Online Seminar Series

Modelling approaches for disease processes

The Online Seminar Series (Zoom) “Modelling approaches for disease processes” is organized by the e:Med project group Modeling of Disease Processes.
Time: Every 1st or 2nd Wednesday of the month, 2 p.m.
Aim/ Focus: Introduction, discussion and comparison of different mathematical modelling approaches. For initial list of topics and speakers see below.
Duration: 30’ talk +15’ discussion. We would like to have a focus on discussion. In cases of 2 speakers the duration can be 40 min + discussion.
Targeted audience: PhD and master students, postdocs, group leaders in the modelling field.

Location: ZOOM

The talks start at 2 p.m. CET

If you missed a seminar, you can watch the video recordings of several the talks and discussions. Please see below in the 'previous seminars'.
* Talks with video are marked by an asteriks.

We look forward to the new insights into disease process modeling and to discussing them with you.

Register for the online seminar

You are very welcome to join the seminar! Please register below to receive information by email. Do you want contribute to the series as speaker? Please apply below and we will get back to you.

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Upcoming Seminars:

May 8, 2024 - Galit Lahav, Harvard Medical School, Boston

June 5, 2024 - Pre-cancer somatic evolution. Thomas Höfer, DKFZ Heidelberg

Previous Seminars:

Semester 23/24

Apr 10, 2024 - Andreas Reichel, Head of Preclinical Modeling and Simulation, Bayer AG

© Andreas Reichel

Dr. Andreas Reichel, Head of Preclinical Modeling and Simulation, Bayer AG

Location: online ZOOM

Abstract

Transforming the discovery and development of targeted protein degraders through application of a comprehensive PK/PD modeling framework

Targeted protein degradation is an emerging new therapeutic concept that attracts an enormous interest with currently more than twenty compounds in clinical trials. As opposed to conventional target protein inhibitors, it is characterized by a much more complex mode of action with simultaneous kinetics of the drug molecule as well as the target protein, followed by the dynamics of ternary complex formation and target degradation and the subsequent downstream pharmacological responses. The simultaneous occurrence of these processes requires integrative PK/PD modeling to fully comprehend and predict the actions and effects of targeted protein degraders. We therefore have developed a comprehensive mechanistic PK/PD modeling framework that, starting with accurate description of biochemical and cellular degradation in vitro data, allows a priori predictions of target protein degradation profiles in vivo as rational guidance in degrader projects. Our predictions have become a key component of the design of in vivo studies aimed to demonstrate target degradation in animal PD models. They facilitate the optimization and selection of i) the most suitable compounds, ii) the doses and schedules with the highest likelihood for reaching the desired effect level, and iii) the optimal time points for measuring PK and PD. The talk will introduce the transformative power of the modeling framework using case examples which illustrate its application for compound progression and the translational understanding of targeted protein degraders.

March 6, 2024 - Chengzhe Tian, University of Stuttgart

© Chengzhe Tian

Prof. Dr. Chengzhe Tian, University of Stuttgart

Location: online ZOOM

Abstract

Towards a single-cell longitudinal characterization of cancer therapeutic resistance 

Despite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment. Cells that escape drug rely on ATF4 stress signaling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment. Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.

Feb 7, 2024 - Anmar Khadra, McGill University, Montréal

© Anmar Khadra

Prof. Dr. Anmar Khadra, Department of Physiology, Co-Director, Centre for Applied Mathamtics in BioScience and Medicine (CAMBAM), McGill University

Location: online ZOOM

Abstract

Characterizing Neural Signaling in Neuropathic Pain Using Computational Modeling.

Neuropathic pain is a complex condition with a huge unmet medical need. Owing to our incomplete understanding of its perplexing pathology, current therapeutic strategies for treating neuropathic pain remain limited in their efficacy. Computational modeling has emerged as a promising tool to unravel the intricate neural mechanisms underlying neuropathic pain; it has significantly advanced our knowledge of the molecular, cellular, and neural network-level signaling pathways underpinning the disease. The integration of this approach with experimental methods has indeed yielded crucial insights into neuropathic pain pathophysiology, with great potential to inform novel pharmacological and neurostimulation-based treatments for the disease. In this talk, I will provide an overview of our recent computational modeling work that has allowed us to define the role of certain ionic currents in altering neural responses implicated in neuropathic pain.

