Investigating modularity in the analysis of process algebra models of biochemical systems

Compositionality is a key feature of process algebras which is often cited as one of their advantages as a modelling technique. It is certainly true that in biochemical systems, as in many other systems, model construction is made easier in a formalism which allows the problem to be tackled compositionally. In this paper we consider the extent to which the compositional structure which is inherent in process algebra models of biochemical systems can be exploited during model solution. In essence this means using the compositional structure to guide decomposed solution and analysis. Unfortunately the dynamic behaviour of biochemical systems exhibits strong interdependencies between the components of the model making decomposed solution a difficult task. Nevertheless we believe that if such decomposition based on process algebras could be established it would demonstrate substantial benefits for systems biology modelling. In this paper we present our preliminary investigations based on a case study of the pheromone pathway in yeast, modelling in the stochastic process algebra Bio-PEPA

Design Environments for Complex Systems

The paper describes an approach for modeling complex systems by hiding as much formal details as possible from the user, still allowing verification and simulation of the model. The interface is based on UML to make the environment available to the largest audience. To carry out analysis, verification and simulation we automatically extract process algebras specifications from UML models. The results of the analysis is then reflected back in the UML model by annotating diagrams. The formal model includes stochastic information to handle quantitative parameters. We present here the stochastic -calculus and we discuss the implementation of its probabilistic support that allows simulation of processes. We exploit the benefits of our approach in two applicative domains: global computing and systems biology

Population models from PEPA descriptions

Stochastic process algebras such as PEPA have enjoyed considerable success as CTMC-based system description languages for performance evaluation of computer and communication systems. However they have not been able to escape the problem of state space explosion, and this problem is exacerbated when other domains such as systems biology are considered. Therefore we have been investigating alternative semantics for PEPA models which give rise to a population view of the system, in terms of a set of nonlinear ordinary differential equations. This extended abstract gives an overview of this mapping

Modeling formalisms in systems biology

Systems Biology has taken advantage of computational tools and high-throughput experimental data to model several biological processes. These include signaling, gene regulatory, and metabolic networks. However, most of these models are specific to each kind of network. Their interconnection demands a whole-cell modeling framework for a complete understanding of cellular systems. We describe the features required by an integrated framework for modeling, analyzing and simulating biological processes, and review several modeling formalisms that have been used in Systems Biology including Boolean networks, Bayesian networks, Petri nets, process algebras, constraint-based models, differential equations, rule-based models, interacting state machines, cellular automata, and agent-based models. We compare the features provided by different formalisms, and discuss recent approaches in the integration of these formalisms, as well as possible directions for the future.Research supported by grants SFRH/BD/35215/2007 and SFRH/BD/25506/2005 from the Fundacao para a Ciencia e a Tecnologia (FCT) and the MIT-Portugal Program through the project "Bridging Systems and Synthetic Biology for the development of improved microbial cell factories" (MIT-Pt/BS-BB/0082/2008)

COMPUTER SIMULATION AND COMPUTABILITY OF BIOLOGICAL SYSTEMS

The ability to simulate a biological organism by employing a computer is related to the ability of the computer to calculate the behavior of such a dynamical system, or the "computability" of the system.* However, the two questions of computability and simulation are not equivalent. Since the question of computability can be given a precise answer in terms of recursive functions, automata theory and dynamical systems, it will be appropriate to consider it first. The more elusive question of adequate simulation of biological systems by a computer will be then addressed and a possible connection between the two answers given will be considered. A conjecture is formulated that suggests the possibility of employing an algebraic-topological, "quantum" computer (Baianu, 1971b) for analogous and symbolic simulations of biological systems that may include chaotic processes that are not, in genral, either recursively or digitally computable. Depending on the biological network being modelled, such as the Human Genome/Cell Interactome or a trillion-cell Cognitive Neural Network system, the appropriate logical structure for such simulations might be either the Quantum MV-Logic (QMV) discussed in recent publications (Chiara, 2004, and references cited therein)or Lukasiewicz Logic Algebras that were shown to be isomorphic to MV-logic algebras (Georgescu et al, 2001)

Łukasiewicz-Moisil Many-Valued Logic Algebra of Highly-Complex Systems

A novel approach to self-organizing, highly-complex systems (HCS), such as living organisms and artificial intelligent systems (AIs), is presented which is relevant to Cognition, Medical Bioinformatics and Computational Neuroscience. Quantum Automata (QAs) were defined in our previous work as generalized, probabilistic automata with quantum state spaces (Baianu, 1971). Their next-state functions operate through transitions between quantum states defined by the quantum equations of motion in the Schroedinger representation, with both initial and boundary conditions in space-time. Such quantum automata operate with a quantum logic, or Q-logic, significantly different from either Boolean or Łukasiewicz many-valued logic. A new theorem is proposed which states that the category of quantum automata and automata--homomorphisms has both limits and colimits. Therefore, both categories of quantum automata and classical automata (sequential machines) are bicomplete. A second new theorem establishes that the standard automata category is a subcategory of the quantum automata category. The quantum automata category has a faithful representation in the category of Generalized (M,R)--Systems which are open, dynamic biosystem networks with defined biological relations that represent physiological functions of primordial organisms, single cells and higher organisms

