20 research outputs found
Cooperative development of logical modelling standards and tools with CoLoMoTo
The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments. Contact: [email protected]
Cooperative development of logical modelling standards and tools with CoLoMoTo.
The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments
Addressing barriers in comprehensiveness, accessibility, reusability, interoperability and reproducibility of computational models in systems biology
Computational models are often employed in systems biology to study the dynamic behaviours of complex systems. With the rise in the number of computational models, finding ways to improve the reusability of these models and their ability to reproduce virtual experiments becomes critical. Correct and effective model annotation in community-supported and standardised formats is necessary for this improvement. Here,we present recent efforts toward a common framework for annotated, accessible, reproducible and interoperable computational models in biology, and discuss key challenges of the field.
Scientists from different systems biology fields have long been developing community-driven guidelines and best practices for annotation, interoperability and reusability of computational models in biology. However, the parallel work, grounded on shared needs and similar aims, of separate communities creates a need for exchange and alignment of the different efforts to harmonise best practices. Hence, members of the Consortium for Logical Models and Tools (CoLoMoTo, http://colomoto.org) and the Computational Modelling of Biological Systems community of the International Society for Computational Biology (SysMod, https:// sysmod.info/) organised aworkshop to discusscommunitydriven guidelines and efforts for the curation and annotation of computational models during [BC]2 2021. The workshop grew from a previous edition organised during [BC]2 2019 focused on logical modelling [1]. The second edition brought together scientists with various research backgrounds and from different working groups such as BioModels [2], a central repository of mathematical models of biological/biomedical processes; the Computational Modelling in Biology Network initiative (COMBINE) [3]; CoLoMoTo, [4]; SysMod, [5]; the Systems Biology Graphical Notation (SBGN) project [6]; the systems biology markup language (SBML) [7] and simulation experiment description markup language (SED-ML) [8], to exchange and expand on several key topics of common interest (Figure 1). While the modelling approaches across these communities differ, several critical points are shared, such as (i) the importance of annotations for reproducibility, (ii) the use of community standards for exchange and annotation encoding, (iii) the need to implement standards in tools and platforms to boost reusability and interoperability, (iv) the importance of transparency of modelling frameworks in publications and (v) the use of shared repositories to enhance model accessibility (Figure 2). We use the term annotation to describe âa computeraccessible metadata item that captures, entirely or in part, the meaning of a model, model component or data elementâ. We borrow this definition from [9] which is in accordance with its use in [1]. We discuss the identified needs in the following sections
Setting the basis of best practices and standards for curation and annotation of logical models in biology
International audienceThe fast accumulation of biological data calls for their integration, analysis and exploitation through more systematic approaches. The generation of novel, relevant hypotheses from this enormous quantity of data remains challenging. Logical models have long been used to answer a variety of questions regarding the dynamical behaviours of regulatory networks. As the number of published logical models increases, there is a pressing need for systematic model annotation, referencing and curation in community-supported and standardised formats. This article summarises the key topics and future directions of a meeting entitled âAnnotation and curation of computational models in biologyâ, organised as part of the 2019 [BC]2 conference. The purpose of the meeting was to develop and drive forward a plan towards the standardised annotation of logical models, review and connect various ongoing projects of experts from different communities involved in the modelling and annotation of molecular biological entities, interactions, pathways and models. This article defines a roadmap towards the annotation and curation of logical models, including milestones for best practices and minimum standard requirements
Basins of Attraction, Commitment Sets and Phenotypes of Boolean Networks
The attractors of Boolean networks and their basins have been shown to be
highly relevant for model validation and predictive modelling, e.g., in systems
biology. Yet there are currently very few tools available that are able to
compute and visualise not only attractors but also their basins. In the realm
of asynchronous, non-deterministic modeling not only is the repertoire of
software even more limited, but also the formal notions for basins of
attraction are often lacking. In this setting, the difficulty both for theory
and computation arises from the fact that states may be ele- ments of several
distinct basins. In this paper we address this topic by partitioning the state
space into sets that are committed to the same attractors. These commitment
sets can easily be generalised to sets that are equivalent w.r.t. the long-term
behaviours of pre-selected nodes which leads us to the notions of markers and
phenotypes which we illustrate in a case study on bladder tumorigenesis. For
every concept we propose equivalent CTL model checking queries and an extension
of the state of the art model checking software NuSMV is made available that is
capa- ble of computing the respective sets. All notions are fully integrated as
three new modules in our Python package PyBoolNet, including functions for
visualising the basins, commitment sets and phenotypes as quotient graphs and
pie charts
SBML Level 3: an extensible format for the exchange and reuse of biological models
Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution
Model Checking to Assess T-Helper Cell Plasticity