Jan 10, 2024 - The Architecture of Biological Adaptation: Deciphering the Balancing Acts Behind Health and Disease. Mustafa Khammash

© Mustafa Khammash

Mustafa Khammash, ETH Zürich

 

Abstract

The Architecture of Biological Adaptation: Deciphering the Balancing Acts Behind Health and Disease

This presentation delves into the concept of 'robust perfect adaptation' in biological systems, a fundamental mechanism enabling organisms to maintain homeostasis amidst diverse environmental stimuli. We explore how this adaptive resilience is pivotal for health, with its failure often leading to disease states. Focusing on Calcium homeostasis as a case study, the talk will elucidate the essential structural constraints in biological networks that facilitate robust adaptation. These constraints represent universal principles governing biological function and adaptation. The discussion extends to the implications of these findings in systems and synthetic biology, emphasizing the potential to transcend specific system implementations. By understanding the underlying principles of biological adaptation, we can gain comprehensive insights into regulatory complexities in both health and disease.

Dez 6, 2023 - Inference of temporal dynamics from single-cell high-throughput data. Laleh Haghverdi >>> including video

© Laleh Haghverdi

Laleh Haghverdi, Max Delbrück Center, Berlin

Location: online ZOOM

 

Abstract

Inference of temporal dynamics from single-cell high-throughput data

For several biological processes e.g., development, cell differentiation and disease progression, researchers are interested in understanding the temporal sequence of molecular events, and how they lead to certain final observations on the system. I will discuss a few approaches of dynamical inference from one or a few snapshots of high-throughput single-cell measurements, covering cell state velocities, and response pseudotime inference from time-series data in our recent publications. 

Video:

Nov 8, 2023 - Computer models of tissue regeneration through agent-based modeling approaches. Sara Checa Estebán >>>including video<<<

© Sara Checa

Prof. Dr. Sara Checa, Julius Wolff Institute, Berlin Institute of Health (BIH), Charité - Universitätsmedizin Berlin

 

Abstract

Computer models of tissue regeneration through agent-based modeling approaches.

Several tissues within the body have the amazing ability to self-regenerate, e.g. skin, bone. Understanding the mechanisms behind this process might serve as a fingerprint to foster regeneration in other tissues that have none or limited regeneration capacity. The regeneration of injured tissues within the body is a highly complex process, where different cell phenotypes interact in a highly coordinated manner. In this process, cells migrate, proliferate, differentiate and deposite new extracellular matrix over time; ideally leading to the reconstitution of the original tissue function. In this talk, I will present current methods and applications on the modelling of bone tissue regeneration, with a focus on agent-based modeling approaches. I will show the application of these models to investigate the mechanisms behind successful and unsucessful regeneration as well for the development of treatment strategies.

Video:

Semester 22/23

June 7, 2023. From mechanisms to prediction: Designing personalised treatment strategies for eczema. Reiko J. Tanaka.

Reiko J. Tanaka, Imperial College London

Location:

ZOOM

Abstract

From mechanisms to prediction: Designing personalised treatment strategies for eczema   

Atopic dermatitis (or eczema, AD) is the most common inflammatory skin disease characterised by inflamed, dry and itchy skin leading to substantial quality of life impairment and significant socioeconomic impact. Designing personalised treatment strategies for AD is challenging, given the apparent unpredictability and large variation in AD symptoms and treatment responses within and across individuals. A first step toward developing personalised treatment strategies is to better predict the consequences of possible treatments at an individual level, rather than at population level, to deal with the variability across patients.  
We developed a mechanistic model of AD pathogenesis which provided a coherent mechanistic explanation of the dynamic onset, progression, and prevention of AD, as a result of interactions between skin barrier, immune responses and environmental stressors. Model predictive control using the mechanistic model suggested a possibility for designing personalized treatment strategies. We also adapted the structure of the mechanistic model to real patient data and developed a Bayesian mechanistic model tailored to each individual, that can predict the next day’s AD severity score given their score and treatments used on that day.   
I would like to discuss hopes and challenges in designing personalized treatment strategies, for which detailed dynamic data is required but not often available.    
 

