Professor Emeritus of Cell and Developmental Biology
Ordered Heterogeneity as a Basic Biological Principle: Its Disordering in Aging and Cancer
Rollin Hotchkiss, a pioneer of molecular genetics, defined life as the repetitive production of ordered heterogeneity. Walter Elsasser, the distinguished theoretical physicist, adapted the concept for the first principle of his theory of organisms as “order above heterogeneity” in which there can be regularity in the large where there is heterogeneity in the small. He was referring to order at the cellular level invariant relative to the heterogeneity at the molecular level. Increasing order is seen in a hierarchy extending beyond the cell to the tissue and the organism. This hierarchy became particularly evident in the widespread use of monolayer culture of animal cells over the past 50 years. There it was found that great heterogeneity of size and substance are introduced among cells when a tissue is dissociated into its cellular components which are grown as individuals on the floor of the culture dish. They also tend to lose their differentiated properties and transform into the neoplastic state. The advent of the neoplastic state can be greatly accelerated by serially subculturing the cells at high density which selects for cells of continuously increasing propensity to overcome contact inhibition between the cells.
Paradoxically, the transformed state of solitary neoplastic cells can be phenotypically normalized if they are co-cultured surrounded by a large excess of normal homotypic cells that are sensitive to contact inhibition. These observations made with fibroblasts in cell culture have been extended to neoplastic epithelial cells in the animal, which has deepened our understanding of how the many cells bearing oncogenic mutations in mammals can be maintained in the phenotypically normal “initiated” state for the lifetime of the organism. That ordered heterogeneity can be transformed into the full expression of the disordered tumorigenic state by chronic treatment of the initiated tissue with a non-mutagenic “promoting agent”.
The tumors themselves are exemplars of the loss of ordered heterogeneity, especially if they have advanced to the malignant or cancerous state. Different parts of a single cancer vary with regard to a large number of biochemical and behavioral characteristics, indicating that the ordering capacity of the tissue for those cells has been greatly diminished. Even normal tissues exhibit increasing heterogeneity of cellular growth properties and mutational spectrum as the organism ages. Such a decrease in ordering capacity may underlie the large increase in the incidence of cancer with age. It has been demonstrated by the transplantation of rat liver cancer cells into the liver of rats, where they are normalized in young rats but not in old ones.
While I have done experimental research on the role of the cellular microenvironment in the regulation of tumor development, my present work is concerned with presenting a general overview of the field, and its relation to the fundamental biological principle of ordered heterogeneity.
Rubin H. Synergistic mechanisms in carcinogenesis by polycyclic aromatic hydrocarbons and tobacco smoke: a biohistorical perspective with updates. Carcinogenesis 2001; 22:1903-30.
Rubin H. Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis. Oncogene 2002; 21:7392-411.
Rubin H. Microenvironmental regulation of the initiated cell. Adv Cancer Res 2003; 90:1-62.
Rubin H. Microenvironmental regulation of tumor development. Sem Cancer Biol 2005; 15:73-157.
Rubin H. Degrees and kinds of selection in spontaneous neoplastic transformation: An operational analysis. Proc Natl Acad Sci USA 2005; 102:9276-81.
Rubin H. What keeps cells in tissues behaving normally in the face of myriad mutations? BioEssays 2006; 28:515-24.
Photo credit: Mark Joseph Hanson of Mark Joseph Studio.
Last Updated 2006-08-23