Non-necrotic cellular death is controlled by a genetic program termed Program Cell Death or Apoptosis. When a cell receives a death signal, it turns on this program which leads to systematic degradation of macromolecules and structures and its eventual phagocytic elimination. In the absence of this program, a cell lives or survives (LIFE). It is, however, not clear whether there is a distinct genetic program for LIFE as in the case of death. At present, knowledge on cell LIFE and DEATH is scanty and a clear working hypothesis is lacking. Current conception holds that the program for cell death is constitutive and cells survive only because survival regulatory proteins such as bcl-2, bcl-xL, A1 and Mcl1 inhibit the program. Death regulators such as bax, bak, bad, and bik are believed to accelerate the death program. However, something is not quite right with this hypothesis. From the Darwinian theory of evolution, we deduce that the primary goal of an organism is to survive so as to ensure the preservation of its species. It chooses to die only when natural selection no longer favors its genetic makeup. Knowing that a cell is the fundamental unit of the organism and that in some cases, the organism consists of just a cell, why then would cells create a reverse genetic program in which death is the primary purpose and survival is conditional? It would be more logical that cells have two mutually exclusive programs; one for life and the other for death. Survival regulators would sustain the LIFE program and DEATH regulators would activate the death program only when the life program fails. If a specific genetic program for LIFE exists, understanding it may fundamentally change the way we view life or devise medical treatment for diseases. A novel approach to test these concepts is to perturb the LIFE/DEATH process by enforced in vivo overexpression of bcl-2 (or any of the other survival regulators), and then analyze for genes which expression are significantly modulated. Such genes could constitute indirect targets through which the regulators enhance LIFE and suppress DEATH. When I performed such an analysis using differential RNA display technique, a few gene fragments were observed to be differentially expressed in response to bcl-2 overexpression. They are all previously unknown genes since their sequences lack significant homology to genes filed in nucleic acid databases. They are currently being evaluated for functional relevance.
