Example models in D2D

Examples with experimental data

• Becker_Science2010 is an Epo receptor model in BaF3 cells. It provides a nice interpretation in terms of systems properties of two mechanistic processes at the receptor level allowing ligand sensing by the pathway over several orders of magnitudes of the ligand's concentration.

More details are provided in the following publication:

Becker V, Schilling M, Bachmann J, Baumann U, Raue A, Maiwald T, Timmer J, Klingmüller U. Covering a broad dynamic range: information processing at the erythropoietin receptor. Science. 2010 Jun 11;328(5984):1404-8. doi: 10.1126/science.1184913

• Bachmann_MSB2011 provides a systemic interpretation of the function of the two transcriptional negative feedbacks in the JAK2/STAT5 pathway in EPO-treated CFU-E cells.

More details are provided in the following publication:

Bachmann J, Raue A, Schilling M, Böhm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmüller U. Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range. Mol Syst Biol. 2011 Jul 19;7:516. doi: 10.1038/msb.2011.50.

• Beer_MolBioSyst2014 is a model of Indigoidine synthesis in E. coli.

More details are provided in the following publication:

Beer R, Herbst K, Ignatiadis N, Kats I, Adlung L, Meyer H, Niopek D, Christiansen T, Georgi F, Kurzawa N, Meichsner J, Rabe S, Riedel A, Sachs J, Schessner J, Schmidt F, Walch P, Niopek K, Heinemann T, Eils R, Di Ventura B. Creating functional engineered variants of the single-module non-ribosomal peptide synthetase IndC by T domain exchange. Mol Biosyst. 2014 Jul;10(7):1709-18. doi: 10.1039/c3mb70594c.

• Boehm_JProteomeRes2014 describes STAT5 activation model in BaF3-EpoR cells.

More details are provided in the following publication:

Boehm ME, Adlung L, Schilling M, Roth S, Klingmüller U, Lehmann WD. Identification of isoform-specific dynamics in phosphorylation-dependent STAT5 dimerization by quantitative mass spectrometry and mathematical modeling. J Proteome Res. 2014 Dec 5;13(12):5685-94. doi: 10.1021/pr5006923.

• Lucarelli_CellSystems2011 utilized L1-penalization based on CoIP Mass Spec measurements to identify the relevant complexes of TGFb signalling in Hepa1.6. In addition, the impact of these complexes on gene expression of TGFb target genes has been investigated.

More details are provided in the following publication:

Philippe Lucarelli, Marcel Schilling, Clemens Kreutz, Artyom Vlasov, Martin E. Boehm, Nao Iwamoto, Bernhard Steiert, Susen Lattermann, Marvin Wasch, Markus Stepath, Matthias S. Matter, Mathias Heikenwalder, Katrin Hoffmann, Daniela Deharde, Georg Damm, Daniel Seehofer, Maria Muciek, Norbert Gretz, Wolf D. Lehmann, Jens Timmer and Ursula Klingmueller Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression, Cell Systems, 2017

• Merkle_PCB2016 shows how to identify parameter differences in the JAK2/STAT5 pathway in EPO-treated CFU-E and H838 cells.

More details are provided in the following publication:

Merkle R, Steiert B, Salopiata F, Depner S, Raue A, Iwamoto N, Schelker M, Hass H, Wäsch M, Böhm ME, Mücke O, Lipka DB, Plass C, Lehmann WD, Kreutz C, Timmer J, Schilling M, Klingmüller U. Identification of cell type-specific differences in erythropoietin receptor signaling in primary erythroid and lung cancer cells. PLOS Comp Biol. 2016.

• Raia_CancerResearch2011 is a model of the JAK2/STAT5 signalling after IL13 stimulation in two lymphoma-derived cell lines.

More details are provided in the following publication:

Raia V, Schilling M, Böhm M, Hahn B, Kowarsch A, Raue A, Sticht C, Bohl S, Saile M, Möller P, Gretz N, Timmer J, Theis F, Lehmann WD, Lichter P, Klingmüller U. Dynamic mathematical modeling of IL13-induced signaling in Hodgkin and primary mediastinal B-cell lymphoma allows prediction of therapeutic targets. Cancer Res. 2011 Feb 1;71(3):693-704. doi: 10.1158/0008-5472.CAN-10-2987.