Computational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific Th cell polarizing or reprograming events.LabEx MemoLife, Ecole Normale Supérieure, FCT grants: (PEst-OE/EEI/LA0021/2013, IF/01333/2013), Ph.D.program of the Agence National de Recherche sur Le Sida (ANRS), European Research Council consolidator grant
A computational modelling of cellular and supra-cellular networks to unravel the control of EMT
"Over the last decade, Epithelial-to-Mesenchymal Transition (EMT) has gained the
attention of cancer researchers due to its potential to promote cancer migration
and metastasis. However, the complexity of EMT intertwined regulation and the
involvement of multiple signals in the tumour microenvironment have been
limiting the understanding of how this process can be controlled. Cell-cell
adhesion and focal adhesion dynamics are two critical properties that change
during EMT, which provide a simple way to characterize distinct modes of cancer
migration. Therefore, the main focus of this thesis is to provide a framework to
predict critical microenvironment and de-regulations in cancer that drive interconversion
between adhesion phenotypes, accounting for main
microenvironment signals and signalling pathways in EMT. Here, we address this
issue through a systems approach using the logical modelling framework to
generate new testable predictions for the field.(...)"Instituto Gulbenkian de CiĂȘncia (FCG-IGC
SBML Level 3: an extensible format for the exchange and reuse of biological models
Abstract Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reactionâbased models and packages that extend the core with features suited to other model types including constraintâbased models, reactionâdiffusion models, logical network models, and ruleâbased models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as singleâcell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution
Applications of Boolean modelling to study and stratify dynamics of a complex disease
Interpretation of omics data is needed to form meaningful hypotheses about
disease mechanisms. Pathway databases give an overview of disease-related processes, while mathematical models give qualitative and quantitative insights into
their complexity. Similarly to pathway databases, mathematical models are stored
and shared on dedicated platforms. Moreover, community-driven initiatives such
as disease maps encode disease-specific mechanisms in both computable and
diagrammatic form using dedicated tools for diagram biocuration and visualisation. To investigate the dynamic properties of complex disease mechanisms,
computationally readable content can be used as a scaffold for building dynamic
models in an automated fashion. The dynamic properties of a disease are extremely complex. Therefore, more research is required to better understand the
complexity of molecular mechanisms, which may advance personalized medicine
in the future.
In this study, Parkinsonâs disease (PD) is analyzed as an example of a complex
disorder. PD is associated with complex genetic, environmental causes and
comorbidities that need to be analysed in a systematic way to better understand
the progression of different disease subtypes. Studying PD as a multifactorial
disease requires deconvoluting the multiple and overlapping changes to identify
the driving neurodegenerative mechanisms. Integrated systems analysis and
modelling can enable us to study different aspects of a disease such as progression,
diagnosis, and response to therapeutics. Therefore, more research is required to
better understand the complexity of molecular mechanisms, which may advance
personalized medicine in the future. Modelling such complex processes depends
on the scope and it may vary depending on the nature of the process (e.g. signalling
vs metabolic). Experimental design and the resulting data also influence model
structure and analysis. Boolean modelling is proposed to analyse the complexity
of PD mechanisms. Boolean models (BMs) are qualitative rather than quantitative
and do not require detailed kinetic information such as Petri nets or Ordinary
Differential equations (ODEs). Boolean modelling represents a logical formalism
where available variables have binary values of one (ON) or zero (OFF), making it
a plausible approach in cases where quantitative details and kinetic parameters
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are not available. Boolean modelling is well validated in clinical and translational
medicine research.
In this project, the PD map was translated into BMs in an automated fashion
using different methods. Therefore, the complexity of disease pathways can be
analysed by simulating the effect of genomic burden on omics data. In order to
make sure that BMs accurately represent the biological system, validation was
performed by simulating models at different scales of complexity. The behaviour
of the models was compared with expected behavior based on validated biological
knowledge. The TCA cycle was used as an example of a well-studied simple
network. Different scales of complex signalling networks were used including the
Wnt-PI3k/AKT pathway, and T-cell differentiation models. As a result, matched
and mismatched behaviours were identified, allowing the models to be modified
to better represent disease mechanisms. The BMs were stratified by integrating
omics data from multiple disease cohorts. The miRNA datasets from the Parkinsonâs Progression Markers Initiative study (PPMI) were analysed. PPMI provides
an important resource for the investigation of potential biomarkers and therapeutic targets for PD. Such stratification allowed studying disease heterogeneity and
specific responses to molecular perturbations. The results can support research
hypotheses, diagnose a condition, and maximize the benefit of a treatment. Furthermore, the challenges and limitations associated with Boolean modelling in
general were discussed, as well as those specific to the current study.
Based on the results, there are different ways to improve Boolean modelling
applications. Modellers can perform exploratory investigations, gathering the
associated information about the model from literature and data resources. The
missing details can be inferred by integrating omics data, which identifies missing
components and optimises model accuracy. Accurate and computable models
improve the efficiency of simulations and the resulting analysis of their controllability. In parallel, the maintenance of model repositories and the sharing of
models in easily interoperable formats are also important