of CD95 ligand is required for cell death to occur. One candidate that might control the threshold is c-FLIP, whose binding to the CD95-containing complex competes with activation of caspase-8. Death simulations run in the absence of c-FLIP abolished the threshold. Cell death now occurred under low concentrations of the ligand that did not cause death in the presence of c-FLIP. Lab experiments in which c-FLIP expression was inhibited confirmed that c-FLIP is the threshold switch. The authors hope that biologists will use modeling approaches to improve benchwork experiments for finding the important players in complex pathways. ▪