• biological systems
• model checking
• modular verification

Systems of interest in systems biology (such as metabolic pathways, signalling pathways and gene regulatory networks) often consist of a huge number of components interacting in different ways, thus exhibiting very complex behaviours. In biology, such behaviours are usually explored by means of simulation techniques applied to models defined on the basis of system observation and of hypotheses on its functioning.
Model checking has also been recently applied to the analysis of biological systems. This analysis technique typically relies on a state space representation whose size, unfortunately, makes the analysis often intractable for realistic models. A method for trying to avoid the state space explosion problem is to consider a decomposition of the system, and to apply a modular verification technique.
In particular, properties to be verified often concern only a small portion of the modelled system rather than the system as a whole. Hence, for each property it would be useful to be able to isolate a minimal fragment of the model that is necessary to verify such a property.

In this thesis we introduce a modular verification technique in which the system of interest is described by means of an automata-based formalism, called sync-programs, that supports modular construction. Our modular verification technique is based on results of Grumberg et al.~and on their application to the theory of concurrent systems proposed by Attie and Emerson. In particular, we adapt Attie and Emerson's approach to deal with biological systems by allowing automata to synchronise by performing transitions simultaneously.

Modular verification allows qualitative aspects of systems to be analysed with the guarantee that properties proved to hold in a suitable model fragment also hold in the whole model. The correctness of the verification technique is proved. The class of properties preserved is ACTL$^{-}$, the universal fragment of temporal logic CTL. The preservation holds only for positive answers and negative answers are not necessarily preserved.

In order to verify properties we use the NuSMV model checker, which is a well-established and efficient instrument. We provide a formal translation of sync-programs to simpler automata, which can be given as input to NuSMV. We prove the correspondence of the verification problems.

We show the application of our verification technique in some biological case studies. We compare the time required to verify the property on the whole model with the time needed to verify the same property by only considering those modules which are involved in the behaviour of the system related to the property.

In order to handle modelling and verification of more realistic biological scenarios, we propose also a dynamic version of our formalism. It allows entities to be created dynamically, in particular by other already running entities, as it often happens in biological systems. Moreover, multiple copies of the same entities can be present at the same time in a system. We show a correspondence of our model with Petri Nets. This has a consequence that tools developed for Petri Nets could be used also for dynamic sync-programs. Modular verification allows properties expressed as DACTL- formulae (dynamic version of ACTL-) to be verified on a portion of the model.

The results of analysis of the case study of the MAP kinase cascade activated by surface and internalised EGF receptors, which consists of 143 species and 80 reactions, suggest applicability and scalability of the approach.

The results raise the prospect of rendering tractable problems that are currently intractable in the verification of biological systems. In addition, we expect that the techniques developed in the thesis could be applied with profit not only to models of biological systems, but more generally to models of concurrent systems.