We propose a theoretical framework to model the behavior of cells in tissues and develop an application in the case of duct morphogenesis in mammary glands.
Abstract
We developed 3D culture methods that reproduce in vitro mammary gland ductal morphogenesis. We are proposing a conceptual framework to understand morphogenetic events based on epistemologically sound biological principles instead of the common practice of using only physical principles. More specifically, our theoretical framework is based on the principle that the default state of cells is proliferation with variation and motility. We emphasize the role played by the agency of cells embedded in a gel and the circularity that is relevant for the intended process, whereby cells act upon other cells and on matrix elements, and are subject to the agentivity of neighboring cells. This circularity strongly differs from classical linear causality. Finally, our approach opens up the study of causal determination to multilevel explanations rather than to reductive ones involving only molecules in general and genes in particular.
Keywords: Morphogenesis, extracellular matrix, theoretical principles, default state of cells, modelization.
We developed a mathematical model of mammary gland based on proper biological principles: the default state of cells and the principle of organization.
Abstract
Abstract In multicellular organisms, relations among parts and between parts and the whole are contextual and interdependent. These organisms and their cells are ontogenetically linked: an organism starts as a cell that divides producing non-identical cells, which organize in tri-dimensional patterns. These association patterns and cells types change as tissues and organs are formed. This contextuality and circularity makes it difficult to establish detailed cause and effect relationships. Here we propose an approach to overcome these intrinsic difficulties by combining the use of two models; 1) an experimental one that employs 3D culture technology to obtain the structures of the mammary gland, namely, ducts and acini, and 2) a mathematical model based on biological principles. The typical approach for mathematical modeling in biology is to apply mathematical tools and concepts developed originally in physics or computer sciences. Instead, we propose to construct a mathematical model based on proper biological principles. Specifically, we use principles identified as fundamental for the elaboration of a theory of organisms, namely i) the default state of cell proliferation with variation and motility and ii) the principle of organization by closure of constraints. This model has a biological component, the cells, and a physical component, a matrix which contains collagen fibers. Cells display agency and move and proliferate unless constrained; they exert mechanical forces that i) act on collagen fibers and ii) on other cells. As fibers organize, they constrain the cells on their ability to move and to proliferate. The model exhibits a circularity that can be interpreted in terms of closure of constraints. Implementing the mathematical model shows that constraints to the default state are sufficient to explain ductal and acinar formation, and points to a target of future research, namely, to inhibitors of cell proliferation and motility generated by the epithelial cells. The success of this model suggests a step-wise approach whereby additional constraints imposed by the tissue and the organism could be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace.
Biological variation should be given the status of a fundamental theoretical principle in biology. Variation goes with randomness, historicity and contextuality.
Abstract
Abstract Darwin introduced the concept that random variation generates new living forms. In this paper, we elaborate on Darwin’s notion of random variation to propose that biological variation should be given the status of a fundamental theoretical principle in biology. We state that biological objects such as organisms are specific objects. Specific objects are special in that they are qualitatively different from each other. They can undergo unpredictable qualitative changes, some of which are not defined before they happen. We express the principle of variation in terms of symmetry changes, where symmetries underlie the theoretical determination of the object. We contrast the biological situation with the physical situation, where objects are generic (that is, different objects can be assumed to be identical) and evolve in well-defined state spaces. We derive several implications of the principle of variation, in particular, biological objects show randomness, historicity and contextuality. We elaborate on the articulation between this principle and the two other principles proposed in this special issue: the principle of default state and the principle of organization.
Keywords: Variability, Historicity, Genericity, Biological randomness, Organization, Theory of organisms
In the search of a theory of biological organisms, we propose to adopt organization as a theoretical principle and define it as closure of constraints.
Abstract
Abstract In the search of a theory of biological organisms, we propose to adopt organization as a theoretical principle. Organization constitutes an overarching hypothesis that frames the intelligibility of biological objects, by characterizing their relevant aspects. After a succinct historical survey on the understanding of organization in the organicist tradition, we offer a specific characterization in terms of closure of constraints. We then discuss some implications of the adoption of organization as a principle and, in particular, we focus on how it fosters an original approach to biological stability, as well as and its interplay with variation.
We articulate three principles for a theory of organisms proposed, namely: the default state the principle of variation and the principle of organization.
Abstract
Abstract Organisms, be they uni- or multi-cellular, are agents capable of creating their own norms; they are continuously harmonizing their ability to create novelty and stability, that is, they combine plasticity with robustness. Here we articulate the three principles for a theory of organisms, namely: the default state of proliferation with variation and motility, the principle of variation and the principle of organization. These principles profoundly change both biological observables and their determination with respect to the theoretical framework of physical theories. This radical change opens up the possibility of anchoring mathematical modeling in biologically proper principles.
We propose a biological default state of proliferation with variation and motility by analogy with physics inertia. Then, quiescence requires an explanation.
Abstract
Abstract The principle of inertia is central to the modern scientific revolution. By postulating this principle Galileo at once identified a pertinent physical observable (momentum) and a conservation law (momentum conservation). He then could scientifically analyze what modifies inertial movement: gravitation and friction. Inertia, the default state in mechanics, represented a major theoretical commitment: there is no need to explain uniform rectilinear motion, rather, there is a need to explain departures from it. By analogy, we propose a biological default state of proliferation with variation and motility. From this theoretical commitment, what requires explanation is proliferative quiescence, lack of variation, lack of movement. That proliferation is the default state is axiomatic for biologists studying unicellular organisms. Moreover, it is implied in Darwin’s “descent with modification”. Although a “default state” is a theoretical construct and a limit case that does not need to be instantiated, conditions that closely resemble unrestrained cell proliferation are readily obtained experimentally. We will illustrate theoretical and experimental consequences of applying and of ignoring this principle.
Software for Automated Morphological Analysis is a method by which epithelial structures grown in 3D cultures can be imaged, reconstructed and analyzed.
Abstract
Three-dimensional (3D) culture models are critical tools for understanding tissue morphogenesis. A key requirement for their analysis is the ability to reconstruct the tissue into computational models that allow quantitative evaluation of the formed structures. Here, we present Software for Automated Morphological Analysis (SAMA), a method by which epithelial structures grown in 3D cultures can be imaged, reconstructed and analyzed with minimum human intervention. SAMA allows quantitative analysis of key features of epithelial morphogenesis such as ductal elongation, branching and lumen formation that distinguish different hormonal treatments. SAMA is a user-friendly set of customized macros operated via FIJI (http://fiji.sc/Fiji), an open-source image analysis platform in combination with a set of functions in R (http://www.r-project.org/), an open-source program for statistical analysis. SAMA enables a rapid, exhaustive and quantitative 3D analysis of the shape of a population of structures in a 3D image. SAMA is cross-platform, licensed under the GPLv3 and available at http://montevil.theobio.org/content/sama.
