An attempt to understand the multiparametric control of the initiation of apoptosis

The paper ‘‘Mathematical modeling identified c-FLIP as an apoptotic switch in death receptor induced apoptosis’’ by Lihui Han, Yishu Zhao, and Xiaoqing Jia will strike most readers as unusual and may leave some readers uncomfortable. It is a very challenging but interesting paper. The authors perform a mathematical simulation to demonstrate that, in the constrained conditions of the interactions of NFjB and c-FLIP, the experimental parameters provided by the results of others indicate that c-FLIP and caspase 8 could compete for position and activation at the DISC, and that NFjB could intersect with this interaction in favor of FLIP and other IAPs, stabilizing the cell. The result of these interactions, taking up to 33 other variables into account, yields a situation in which the cell has two stable states: healthy or apoptotic, and the transition between these states is abrupt and irreversible. In other words, if the concentration of FLIP drops below a distinct threshold, the cell will tumble into apoptosis. In many ways to a more biologically oriented researcher the argument is naive, making assumptions about simplified interactions that must be far more complex in vivo. By the authors’ admission the modeling is restricted to a single cell type, and they make assumptions, based to be sure on published data, that activated caspase-3 could be quickly degraded. The authors do not consider the relative roles of synthesis or degradation of apoptosis modulators as opposed to activation and deactivation of the modulators. They address only the protein components of the machinery of apoptosis, whereas many recent papers have focused on the ability of ion concentrations; redox states, free radicals, and redox-controlling molecules (redox: [8, 14, 20, 21]; metabolites, growth hormones and small molecules [1]; ubiquitin [9] and chaperones [3, 7, 16, 24]; cytoskeleton [11, 13]; and even lipids [12, 22, 23]). Other researchers have emphasized that, following severe insult to a cell, even if part of the apoptosis machinery is not operative, the cell will still die, whether by pursuing an alternative route to apoptosis (for instance, the ability of tBID to mediate between extrinsic and intrinsic pathways, or of caspase-7 to replace caspase-3) or by non-apoptotic routes involving autophagy, cannibalism, controlled necrosis, or simple necrotic lysis [2, 10, 18, 21, 25, 29]. Also, physiologists and developmental biologists are well aware of, though perhaps not mathematically conversant with, the idea that the rare positive feedback loops in living organisms are very vigorously defended until they reach threshold and flip to irreversibility—witness thermoregulation, nerve or muscle action potential, sexual differentiation, engagement of a baby in the birth canal, etc. [4, 15, 17, 19]. Thus in one sense this paper mathematically defines what at a phenomenological level has been obvious. On the other hand, at some point we will have to understand the many parameters that feed into the decision to commit to apoptosis—probably even much more complex in mitochondria-driven apoptosis than in the extrinsically-controlled apoptosis considered here. After all, in almost every experimental and therapeutic situation some cells escape severe noxious stimuli, most likely because they are in a different metabolic or dynamic state (the nature of which is unknown) than their neighbors. As the authors note concerning the sharpness of the threshold, ‘‘This may explain to a certain degree why a small increase in c-FLIPL expression may result in a total resistance to death receptor induced apoptosis.’’ In other words, in most R. A. Lockshin (&) Department of Biological Sciences, St. John’s University, Jamaica, NY, USA e-mail: lockshin@stjohns.edu