Ecological Models for Gene Therapy. I. Models for Intraorganismal Ecology
We discuss the perspective of intra-organismal ecology by investigating a family of models of niche construction. We consider first and second order models.
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
CitationPocheville, A., and Maël Montévil. 2014. “Ecological Models for Gene Therapy. I. Models for Intraorganismal Ecology.” Biological Theory 9 (4): 401–13. https://doi.org/10.1007/s13752-014-0190-y
Ecological Models for Gene Therapy. II. Niche Construction, Nongenetic Inheritance, and Ecosystem Perturbations
We apply the perspective of intra-organismal ecology by investigating a family of ecological models suitable to describe a gene therapy.
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
CitationPocheville, A., Maël Montévil, and R. Ferrière. 2014. “Ecological Models for Gene Therapy. II. Niche Construction, Nongenetic Inheritance, and Ecosystem Perturbations.” Biological Theory 9 (4): 414–22. https://doi.org/10.1007/s13752-014-0191-x
Aléatoire, historicité et complexité biologique
Introduction to New Perspectives in Biology
Essays for the Luca Cardelli Fest
This note introduces work in Theoretical Biology in the book: Perspectives on Organisms: Biological Time, Symmetries and Singularities.
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.
CitationLongo, G., and Maël Montévil. 2014. “Introduction to New Perspectives in Biology.” In Essays for the Luca Cardelli Fest, edited by Martin Abadi, Philippa Gardner, Andrew D. Gordon, and Radu Mardare, 187–201. MSR-TR-2014-104. Microsoft Research. http://research.microsoft.com/apps/pubs/default.aspx?id=226237
From the tissue organization field theory of carcinogenesis to a theory of organisms.
In 1999, C Sonnenschein and AM Soto proposed the tissue organization field theory (TOFT). The TOFT posits 1) that cancer is a tissue-based disease whereby carcinogens (directly) and germ-line mutations (indirectly) alter normal interactions between the stroma and adjacent epithelium; and 2) the default state of all cells is proliferation with variation and motility. This later premise is relevant to and compatible with evolutionary theory, and is diametrically opposed to that of the somatic mutation theory. This theoretical change is incompatible with the reductionist genocentric perspective generated by the molecular biology revolution. Rather than forcing a “bricolage” we decided to frontally attack the problem by joining efforts with philosophers, mathematicians and theoretical biologists to search for principles upon which to build a theory of organisms (this work is currently supported by the Pascal Chair). While the theory of evolution has provided an increasingly adequate explanation of phylogeny, biology still lacks a theory of organisms that would encompass ontogeny and life cycles, and thus phenomena on a conception to death time-scale. To achieve this goal we propose that theoretical extensions of physics are required in order to grasp the living state of matter. Such extensions will help to describe the proper biological observables, i.e. the phenotypes. Biological entities must also follow the underlying principles used to understand inert matter. However, these physical laws and principles may not suffice to make the biological dynamics intelligible at the phenotypic level. By analogy with classical mechanics, where the principle of inertiais the default state of inert matter, we are proposing two aspects of the default state in biology, and a framing principle, namely: i) Default state: cell proliferation with variation as a constitutive property of the living. Variation is generated in particular by the mere fact that cell division generates two overall similar, but not identical cells. ii) Default state: motility, which encompasses cell and organismic movements as well as movement within cells. iii) Framing principle: life phenomena exhibit never identical iterations of a morphogenetic process. Organisms are the consequence of the inherent variability generated by proliferation, motility and auto-organization which operate within the framing principle. From these basic premises, we will elaborate on the generation of robustness, the structure of theoretical determination, and the identification of biological proper observables.
IAS-IHPST Workshop: Boundaries and levels of biological organization
The workshop will discuss the notion of biological organization from a systemic- perspective. In particular it will focus on its intrinsic hierarchical dimension, and on the role organization plays in the understanding of the transition from pre-biotic to minimal living systems and of more complex forms of biological, cognitive and ecological systems.
Objets physiques, objets biologiques.
Les objets physiques sont définis théoriquement et mathématiquement comme des objets génériques. Ainsi, du point de vue de la gravitation newtonienne, une pomme ou une planète sont interchangeables, de même que le moment ou l'endroit où des phénomènes ont lieu. Un objet physique a une trajectoire spécifique, déterminée dans un espace de description stable. Au cœur de cette approche des phénomènes naturels se trouve la notion de symétrie théorique, qui justifie que des transformations (réelles ou virtuelles) ne changent pas les aspects pertinents d'un objet, en particulier et surtout la forme de sa détermination équationnelle. Les symétries justifient l'articulation des mathématiques avec le réel et permettent la dérivation mathématique des trajectoires. En biologie, nous proposons que les symétries théoriques sont instables. Ceci a de nombreuses conséquences puisque c'est la définition même des objets qui ne peut être opérée comme en physique. La première de ces conséquences est que l'objet doit être pensé comme spécifique, étant donné qu'il altère ses symétries au cours du temps (ontogénétique et phylogénétique). Ceci confère à l'objet biologique une nature fondamentalement historique. De plus, l'espace de description biologique est alors lui-même défini comme résultat d'une histoire. Enfin, les trajectoires biologiques ne peuvent alors pas être dérivées mathématiquement puisque ce sont les symétries déterminant ces trajectoires qui changent au cours du temps.
A Novel 3D Model to Study the Link Between Hormonal Exposure and Mammographic Density in Breast Cancer
Lower type 1 collagen concentration (0.5 mg/ml) increases elongation of structures compared to 1 mg/ml. Fibroblasts enhances elongation of structures in 1 mg/ml, but not 0.5 mg/ml. In 1 mg/ml collagen, elongated epithelial structures had lumen formation when co‐cultured with fibroblasts. Hormones in co-‐cultures of T47D + fibroblasts, significantly altered the phenotype in terms of elongation.
Development of Software for Automated Morphology Analysis (SAMA) to analyze morphogenic effects of mammotrophic hormones in vitro
In vitro 3D simulations of biological systems are critical for understanding morphogenesis and patterns of normal and abnormal development in tissues. Here we present SAMA, a novel method through which epithelial structures grown in 3D cultures can be imaged, reconstructed in 3D and analyzed with minimum human intervention and, therefore, bias. SAMA gives us an accurate picture of the epithelial structures and hence, more information compared to 2D morphometric analysis. In addition, this automated method is less time consuming than regular 2D morphometrics.