*April 5, 2023. Dynamic logic models complement machine learning for personalized medicine. Julio Saez-Rodriguez. >>>including video<<<

© Julio Saez-Rodriguez

Julio Saez-Rodriguez, University of Heidelberg

Location: online ZOOM - see video below

Abstract

Dynamic logic models complement machine learning for personalized medicine

Multi-omics technologies, and in particular those with single-cell and spatial resolution, provide unique opportunities to study the deregulation of intra- and inter-cellular signaling processes in disease. I will present recent methods and applications from our group toward this aim, focusing on computational approaches that combine data with biological knowledge within statistical and machine learning methods. This combination allows us to increase both the statistical power of our analyses and the mechanistic interpretability of the results. These approaches allow us to identify key processes, that can be in turn studied in detailed with dynamic mechanistic models. I will then present how cell-specific logic models, trained with measurements upon perturbations, can provides new biomarkers and treatment opportunities. Finally, I will show how, using novel microfluidics-based technologies, this approach can also be applied directly to biopsies, allowing to build mechanistic models for individual cancer patients, and use these models to prose new therapies.  
 

 

Video:

*February 1, 2023. Mechanistic insights into sensitization and desensitization of the Interferon α signal transduction pathway. Marcus Rosenblatt, Jens Timmer >>>including video <<<

© Rosenblatt & Timmer 

Marcus Rosenblatt, Jens Timmer, Institute of Physics, University of Freiburg

 

 

Location: online ZOOM - see video below

Abstract

Mechanistic insights into sensitization and desensitization of the Interferon α signal transduction pathway

 As a key component of the innate immune system, Interferon alpha (IFNα) orchestrates the antiviral response in hepatocytes. The IFNα signal transduction pathway is known to desensitize upon activation which constitutes a major problem for the usage of IFNα as treatment against chronic viral infections or as an anti-tumor drug. However, the mechanisms that lead to this desensitization remain poorly understood.
Here, an ODE model is presented that describes the biochemical reaction network of IFNα signaling in different hepatoma cell lines as well as primary human hepatocytes (PHH). The calibrated model shows that besides a dose-dependent desensitization mediated by the negative feedback components SOCS1 and USP18 that act at the receptor level, the signaling pathway can also show (hyper-)sensitization in consequence of an upregulation of the intra-cellular components IRF9 and STAT2. 
The model predicted the dose-dependent dynamics of transcriptionally active complexes in the signaling pathway and their effect on mRNA production, as shown by independent validation experiments. Furthermore, the model-based analysis of measurement data from PHH unraveled that each cell system establishes a particular dose-depending sensitization behavior whose shape is strongly determined by the abundance of the feedback components USP18 and STAT2. We show that our findings help to understand the dynamics of production of Interferon Stimulated Genes (ISGs) which exert numerous antiviral effector functions, and serve as a basis for a patient-individual optimization of the antiviral response upon IFNα stimulation.
 

Video:

*January 11, 2023. Modeling and Inference for Biological Systems with Hidden Components. Jae Kyoung Kim. >>> including video<<<

Jae Kyoung Kim, Dept. of Mathematical Sciences, KAIST, South Korea

Location: ZOOM (Video below)

 

Abstract

Modeling and Inference for Biological Systems with Hidden Components

Despite dramatic advances in experimental techniques, many facets of intracellular dynamics remain hidden or can be measured only indirectly. In this talk, I will describe strategies to develop mathematical models with hidden parts: replacement of hidden components with either time delay or quasi-steady-state. Then, I will illustrate how the simplification with the time delay can be used to understand the processes of protein synthesis, which involves multiple steps such as transcription, translation, folding, and maturation, but typically whose intermediates proteins cannot be measured. Furthermore, I will illustrate how the simplification with the quasi-steady-state can be used to develop an accurate method to estimate drug clearance, which occurs in multiple steps of metabolism, which greatly improved the canonical approach used in more than 65,000 published papers for last 30 years.  Finally, I will describe an inference method, GOBI (General Model-based Inference), that identifies hidden regulatory biochemical connections from time-series data. This method adopts the advantage of model-free inference methods (broad applicability) and model-based inference methods (accuracy). 
 

