Default State Of Cells Research Articles

A computational model of organism development and carcinogenesis resulting from cells’ bioelectric properties and communication

A sound theory of biological organization is clearly missing for a better interpretation of observational results and faster progress in understanding life complexity. The availability of such a theory represents a fundamental progress in explaining both normal and pathological organism development. The present work introduces a computational implementation of some principles of a theory of organism development, namely that the default state of cells is proliferation and motility, and includes the principle of variation and organization by closure of constraints. In the present model, the bioelectric context of cells and tissue is the field responsible for organization, as it regulates cell proliferation and the level of communication driving the system’s evolution. Starting from a depolarized (proliferative) cell, the organism grows to a certain size, limited by the increasingly polarized state after successive proliferation events. The system reaches homeostasis, with a depolarized core (proliferative cells) surrounded by a rim of polarized cells (non-proliferative in this condition). This state is resilient to cell death (random or due to injure) and to limited depolarization (potentially carcinogenic) events. Carcinogenesis is introduced through a localized event (a spot of depolarized cells) or by random depolarization of cells in the tissue, which returns cells to their initial proliferative state. The normalization of the bioelectric condition can reverse this out-of-equilibrium state to a new homeostatic one. This simplified model of embryogenesis, tissue organization and carcinogenesis, based on non-excitable cells’ bioelectric properties, can be made more realistic with the introduction of other components, like biochemical fields and mechanical interactions, which are fundamental for a more faithful representation of reality. However, even a simple model can give insight for new approaches in complex systems and suggest new experimental tests, focused in its predictions and interpreted under a new paradigm.

Information, programme, signal: dead metaphors that negate the agency of organisms

ABSTRACT The metaphorical adoption of the concepts of information, programme and signal introduced into biology the logic and implicit causal structure of the mathematical theories of information; this is inimical to biology. In turn, those metaphors have hindered the development of a theory of organisms by transferring the agency of organisms to natural selection and to DNA. Moreover, those metaphors introduced into biology the dualism software–hardware and a Laplacian causal structure. Instead, we propose to uphold the agency of the living by adopting three foundational principles for a theory of organisms: namely, (1) the principle of biological inertia (i.e. the default state of cells is proliferation and motility), (2) the principle of variation, and (3) the principle of organization.

Cancer and the elusive cancer genes

For almost a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcinogenesis. The SMT posits that the accumulation of mutations in the genome of a single normal cell is responsible for the transformation of such cell into a neoplasm. Implicitly, this theory claims that the default state of cells in metazoan is quiescence and that cancer is a cell-based, genetic and molecular disease. From lessons learned while performing our own research on control of cell proliferation and while adopting an organicist perspective, in 1999, we proposed a competing theory, the tissue organization field theory (TOFT). In contraposition to the SMT, (1) the TOFT posits that cancer is a tissue-based disease whereby carcinogens (directly) and mutations in the germ-line (indirectly) may alter normal interactions between the stroma and their adjacent epithelium. And (2) the TOFT explicitly acknowledges that the default state of all cells is proliferation and motility, a premise that is relevant to and compatible with evolutionary theory. Theoretical arguments and experimental evidence are presented to compare the merits of the original SMT and its variants and those of the TOFT in organizing principles, construct objectivity, and ultimately explain carcinogenesis.

The default state of the cell: Quiescence or proliferation?

The default state of the cell: Quiescence or proliferation?

The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory

The somatic mutation theory (SMT) of cancer has been and remains the prevalent theory attempting to explain how neoplasms arise and progress. This theory proposes that cancer is a clonal, cell-based disease, and implicitly assumes that quiescence is the default state of cells in multicellular organisms. The SMT has not been rigorously tested, and several lines of evidence raise questions that are not addressed by this theory. Herein, we propose experimental strategies that may validate the SMT. We also call attention to an alternative theory of carcinogenesis, the tissue organization field theory (TOFT), which posits that cancer is a tissue-based disease and that proliferation is the default state of all cells. Based on epistemological and experimental evidence, we argue that the TOFT compellingly explains carcinogenesis, while placing it within an evolutionarily relevant context.

Somatic mutation theory of carcinogenesis: why it should be dropped and replaced.

The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century. In brief, it proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are that (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence. These two premises have recently been contradicted by evidence. Supporters of the theory have dealt with these lacks of fit by incorporating ad hoc explanations similar to the use of epicycles in pre-Copernican astronomy. We propose the adoption of an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are that (1) proliferation is the default state of all cells and (2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens would act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the "morphogenetic fields" of developing organisms). Stroma appears as the primary target of carcinogens. Carcinogenesis and neoplasia occur entirely through emergent (supracellular) phenomena. Neoplastic cells may be reprogrammed to behave like "normal" cells within normal tissues. We argue that it is necessary to abandon the somatic mutation theory. Researchers will then become free to adopt alternative reliable premises to build a theory that explains carcinogenesis as another outcome, aberrant as it may be, of biological organization.