A Formal Framework for Clock-free Networks of Cells

International audienceno abstrac

Complementary approaches to understanding the plant circadian clock

Circadian clocks are oscillatory genetic networks that help organisms adapt to the 24-hour day/night cycle. The clock of the green alga Ostreococcus tauri is the simplest plant clock discovered so far. Its many advantages as an experimental system facilitate the testing of computational predictions. We present a model of the Ostreococcus clock in the stochastic process algebra Bio-PEPA and exploit its mapping to different analysis techniques, such as ordinary differential equations, stochastic simulation algorithms and model-checking. The small number of molecules reported for this system tests the limits of the continuous approximation underlying differential equations. We investigate the difference between continuous-deterministic and discrete-stochastic approaches. Stochastic simulation and model-checking allow us to formulate new hypotheses on the system behaviour, such as the presence of self-sustained oscillations in single cells under constant light conditions. We investigate how to model the timing of dawn and dusk in the context of model-checking, which we use to compute how the probability distributions of key biochemical species change over time. These show that the relative variation in expression level is smallest at the time of peak expression, making peak time an optimal experimental phase marker. Building on these analyses, we use approaches from evolutionary systems biology to investigate how changes in the rate of mRNA degradation impacts the phase of a key protein likely to affect fitness. We explore how robust this circadian clock is towards such potential mutational changes in its underlying biochemistry. Our work shows that multiple approaches lead to a more complete understanding of the clock

BlenX-based compositional modeling of complex reaction mechanisms

Molecular interactions are wired in a fascinating way resulting in complex behavior of biological systems. Theoretical modeling provides a useful framework for understanding the dynamics and the function of such networks. The complexity of the biological networks calls for conceptual tools that manage the combinatorial explosion of the set of possible interactions. A suitable conceptual tool to attack complexity is compositionality, already successfully used in the process algebra field to model computer systems. We rely on the BlenX programming language, originated by the beta-binders process calculus, to specify and simulate high-level descriptions of biological circuits. The Gillespie's stochastic framework of BlenX requires the decomposition of phenomenological functions into basic elementary reactions. Systematic unpacking of complex reaction mechanisms into BlenX templates is shown in this study. The estimation/derivation of missing parameters and the challenges emerging from compositional model building in stochastic process algebras are discussed. A biological example on circadian clock is presented as a case study of BlenX compositionality

Formal Systems Architectures for Biology

When the word "systems" is used in systems biology, it invokes a variety of assumptions about what defines the subject under investigation, which in turn can lead to divergent research outcomes. We will take the position that systems are defined by their potential organizing and "control" mechanisms, 
which distinguishes complex, living systems from a primordial soup. This will be accomplished by defining and investigating three interesting control motifs in biological systems: dominoes and clocks, futile cycles, and complex feedforward regulation. Additional mechanisms that combine feedback and feedforward mechanisms will also be briefly elaborated upon. Throughout these examples, our focus will be on the connection between top-down control mechanisms and bottom-up self-organizing mechanisms

The century of the incomplete revolution: searching for general relativistic quantum field theory

In fundamental physics, this has been the century of quantum mechanics and general relativity. It has also been the century of the long search for a conceptual framework capable of embracing the astonishing features of the world that have been revealed by these two ``first pieces of a conceptual revolution''. I discuss the general requirements on the mathematics and some specific developments towards the construction of such a framework. Examples of covariant constructions of (simple) generally relativistic quantum field theories have been obtained as topological quantum field theories, in nonperturbative zero-dimensional string theory and its higher dimensional generalizations, and as spin foam models. A canonical construction of a general relativistic quantum field theory is provided by loop quantum gravity. Remarkably, all these diverse approaches have turn out to be related, suggesting an intriguing general picture of general relativistic quantum physics.Comment: To appear in the Journal of Mathematical Physics 2000 Special Issu