Process algebra modelling styles for biomolecular processes

We investigate how biomolecular processes are modelled in process algebras, focussing on chemical reactions. We consider various modelling styles and how design decisions made in the definition of the process algebra have an impact on how a modelling style can be applied. Our goal is to highlight the often implicit choices that modellers make in choosing a formalism, and illustrate, through the use of examples, how this can affect expressability as well as the type and complexity of the analysis that can be performed

Quantum Genetics and Quantum Automata Models of Quantum-Molecular Evolution Involved in the Evolution of Organisms and Species

Previous theoretical or general approaches to the problems of Quantum Genetics and Molecular Evolution are considered in this article from the point of view of Quantum Automata Theory first published by the author in 1971 and further developed in several recent articles. The representation of genomes and Interactome networks in categories of many-valued logic LMn –algebras that are naturally transformed during biological evolution, or evolve through interactions with the environment provide a new insight into the mechanisms of molecular evolution, as well as organismal evolution, in terms of sequences of quantum automata. Phenotypic changes are expressed only when certain environmentally-induced quantum-molecular changes are coupled with an internal re-structuring of major submodules of the genome and Interactome networks related to cell cycling and cell growth. Contrary to the commonly held view of `standard’ Darwinist models of evolution, the evolution of organisms and species occurs through coupled multi-molecular transformations induced not only by the environment but actually realized through internal re-organizations of genome and interactome networks. The biological, evolutionary processes involve certain epigenetic transformations that are responsible for phenotypic expression of the genome and Interactome transformations initiated at the quantum-molecular level. It can thus be said that only quantum genetics can provide correct explanations of evolutionary processes that are initiated at the quantum--multi-molecular levels and propagate to the higher levels of organismal and species evolution.

Biological evolution should be therefore regarded as a multi-scale process which is initiated by underlying quantum (coupled) multi-molecular transformations of the genomic and interactomic networks, followed by specific phenotypic transformations at the level of organism and the variable biogroupoids associated with the evolution of species which are essential to the survival of the species. The theoretical framework introduced in this article also paves the way to a Quantitative Biology approach to biological evolution at the quantum-molecular, as well as at the organismal and species levels. This is quite a substantial modification of the 'established’ modern Darwinist, and also of several so-called `molecular evolution’ theories

Stronger computational modelling of signalling pathways using both continuous and discrete-state methods

Starting from a biochemical signalling pathway model expresses in a process algebra enriched with quantitative information, we automatically derive both continuous-space and discrete-space representations suitable for numerical evaluation. We compare results obtained using approximate stochastic simulation thereby exposing a flaw in the use of the differentiation procedure producing misleading results

Categorical Ontology of Complex Systems, Meta-Systems and Theory of Levels: The Emergence of Life, Human Consciousness and Society

Single cell interactomics in simpler organisms, as well as somatic cell interactomics in multicellular organisms, involve biomolecular interactions in complex signalling pathways that were recently represented in modular terms by quantum automata with ‘reversible behavior’ representing normal cell cycling and division. Other implications of such quantum automata, modular modeling of signaling pathways and cell differentiation during development are in the fields of neural plasticity and brain development leading to quantum-weave dynamic patterns and specific molecular processes underlying extensive memory, learning, anticipation mechanisms and the emergence of human consciousness during the early brain development in children. Cell interactomics is here represented for the first time as a mixture of ‘classical’ states that determine molecular dynamics subject to Boltzmann statistics and ‘steady-state’, metabolic (multi-stable) manifolds, together with ‘configuration’ spaces of metastable quantum states emerging from complex quantum dynamics of interacting networks of biomolecules, such as proteins and nucleic acids that are now collectively defined as quantum interactomics. On the other hand, the time dependent evolution over several generations of cancer cells --that are generally known to undergo frequent and extensive genetic mutations and, indeed, suffer genomic transformations at the chromosome level (such as extensive chromosomal aberrations found in many colon cancers)-- cannot be correctly represented in the ‘standard’ terms of quantum automaton modules, as the normal somatic cells can. This significant difference at the cancer cell genomic level is therefore reflected in major changes in cancer cell interactomics often from one cancer cell ‘cycle’ to the next, and thus it requires substantial changes in the modeling strategies, mathematical tools and experimental designs aimed at understanding cancer mechanisms. Novel solutions to this important problem in carcinogenesis are proposed and experimental validation procedures are suggested. From a medical research and clinical standpoint, this approach has important consequences for addressing and preventing the development of cancer resistance to medical therapy in ongoing clinical trials involving stage III cancer patients, as well as improving the designs of future clinical trials for cancer treatments.\ud \ud \ud KEYWORDS: Emergence of Life and Human Consciousness;\ud Proteomics; Artificial Intelligence; Complex Systems Dynamics; Quantum Automata models and Quantum Interactomics; quantum-weave dynamic patterns underlying human consciousness; specific molecular processes underlying extensive memory, learning, anticipation mechanisms and human consciousness; emergence of human consciousness during the early brain development in children; Cancer cell ‘cycling’; interacting networks of proteins and nucleic acids; genetic mutations and chromosomal aberrations in cancers, such as colon cancer; development of cancer resistance to therapy; ongoing clinical trials involving stage III cancer patients’ possible improvements of the designs for future clinical trials and cancer treatments. \ud \u