ProMoT : Modular Modeling for Systems Biology

Summary: PROMOT is a software designed to support efficient and comprehensible modeling, visualization and analysis of complex and large-scale models. In recent years it has been improved in many aspects. New functionality especially tailored for Systems Biology has been added. It is now a very convenient tool for modular modeling. Availability: PROMOT is an open source project and freely available at http://www.mpi-magdeburg.mpg.de/projects/promot/download.html

The Process-Interaction-Model: a common representation of rule-based and logical models allows studying signal transduction on different levels of detail

BACKGROUND: Signaling systems typically involve large, structured molecules each consisting of a large number of subunits called molecule domains. In modeling such systems these domains can be considered as the main players. In order to handle the resulting combinatorial complexity, rule-based modeling has been established as the tool of choice. In contrast to the detailed quantitative rule-based modeling, qualitative modeling approaches like logical modeling rely solely on the network structure and are particularly useful for analyzing structural and functional properties of signaling systems. RESULTS: We introduce the Process-Interaction-Model (PIM) concept. It defines a common representation (or basis) of rule-based models and site-specific logical models, and, furthermore, includes methods to derive models of both types from a given PIM. A PIM is based on directed graphs with nodes representing processes like post-translational modifications or binding processes and edges representing the interactions among processes. The applicability of the concept has been demonstrated by applying it to a model describing EGF insulin crosstalk. A prototypic implementation of the PIM concept has been integrated in the modeling software ProMoT. CONCLUSIONS: The PIM concept provides a common basis for two modeling formalisms tailored to the study of signaling systems: a quantitative (rule-based) and a qualitative (logical) modeling formalism. Every PIM is a compact specification of a rule-based model and facilitates the systematic set-up of a rule-based model, while at the same time facilitating the automatic generation of a site-specific logical model. Consequently, modifications can be made on the underlying basis and then be propagated into the different model specifications – ensuring consistency of all models, regardless of the modeling formalism. This facilitates the analysis of a system on different levels of detail as it guarantees the application of established simulation and analysis methods to consistent descriptions (rule-based and logical) of a particular signaling system

Agricultural land use changes – a scenario-based sustainability impact assessment for Brandenburg, Germany

AbstractDecisions for agricultural management are taken at farm scale. However, such decisions may well impact upon regional sustainability. Two of the likely agricultural management responses to future challenges are extended use of irrigation and increased production of energy crops. The drivers for these are high commodity prices and subsidy policies for renewable energy. However, the impacts of these responses upon regional sustainability are unknown. Thus, we conducted integrated impact assessments for agricultural intensification scenarios in the federal state of Brandenburg, Germany, for 2025. One Irrigation scenario and one Energy scenario were contrasted with the Business As Usual (BAU) scenario. We applied nine indicators to analyze the economic, social and environmental effects at the regional, in this case district scale, which is the smallest administrative unit in Brandenburg. Assessment results were discussed in a stakeholder workshop involving 16 experts from the state government.The simulated area shares of silage maize for fodder and energy were 29%, 37% and 49% for the BAU, Irrigation, and Energy scenarios, respectively. The Energy scenario increased bio-electricity production to 41% of the demand of Brandenburg, and it resulted in CO2 savings of up to 3.5milliontons. However, it resulted in loss of biodiversity, loss of landscape scenery, increased soil erosion risk, and increased area demand for water protection requirements. The Irrigation scenario led to yield increases of 7% (rapeseed), 18% (wheat, sugar beet), and 40% (maize) compared to the BAU scenario. It also reduced the year-to-year yield variability. Water demand for irrigation was found to be in conflict with other water uses for two of the 14 districts. Spatial differentiation of scenario impacts showed that districts with medium to low yield potentials were more affected by negative impacts than districts with high yield potentials.In this first comprehensive sustainability impact assessment of agricultural intensification scenarios at regional level, we showed that a considerable potential for agricultural intensification exists. The intensification is accompanied by adverse environmental and socio-economic impacts. The novelty lies in the multiscale integration of comprehensive, agricultural management simulations with regional level impact assessment, which was achieved with the adequate use of indicators. It provided relevant evidence for policy decision making. Stakeholders appreciated the integrative approach of the assessment, which substantiated ongoing discussions among the government bodies. The assessment approach and the Brandenburg case study may stay exemplary for other regions in the world where similar economic and policy driving forces are likely to lead to agricultural intensification

