Understanding biological heterogeneity via dynamical modelling

Scientific conference (2012, September 07)

Compréhension de Systèmes Biologiques par la Modélisation Dynamique

Scientific conference (2012, May 25)

Global analysis of dynamical decision-making models through local computation around the hidden saddle

in PLoS ONE (2012), 7(3),

Introduction to Systems Biology

Scientific conference (2012)

Heterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli

in BMC Systems Biology (2011), 5

Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate ... [more ▼]

Background Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. Results This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. Conclusions Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity. [less ▲]

Biological bistable models a local analysis for non local predictions

Conference (2011, June 17)

La biologie intégrative ou biologie systémique

Diverse speeche and writing (2011)

Le décryptage du génome de nombreux organismes a montré que la seule connaissance de la structure des gênes ne suffisait pas à expliquer le fonctionnement d’une cellule, d’un organisme ou d’un individu ... [more ▼]

Le décryptage du génome de nombreux organismes a montré que la seule connaissance de la structure des gênes ne suffisait pas à expliquer le fonctionnement d’une cellule, d’un organisme ou d’un individu. Un même gêne peut jouer un rôle différent selon le contexte physiologique dans lequel il s’exprime ou bien encore, une même fonction peut être assurée par des assemblages de gênes différents. Il semble donc que la biologie doive à présent quitter le réductionnisme qui était le sien pour une vision plus intégrative qui fait la part belle aux réseaux d’interactions entre les différents acteurs (gênes, protéines, métabolites). C’est le domaine de la biologie intégrative ou biologie systémique. Rencontre avec Eric BULLINGER, ingénieur spécialiste des systèmes et de la modélisation à l’Université de Liège et qui intervient désormais dans la biologie. [less ▲]

Feedback control strategies for spatial navigation revealed by dynamic modelling of learning in the Morris water maze

in Journal of Computational Neuroscience (2011), 30(2), 447-454

The Morris water maze is an experimental procedure in which animals learn to escape swimming in a pool using environmental cues. Despite its success in neuroscience and psychology for studying spatial ... [more ▼]

The Morris water maze is an experimental procedure in which animals learn to escape swimming in a pool using environmental cues. Despite its success in neuroscience and psychology for studying spatial learning and memory, the exact mnemonic and navigational demands of the task are not well understood. Here, we provide a mathematical model of rat swimming dynamics on a behavioural level. The model consists of a random walk, a heading change and a feedback control component in which learning is reflected in parameter changes of the feedback mechanism. The simplicity of the model renders it accessible and useful for analysis of experiments in which swimming paths are recorded. Here, we used the model to analyse an experiment in which rats were trained to find the platform with either three or one extramaze cue. Results indicate that the 3-cues group employs stronger feedback relying only on the actual visual input, whereas the 1-cue group employs weaker feedback relying to some extent on memory. Because the model parameters are linked to neurological processes, identifying different parameter values suggests the activation of different neuronal pathways. [less ▲]

Control in Biological Systems - from Intercellular Signalling to the Organism

Scientific conference (2010, April 28)

Review of three Recent Books on the Boundary of Bioinformatics and Systems Biology

in BioMedical Engineering OnLine (2010), 9(1), 33