Session 7 Speakers: IMAG Cell and Multi-cellular modeling (1)

This symposium will focus on modeling of biological systems using single-cells as a natural level of abstraction. Unlike continuum models where cells are represented in the form of density, cell-level modeling provides modelers with deeper insights into biological phenomena and ultimately allows for easy integration with subcellular models. This method is capable of determining single cell phenomena based on more detailed subcellular models than those employed by continuum methods. Currently, various cell-level models are being explored (lattice-based, off-lattice, cellular automata, etc.). As of now, there is little to no consensus amongst scientists and developers to easily and correctly model multicellular systems with single cell resolution. During this symposium, we will explore how different single cell-level models are capable of describing and reproducing biological phenomena at the single-cell and tissue levels. Following scheduled talks, we will have a roundtable discussion covering the gambit of current models and noting similarities and differences in techinques and scientific contents. We hope this discussion will lead to consensus or possible motivation for unification/integration of presented models and modeling methods.

 

Name Email Talk Title
Tom Deisboeck deisboec@helix.mgh.harvard.edu Multiscale Cancer Modeling
Georg Luebeck gluebeck@fhcrc.org Perturbations in Epithelial Tissue Renewal and Cancer
Carlo Maley cmaley@wistar.org Modeling Clonal Expansions and Genetic Diversity in Carcinogenesis
Denise E. Kirschner kirschne@umich.edu A multi-scale approach towards understanding anitgen presentation in the immune response to Mycobacterium tuberculosis
Martin Fink martin.fink@dpag.ox.ac.uk PreDiCT: Computational Prediction of Drug Cardiac Toxicity

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ABSTRACTS

  • Thomas Deisboeck, Massachussetts General Hospital, Boston

Multiscale Cancer Modeling

Based on the concept that tumors behave as complex dynamic and self-organizing biosystems, the talk will describe the development of a data-driven, agent-based multi-scale and multi-resolution brain cancer model. This algorithm is designed to investigate how changes on the molecular level can percolate across the scales of interest, by impacting microscopic behavior as well as multi-cellular patterns. This project is part of The Center for the Development of a Virtual Tumor, CViT (https://www.cvit.org <https://www.cvit.org/> ).

Perturbations in Epithelial Tissue Renewal and Cancer

Mathematical analysis of a general class of multistage carcinogenesis models reveals two basic phases in the age-specific cancer incidence function: a first exponential phase until the age of about 60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, while the linear phase reflects events leading to initiated cells that give rise to premalignant lesions as a result of abrogated growth/differentiation control and/or perturbed tissue renewal due to damaging exposures inflicting wounding. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which can be the result of a recessive inactivation of a gatekeeper gene that maintains normal tissue architecture.

Modeling Clonal Expansions and Genetic Diversity in Carcinogenesis

Carcinogenesis is a dynamic, multiscale process of clonal evolution in which genetic and epigenetic lesions (at the molecular scale) affect the expansion of clones and the accumulation of clonal diversity (at the organ scale). Most of the details of these dynamics remain unknown. For example, we do not understand how clones spread within a neoplasm or how clonal diversity changes over time as clones develop genetic instability and competition drives some clones extinct. These problems are important because suppressing clonal expansions would help to prevent cancer and we have shown that patients with more genetic diversity in their pre-malignant tumors are more likely to progress to cancer. Genetic diversity is also likely to be associated with therapeutic resistance, which is the cause of most cancer deaths. We have developed agent based models to explore the dynamics of clonal expansions and diversity in neoplasms. We are using these models to guide the development of experiments to measures those dynamics in vivo.

A multi-scale approach towards understanding antigen presentation in the immune response to Mycobacterium tuberculosis

The immune system and the process of antigen presentation in particular encompass events that occur at multiple length and time scales. Despite a wealth of information in the biological literature regarding each of these scales, no single representation synthesizing this information into a model of the overall immune response as it depends on antigen presentation is available. In this talk, I outline an approach for integrating information over relevant biological and temporal scales to generate such a representation for MHC class II-mediated antigen presentation. In addition, I begin to address how such models can be used to answer questions about mechanisms of infection and new strategies for treatment and vaccines.

  • Martin Fink
University of Oxford, martin.fink@dpag.ox.ac.uk

PreDiCT: Computational Prediction of Drug Cardiac Toxicity

We will present our multi-scale approach to predict the toxicity of drugs in the heart - ranging from the ion channel level to whole organ models. In collaboration with pharmaceutical industries we will investigate the interaction of various drug compounds on the main sodium, calcium and potassium ion channels. The modelling framework then leads to the possibility to examine the relation between the mode of action of the compounds and the arrhythmic events in the whole heart of rabbit and human.

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