Section: Application Domains

Biological Regulation Networks

Participants : Thomas Chatain, Matthias Fuegger, Stefan Haar, Serge Haddad, Juraj Kolcak, Hugues Mandon, Stefan Schwoon.

We have begun in 2014 to examine concurrency issues in systems biology, and are currently enlarging the scope of our research’s applications in this direction. To see the context, note that in recent years, a considerable shift of biologists’ interest can be observed, from the mapping of static genotypes to gene expression, i.e. the processes in which genetic information is used in producing functional products. These processes are far from being uniquely determined by the gene itself, or even jointly with static properties of the environment; rather, regulation occurs throughout the expression processes, with specific mechanisms increasing or decreasing the production of various products, and thus modulating the outcome. These regulations are central in understanding cell fate (how does the cell differenciate ? Do mutations occur ? etc), and progress there hinges on our capacity to analyse, predict, monitor and control complex and variegated processes. We have applied Petri net unfolding techniques for the efficient computation of attractors in a regulatory network; that is, to identify strongly connected reachability components that correspond to stable evolutions, e.g. of a cell that differentiates into a specific functionality (or mutation). This constitutes the starting point of a broader research with Petri net unfolding techniques in regulation. In fact, the use of ordinary Petri nets for capturing regulatory network (RN) dynamics overcomes the limitations of traditional RN models : those impose e.g. Monotonicity properties in the influence that one factor had upon another, i.e. always increasing or always decreasing, and were thus unable to cover all actual behaviours. Rather, we follow the more refined model of boolean networks of automata, where the local states of the different factors jointly detemine which state transitions are possible. For these connectors, ordinary PNs constitute a first approximation, improving greatly over the literature but leaving room for improvement in terms of introducing more refined logical connectors. Future work thus involves transcending this class of PN models. Via unfoldings, one has access – provided efficient techniques are available – to all behaviours of the model, rather than over-or under-approximations as previously. This opens the way to efficiently searching in particular for determinants of the cell fate : which attractors are reachable from a given stage, and what are the factors that decide in favor of one or the other attractor, etc. Our current research focusses cellular reprogramming on the one hand, and distributed algorithms in wild or synthetic biological systems on the other. The latter is a distributed algorithms’ view on microbiological systems, both with the goal to model and analyze existing microbiological systems as distributed systems, and to design and implement distributed algorithms in synthesized microbiological systems. Envisioned major long-term goals are drug production and medical treatment via synthesized bacterial colonies. We are approaching our goal of a distributed algorithm’s view of microbiological systems from several directions: (i) Timing plays a crucial role in microbiological systems. Similar to modern VLSI circuits, dominating loading effects and noise render classical delay models unfeasible. In previous work we showed limitations of current delay models and presented a class of new delay models, so called involution channels. In [26] we showed that involution channels are still in accordance with Newtonian physics, even in presence of noise. (ii) In [7] we analyzed metastability in circuits by a three-valued Kleene logic, presented a general technique to build circuits that can tolerate a certain degree of metastability at its inputs, and showed the presence of a computational hierarchy. Again, we expect metastability to play a crucial role in microbiological systems, as similar to modern VLSI circuits, loading effects are pronounced. (iii) We studied agreement problems in highly dynamic networks without stability guarantees [28], [27]. We expect such networks to occur in bacterial cultures where bacteria communicate by producing and sensing small signal molecules like AHL. Both works also have theoretically relevant implications: The work in [27] presents the first approximate agreement protocol in a multidimensional space with time complexity independent of the dimension, working also in presence of Byzantine faults. In [28] we proved a tight lower bound on convergence rates and time complexity of asymptotic and approximate agreement in dynamic and classical static fault models. (iv) We are currently working with Manish Kushwaha (INRA), and Thomas Nowak (LRI) on biological infection models for E. coli colonies and M13 phages.