• Swameye_PNAS2003 is an early model of JAK/STAT signaling in BaF3 cells. The model has been used to predict recycling of STAT dimers from the nucleaus back to the cytosol. It is one of the first models combining experimental data and mathematical modelling in the field of molecular biology. It is one of the first applications of statistical parameter estimation techniques in the field of systems biology. The model was also used in the paper to design an informative validation experiment.

More details are provided in the following publication:

Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1028-33. Epub 2003 Jan 27. Identification of nucleocytoplasmic cycling as a remote sensor in cellular signaling by databased modeling. Swameye I, Muller TG, Timmer J, Sandra O, Klingmuller U.

Benchmark Examples

• The Benchmark collection is a set of independently published ODE-models calibrated with experimental data from the field of computational cell biology. This collection can be used for meta analysis studies such as method comparisons or performance assessments regarding parameter estimation and uncertainty quantification. The set of models is available in D2D. In this article we give an overview about how to easily utilize this Benchmark collection.

• The Dream6 example contains three models used in the DREAM6 parameter estimation challenge. DREAM stands for Dialogue for Reverse Engineering Assessments and Methods and aims assessment of state-of-the-art methodology in computational biology. In the DREAM6 challenge, fixed model structures in combination with simulated data were provided to estimate the parameters of gene regulatory network models. Besides parameter estimation, the participants of the challenge were also demanded to select informative experimental setups (in terms of obsvables and pertubations like knockout, knockdown or over-expression). The challenge covered three models which were analyzed by the participants indpendently. The DREAM6 models are excellent benchmark models for assessing methodology for parameter estimation, uncertainty quantification, and experimental design.

Examples from Biomodels Database

• The model DallaMan2007_GlucoseInsulinSystem is a multi-compartement physiological model describing the concentration of glucose and insulin in the blood. It is one of the most famous examples of mathematical modelling because it has been approved by the FDA as the only alternative to animal testing. The model is described in detail here.

• The Elowitz2000_Repressilator model is described here. The model describes three genes which regulate each other via a negative-feedback circle. Parameter values were determined exhibiting oscillatory behaviour.

• Fribourg2014_ImmuneResponseH1N1 is a model of the interplay between the dentritic cell and two different influenza viruses. It is described in more detail here.

• Huang1996_MapKinase is one of the first mathematical models of the MAP-kinase signalling pathway which one of the most important pathways in a large set of biological processes. More details are provided here.

• Kholodenko1999_EGFRsignaling describes Epidermal Growth Factor Receptor signalling in the context of tumor cells. More details are found here.

• Restif2007_VaccinationInvasion is a model for vaccination and the dynamics of immune evasion which is described in more detail here.

• Steckmann2012_Fibrillogenesis represents a model for the dynamics of peptide secondary structure conversion during amyloid β-protein fibrillogenesis. For more details, see here.

Toy Examples

• The ABC_toyModel is a basic model consisting of two consecutive conversion reaction. If not all components are measured, it can be used to illustrate non-identifiablity and non-observability.

• The Advanced_Events model illustrates how events are defined as well as the benefit. Events are required, if the ODEs are not differentiable. This occurs, e.g. if a step is used as an imput, i.e. if the model describes the dynamics starting at time point t=0, but the cells are stimulated at t>0.

• Bolus_Injection_Test

• The Dream6_NonSloppy model provides a model as well as a set of experiments which are not sloppy. The term sloppiness was introduced for the observation that the eigenvalue spectrum of the Hessian for typical models in systems biology cover more than 6 orders of magnitudes. The example invalidates the claim, that sloppiness is a universal property of ODE models representing biochemical interaction networks.

• Event_Test is a basic example for testing and illustrating the implementation of events.

• Input_Tests is a basic example for testing and illustrating the implementation of input functions.

• Merkle_ToyModel_PCB2016 is a basic example for detecting differences between cell types using l1 regularization.

• Splines is an example for illustrating the application of splines for estimating observed inputs.

• Step_Estimation tests optimization of models with complex step functions.

• Stoichiometry is a small test example for reactions with non unity stoichiometry.

• Volume_Estimation is a basic example for testing and illustrating the implementation of compartments with different volumes.

• Washing_and_Injection_Test is another example for the implementation of input functions.