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.
Modéliser des systèmes de cellules est un besoin commun en biologie et pour lequel il n’y pas de méthode standard. Dans ce séminaire, nous présenterons deux approches de ce problème. Nous discuterons en particulier l’interaction entre modélisateurs et biologistes, et l’articulation entre modèles et phénomènes biologiques.
Faculté des Sciences et Technologies, Vandoeuvre les Nancy
L’allométrie est l’analyse de la variation de certaines grandeurs (métabolisme, rythmes, ...) en fonction de la taille de l’objet considéré. Elle procède d’une hypothèse de symétrie entre des objets de tailles différentes et a conduit à des résultats remarquables en biologie. Cependant, ces résultats sont le lieu de conflits d’interprétation entre un point de vue physique, où les relations allométriques sont conçues comme une « loi de la nature » et un point de vue plus biologique où l’historicité du vivant et les exceptions sont mises en valeur. Pour expliciter cette différence de point de vue, nous allons discuter les bases théoriques de la phylogénie, c’est-à-dire la classification évolutive des êtres vivants. Dans la théorie de l’évolution, la variation, une asymétrie, est un principe premier et ce n’est que dans un deuxième temps que certains caractères peuvent être interprétés comme plus ou moins symétriques (conservés). Ici donc, les symétries pertinentes sont les homologies, les caractères ayant une origine commune située historiquement. Nous proposerons enfin un cadre conceptuel permettant d’articuler l’épistémologie de la physique où les symétries fondamentales sont postulées et celle de la biologie, où les symétries apparaissent de manière historique.
We strudy 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 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 agency 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.
This focused issue of Progress in Biophysics and Molecular Biology is entitled "From the century of the genome to the century of the organism: New theoretical approaches." It was developed during Ana M. Soto’s tenure as Blaise Pascal Chair of Biology 2013-15 at the Ecole Normale Supérieure (ENS,...
Abstract
This focused issue of Progress in Biophysics and Molecular Biology is entitled "From the century of the genome to the century of the organism: New theoretical approaches." It was developed during Ana M. Soto’s tenure as Blaise Pascal Chair of Biology 2013-15 at the Ecole Normale Supérieure (ENS, Paris, France). Giuseppe Longo was the Pascal Chair host at the ENS. This ongoing theoretical was also used as the content of a 10 session course attended by graduate students and post-graduates, which took place at the National Museum of Natural History and at the ENS. The attendants of course encouraged the guest editors to make this material easily available, hence the origin of PBMB issue.
Dans cette présentation nous développons deux principes théoriques qui opèrent ensemble pour permettre de comprendre les organismes vivants dans leurs spécificités. Le premier principe est un principe de variation, et nous montrons qu'il conduit à distinguer fortement les objets biologiques des objets physiques. Le second est un principe d'organisation, s’appuyant sur une tradition riche en biologie théorique et qui met l'accent sur l'interdépendance des parties d'un organisme. Ces deux principes, combinés à la notion d'état par défaut, conduisent à un concept de contrainte biologique opératoire, riche et original.
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.
