Emergent Dynamics of Thymocyte Development and Lineage Determination

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Abstract
Experiments have generated a plethora of data about the genes, molecules, and cells involved in thymocyte development. Here, we use a computer-driven simulation that uses data about thymocyte development to generate an integrated dynamic representation—a novel technology we have termed reactive animation (RA). RA reveals emergent properties in complex dynamic biological systems. We apply RA to thymocyte development by reproducing and extending the effects of known gene knockouts: CXCR4 and CCR9. RA simulation revealed a previously unidentified role of thymocyte competition for major histocompatability complex presentation. We now report that such competition is required for normal anatomical compartmentalization, can influence the rate of thymocyte velocities within chemokine gradients, and can account for the disproportion between single-positive CD4 and CD8 lineages developing from double-positive precursors. Biological systems are the embodiment of complexity that defies intuitive understanding. Biologists have accumulated masses of data about the molecules, cells, and discrete interactions that compose living systems, but the list of facts alone cannot explain how such systems work dynamically. We have developed a hybrid, computational approach to the simulation of complex systems called reactive animation (RA). RA uses a bottom-up integration of diverse experimental data to create an integrated and dynamic representation of the system's interacting cells and molecules. RA is faithful to experimental fact, while it plays out the action in animated formats directly accessible to the eye and mind. Most importantly, RA is analytical, interactive, and allows experimentation in silico. Here, we use RA to reveal unexpected emergent properties of thymocyte development. In particular, we now report that competition between thymocytes for sites of stimulation could be important in generating the fine anatomy of the thymus, in selecting for thymocytes with a range of migration velocities, and in explaining the paradox of CD4 to CD8 T cell lineage ratios. This study highlights the explanatory power and the potential aid to experimentation offered by an animated, interactive simulation of complex sets of data.