Publications of 2014

In this article, we discuss the perspective of intraorganismal ecology by investigating a family of ecological models. We consider two types of models. First-order models describe the population dynamics as being directly affected by ecological factors (here understood as nutrients, space, etc). They might be thought of as analogous to Aristotelian physics. Second-order models describe the population dynamics as being indirectly affected, the ecological factors now affecting the derivative of the growth rate (that is, the population acceleration), possibly through an impact on nongenetically inherited factors. Second-order models might be thought of as analogous to Galilean physics. In a companion article, we apply these ideas to a situation of gene therapy.

Keywords: Ecosystem engineering, Inertial dynamics, Intraorganismal ecology, Niche construction, Nongenetic inheritance

In this article, we apply the perspective of intraorganismal ecology by investigating a family of ecological models suitable to describe a gene therapy for a particular metabolic disorder, the adenosine deaminase deficiency. The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the order chosen for the model (a choice that cannot be made on a priori assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intraorganismal ecology.

Keywords: Adenosine deaminase deficiency, Ecosystem engineering, Gene therapy, Intraorganismal ecology, Nongenetic inheritance, Severe combined immunodeficiency

This note introduces recent work in Theoretical Biology by borrowing from the Introduction (chapter 1) of the book by the authors: "Perspectives on Organisms: Biological Time, Symmetries and Singularities", Springer, 2014. The idea is to work towards a Theory of Organisms analogue and along the Theory of Evolution, where ontogenesis could be considered as part of phylogenesis. As a matter of fact, the latter is made out of "segments" of the first: phylogenesis is the "sum" of ontogenetic paths and they should be made intelligible by similar principles. To this aim, we look at ontogenesis from different perspectives. By this, we shed light on the unity of the organism from different points of view, yet constantly keeping that unity as a core invariant. The analysis of invariance, as the result of theoretical symmetries, and of symmetry changes, is a key theme of the approach in the book and in the discussion in this note.

Background: Mammary gland morphogenesis involves ductal elongation, branching, and budding. All of these processes are mediated by stroma - epithelium interactions. Biomechanical factors, such as matrix stiffness, have been established as important factors in these interactions. For example, epithelial cells fail to form normal acinar structures in vitro in 3D gels that exceed the stiffness of a normal mammary gland. Additionally, heterogeneity in the spatial distribution of acini and ducts within individual collagen gels suggests that local organization of the matrix may guide morphogenesis. Here, we quantified the effects of both bulk material stiffness and local collagen fiber arrangement on epithelial morphogenesis. Results: The formation of ducts and acini from single cells and the reorganization of the collagen fiber network were quantified using time-lapse confocal microscopy. MCF10A cells organized the surrounding collagen fibers during the first twelve hours after seeding. Collagen fiber density and alignment relative to the epithelial surface significantly increased within the first twelve hours and were a major influence in the shaping of the mammary epithelium. The addition of Matrigel to the collagen fiber network impaired cell-mediated reorganization of the matrix and increased the probability of spheroidal acini rather than branching ducts. The mechanical anisotropy created by regions of highly aligned collagen fibers facilitated elongation and branching, which was significantly correlated with fiber organization. In contrast, changes in bulk stiffness were not a strong predictor of this epithelial morphology. Conclusions: Localized regions of collagen fiber alignment are required for ductal elongation and branching suggesting the importance of local mechanical anisotropy in mammary epithelial morphogenesis. Similar principles may govern the morphology of branching and budding in other tissues and organs.

Keywords: Collagens, Morphogenesis, Extracellular matrix, Gels, Anisotropy, Stiffness, Scanning electron microscopy, Mammary gland development

En parcourant un fil conducteur de l’évolution darwinienne, on trouve çà et là la formation du simple, comme résultat de la complexité des trajectoires évolutives : par exemple, la variété, la richesse, la … complexité des bauplan de la faune de Burgess et Ediacara (Gould, 1989) s’est transformée en la « simplicité » des bauplan qui suivront et de l’activité qu’ils rendent possible. Tout en prolongeant l’évolution des espèces, l’évolution de l’homme, jusqu’à son histoire, paraît aussi fournir, çà et là, des éléments de cette simplification qui choisit, transforme, organise l’action dans le monde, dont nous parlerons. On pourrait alors donner un sens historique à la notion de simplexité dans (Berthoz, 2009): - c’est le simple qui résulte d’une histoire complexe, - du simple qui n’est jamais élémentaire (atomique, irréductible). En physique, cette histoire peut être remplacée par une dynamique de modèles mathématiques qui aide à passer d’un système d’interactions locales, très complexe, à une situation globale, relativement plus simple, limite de la dynamique considérée. Ces dynamiques permettent de traiter les transitions critiques. Dans ce cas aussi, mais de façon fortement mathématisée, l’intégration globale de réseaux localement intelligibles, mais trop riches pour être saisis comme un tout, peut proposer une autre exemple de simplexité, plus technique, un exemple qui trouve son sens à la limite asymptotique. Les méthodes de renormalisation, auxquels nous ferons informellement référence, en donnent un aperçu de grande puissance physico-mathématique. Nous considérons le passage de l’analyse mathématique de la criticité physique à l’analyse du biologique, en tant que situation critique étendue, une transition conceptuelle possible de la théorisation physique à celle de l’état vivant de la matière.

This authored monograph introduces a genuinely theoretical approach to biology. Starting point is the investigation of empirical biological scaling including their variability, which is found in the literature, e.g. allometric relationships, fractals, etc. The book then analyzes two different aspects of biological time: first, a supplementary temporal dimension to accommodate proper biological rhythms; secondly, the concepts of protension and retention as a means of local organization of time in living organisms. Moreover, the book investigates the role of symmetry in biology, in view of its ubiquitous importance in physics. In relation with the notion of extended critical transitions, the book proposes that organisms and their evolution can be characterized by continued symmetry changes, which accounts for the irreducibility of their historicity and variability. The authors also introduce the concept of anti-entropy as a measure for the potential of variability, being equally understood as alterations in symmetry. By this, the book provides a mathematical account of Gould’s analysis of phenotypic complexity with respect to biological evolution. The target audience primarily comprises researchers interested in new theoretical approaches to biology, from physical, biological or philosophical backgrounds, but the book may also be beneficial for graduate students who want to enter this field.