Ana M. Soto

Endocrinologists apply the idea of feedback loops to explain how hormones regulate certain bodily functions such as glucose metabolism. In particular, feedback loops focus on the maintenance of the plasma concentrations of glucose within a narrow range. Here, we put forward a different, organicist perspective on the endocrine regulation of glycaemia, by relying on the pivotal concept of closure of constraints. From this perspective, biological systems are understood as organized ones, which means that they are constituted of a set of mutually dependent functional structures acting as constraints, whose maintenance depends on their reciprocal interactions. Closure refers specifically to the mutual dependence among functional constraints in an organism. We show that, when compared to feedback loops, organizational closure can generate much richer descriptions of the processes and constraints at play in the metabolism and regulation of glycaemia, by making explicit the different hierarchical orders involved. We expect that the proposed theoretical framework will open the way to the construction of original mathematical models, which would provide a better understanding of endocrine regulation from an organicist perspective.

For the last 50 years the dominant stance in experimental biology has been reductionism in general, and genetic reductionism in particular. Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon, experimental data confirmed these misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems has now been tempered by the difficulties encountered when applying the same simple ideas to complex problems. We analyze three examples taken from experimental data that illustrate the shortcomings of this sort of reductionism. In the first, alterations in the expression of a large number of genes coexist with normal phenotypes at supra-cellular levels of organization; in the second, the supposed intrinsic specificity of hormonal signals is negated; in the third, the notion that cancer is a cellular problem caused by mutated genes is challenged by data gathered both from the reductionist viewpoint and the alternative view proposing that carcinogenesis is development gone awry. As an alternative to reductionism, we propose that the organicist view is a good starting point from which to explore these phenomena. However, new theoretical concepts are needed to grapple with the apparent circular causality of complex biological phenomena.

The dominant position in Philosophy of Science contends that downward causation is an illusion. Instead, we argue that downward causation doesn’t introduce vicious circles either in physics or in biology. We also question the metaphysical claim that “physical facts fix all the facts.” Downward causation does not imply any contradiction if we reject the assumption of the completeness and the causal closure of the physical world that this assertion contains. We provide an argument for rejecting this assumption. Furthermore, this allows us to reconsider the concept of diachronic emergence.

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.magnified imagemagnified imageAna Soto and Carlos Sonnenschein are at Tufts University School of Medicine, Boston, MA, USA.

Unlike inert objects, organisms and their cells have the ability to initiate activity by themselves and thus change their properties or states even in the absence of an external cause. This crucial difference led us to search for principles suitable for the study organisms. We propose that cells follow the default state of proliferation with variation and motility, a principle of biological inertia. This means that in the presence of sufficient nutrients, cells will express their default state. We also propose a principle of variation that addresses two central features of organisms, variation and historicity. To address interdependence between parts, we use a third principle, the principle of organization, more specifically, the notion of the closure of constraints. Within this theoretical framework, constraints are specific theoretical entities defined by their relative stability with respect to the processes they constrain. Constraints are mutually dependent in an organized system and act on the default state.Here we discuss the application and articulation of these principles for mathematical modeling of morphogenesis in a specific case, that of mammary ductal morphogenesis, with an emphasis on the default state. Our model has both a biological component, the cells, and a physical component, the matrix that contains collagen fibers. Cells are agents that move and proliferate unless constrained; they exert mechanical forces that act (i) on collagen fibers and (ii) on other cells. As fibers are organized, they constrain the cells’ ability to move and to proliferate. This model exhibits a circularity that can be interpreted in terms of the closure of constraints. Implementing our mathematical model shows that constraints to the default state are sufficient to explain the formation of mammary epithelial structures. Finally, the success of this modeling effort suggests a stepwise approach whereby additional constraints imposed by the tissue and the organism can be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace.

It would be ahistorical to ridicule vitalists. When one reads the writings of one of the leading vitalists like Driesch one is forced to agree with him that many of the basic problems of biology simply cannot be solved by a philosophy as that of Descartes, in which the organism is simply considered a machine…. The logic of the critique of the vitalists was impeccable.At the turn of the new millennium, concomitant with the development of the evo-devo and eco-devo disciplines within developmental biology, critical appraisals of the reductionist stance of the molecular biology revolution became more numerous and noticeable. Several books and papers address the problems posed by this reductionist agenda and suggest...

David Waldron Smithers was, among other things, a physician and a pioneer of cancer radiotherapy and a well-respected figure in British medicine and public health. From the 1940s until his retirement from medical practice in 1973, he was the director of the Radiotherapy Department at the Royal Marsden Hospital and London University Chair of Radiotherapy at the Institute of Cancer Research. Using massive amounts of clinical observations, which he interpreted from an organicist viewpoint, and his impressive synthetic thinking, he proposed a coherent alternative perspective to the somatic mutation theory (SMT) which was then, and still is, the dominant theory of cancer. The purpose of this essay is to acquaint the modern audience with his seminal paper, published in 1962, because it deserves to be recognized as a true classic. In it, he examined the lack of fit between clinical observations and the SMT and proposed the rejection of this reductionist perspective. In addition, he built an organicist alternative in which carcinogenesis is seen as a problem of biological organization. His conceptual contribution to the cancer problem has inspired us and other authors over the last two decades. His essay “Cancer: An Attack on Cytologism,” originally published in The Lancet in 1962, is available as supplementary material in the online version of this article.

The somatic mutation theory has been the prevailing paradigm in cancer research for the last 50 years. Its premises are: (1) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations, (2) the default state of cell proliferation in metazoa is quiescence, and (3) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. From this compelling simplicity, an increasingly complicated picture has emerged as more than 100 oncogenes and 30 tumor suppressor genes have been identified. To accommodate this complexity, additional ad hoc explanations have been postulated. After a critical review of the data gathered from this perspective, an alternative research program has been proposed. It is based on the tissue organization field theory, the premises of which are that carcinogenesis represents a problem of tissue organization, comparable to organogenesis, and that proliferation is the default state of all cells. The merits of these competing theories are evaluated herein. BioEssays 26:1097–1107, 2004. © 2004 Wiley Periodicals, Inc.