Automatic Compilation from High-Level Biologically-Oriented Programming Language to Genetic Regulatory Networks

Background The field of synthetic biology promises to revolutionize our ability to engineer biological systems, providing important benefits for a variety of applications. Recent advances in DNA synthesis and automated DNA assembly technologies suggest that it is now possible to construct synthetic systems of significant complexity. However, while a variety of novel genetic devices and small engineered gene networks have been successfully demonstrated, the regulatory complexity of synthetic systems that have been reported recently has somewhat plateaued due to a variety of factors, including the complexity of biology itself and the lag in our ability to design and optimize sophisticated biological circuitry. Methodology/Principal Findings To address the gap between DNA synthesis and circuit design capabilities, we present a platform that enables synthetic biologists to express desired behavior using a convenient high-level biologically-oriented programming language, Proto. The high level specification is compiled, using a regulatory motif based mechanism, to a gene network, optimized, and then converted to a computational simulation for numerical verification. Through several example programs we illustrate the automated process of biological system design with our platform, and show that our compiler optimizations can yield significant reductions in the number of genes () and latency of the optimized engineered gene networks. Conclusions/Significance Our platform provides a convenient and accessible tool for the automated design of sophisticated synthetic biological systems, bridging an important gap between DNA synthesis and circuit design capabilities. Our platform is user-friendly and features biologically relevant compiler optimizations, providing an important foundation for the development of sophisticated biological systems.National Institutes of Health (U.S.) (Grant # 7R01GM74712-5)United States. Defense Advanced Research Projects Agency (contract HR0011-10-C-0168)National Science Foundation (U.S.) (NSF CAREER award 0968682)BBN Technologie

Multi-state Modeling of Biomolecules

Multi-state modeling of biomolecules refers to a series of techniques used to represent and compute the behavior of biological molecules or complexes that can adopt a large number of possible functional states. Biological signaling systems often rely on complexes of biological macromolecules that can undergo several functionally significant modifications that are mutually compatible. Thus, they can exist in a very large number of functionally different states. Modeling such multi-state systems poses two problems: the problem of how to describe and specify a multi-state system (the “specification problem”) and the problem of how to use a computer to simulate the progress of the system over time (the “computation problem”). To address the specification problem, modelers have in recent years moved away from explicit specification of all possible states and towards rule-based formalisms that allow for implicit model specification, including the κ-calculus [1], BioNetGen [2]–[5], the Allosteric Network Compiler [6], and others [7], [8]. To tackle the computation problem, they have turned to particle-based methods that have in many cases proved more computationally efficient than population-based methods based on ordinary differential equations, partial differential equations, or the Gillespie stochastic simulation algorithm [9], [10]. Given current computing technology, particle-based methods are sometimes the only possible option. Particle-based simulators fall into two further categories: nonspatial simulators, such as StochSim [11], DYNSTOC [12], RuleMonkey [9], [13], and the Network-Free Stochastic Simulator (NFSim) [14], and spatial simulators, including Meredys [15], SRSim [16], [17], and MCell [18]–[20]. Modelers can thus choose from a variety of tools, the best choice depending on the particular problem. Development of faster and more powerful methods is ongoing, promising the ability to simulate ever more complex signaling processes in the future

Visualization of complex biochemical models with ProMoT

In recent years modeling of reaction systems tend to be more complex. Especially in systems biology researchers are faced with large and highly interconnected network models that become hard to understand and navigate. The hierarchical decomposition of models into modules and the consequent graphical representation of these units can help to understand complex models and make them more manageable. However, in terms of visualization, this approach has some limitations due to the size and complexity of models and the lack of screen real estate. In this talk, visualization and navigation techniques for complex biochemical network models are introduced. They provide basically two functionalities - (i) the interactive visual exploration of model parts in context of the whole model and (ii) a highly flexible handling of visual properties of the network model tailored to user preferences and the modeling task. The techniques are illustrated by applying them to different application areas including chemical engineering and systems biology but with focus on intracellular reaction systems such as signaling networks. Furthermore, it is discussed how these techniques are used for the adequate visual representation of the logical/Boolean modeling formalism and for the visualization of data derived from model analysis. This talk also presents a first approach for the semi-automatic layout of models with hierarchical and modular structure. The techniques are implemented in the process modeling tool ProMoT (http://www.mpi-magdeburg.mpg.de/projects/promot)