On the nature of enduring modifications induced in cells and organisms.

The clarity of Mendelian genetics and the elegance of the molecular mechanisms of replication and readout of DNA have tended to obscure a solid body of evidence demonstrating that nongenetic, enduring modifications can be induced in the behavior of cells, modifications that continue to be expressed for many divisions after withdrawal of the inducing stimulus. The most prosaic case is the differentiated state of metazoan cells, which persists throughout the lifetime of the organism. Much less widely known but well-characterized examples are also cited for bacteria, protozoa, and cultured cells of higher plants and animals. The spontaneous neoplastic transformation of cultured mouse NIH 3T3 cells is introduced as an enduring adaptive response to moderate growth constraints. Evidence in support of the thesis that physiological adaptation is the driving force for chemically induced carcinogenesis in the intact animal is also presented. The cases described here involve integrated responses of many if not all of the regulatory components of the cell, rather than singular molecular mechanisms. The continuous generation of phenotypic heterogeneity, a process observed readily in cell culture, provides the basis for a model that accounts for enduring modifications. This model, designated progressive state selection, makes no attempt at a detailed biochemical explanation of heterogeneity, but uses it as a fundamental postulate to represent the adaptive behavior of the cells.