 

Video:

*December 7, 2022. Semi-quantitative modeling in systems biology: the Petri net formalism. Ina Koch. >>>including slides<<<

Ina Koch, University Frankfurt

Location: ZOOM

Abstract

Semi-quantitative modeling in systems biology: the Petri net formalism

Modeling disease pathways requires the integration of various data of different type and quality. Whereas the data needed for deterministic approaches, such as ODE-based modeling, are often rare or not available, a huge amount of qualitative data have been generated by high-throughput methods in the last years. This causes the need for developing and applying new modeling approaches. Besides Boolean modeling, semi-quantitative modeling using Petri nets has been successfully applied to model biochemical systems, covering metabolic systems, signal transduction pathways, gene-regulatory pathways and hybrid systems.
In the talk, we will first introduce the basics of the Petri net formalism and its static and dynamic analysis techniques. The techniques range from basic graph-theoretical considerations and integer linear programming techniques to dynamic simulations. We will focus on invariant-based analysis approaches, in particular on transition invariants and Manatee invariants. We will illustrate the introduced terms using a case study of signal transduction in the NF-kB pathway before considering an exhaustive Petri net model of the TNFR1-induced signaling pathway, which covers cell survival, apoptosis and necroptosis processes. We will present the main results and additionally discuss the results of in silico knockout analysis based on the Petri net model.

November 9, 2022. Models of metabolism for biomedical research. Ralf Steuer.

Ralf Steuer, Institute for Theoretical Biology, Humboldt University Berlin

Location: ZOOM

 

Abstract

Models of metabolism for biomedical research

Cellular metabolism is the ultimate driving force of life. Metabolism provides the chemical energy required to run cellular processes, ensures cellular functions and removal of byproducts, and synthesises the building blocks for growing cells. Metabolic processes and the resulting metabolite levels can be interpreted as "end products" of cellular regulatory processes, and metabolic dysfunctions are the underlying cause of a multitude of diseases, including cancer. 
The talk aims to discuss the current dichotomy between small-scale kinetic models, and comprehensive genome-scale metabolic reconstructions of metabolism in the context of biochemical research. In particular, while genome-scale reconstructions offer unprecedented possibilities to study the organization of human metabolism, their analysis is typically restricted to stoichiometric properties and stationary fluxes. In contrast, kinetic models of metabolism based on ordinary differential equations allow for a dynamic description, but their reconstruction requires extensive (and currently often not available) knowledge about enzyme-kinetic parameters. The talk will explore intermediate methods that (a) seek to derive smaller coarse-grained models from genome-scale reconstructions, and (b) use Monte-Carlo methods to account for unknown or uncertain parameters. 

 

Semester 22

June 15, 2022. How mathematical models support clinical drug development: an industry perspective. Bernhard Steiert

Dr. Bernhard Steiert, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

Location: ZOOM

 

Abstract


How mathematical models support clinical drug development: an industry perspective

Mathematical modelling is a key component of drug development and is applied at all stages of a molecule progressing along the value chain. In clinical development, it is essential to find the right dose for every patient, which is composed of the right amount of drug and the right treatment interval for the right patient population. Modelling is also used to leverage and extrapolate the available data, informing decisions on which programs to accelerate and which ones to stop.
In this talk, an overview of the Roche Pharma Research and Early Development (pRED) setup for modelling will be provided. Typical models used in the pharmaceutical industry will be exemplified and, based on those, more general modelling themes are outlined and discussed. Involvement of key internal and external stakeholders is crucial for impacting decisions with modelling. I will summarize who they are and which communication strategies are most suitable for building trust in modelers and their models. The talk will close with examples where modelling was impactful and helped to bring safe and efficacious medicines to patients faster.

 

*May 4, 2022. Easy implementation and acceleration of spatial agent-based modelling of biological processes using rule-based modelling. Gavin Fullstone, Markus Morrison. >>>including video<<<

Dr. Gavin Fullstone, University of Stuttgart, Stuttgart Research Centre Systems Biology

Prof. Dr. Markus Morrison, University of Stuttgart, Institute of Cell Biology and Immunology

Location: ZOOM

Abstract

Easy implementation and acceleration of spatial agent-based modelling of biological processes using rule-based modelling

Agent-based modelling is particularly adept at modelling complex features of cell signalling pathways, where heterogeneity, stochastic and spatial effects are important, thus increasing our understanding of decision processes in biology in such scenarios. However, agent-based modelling often is computationally prohibitive to implement. Parallel computing, either on central processing units (CPUs) or graphical processing units (GPUs), can provide a means to improve computational feasibility of agent- based applications but generally requires specialist coding knowledge and extensive optimisation. In this seminar, we will demonstrate how we implemented and utilise a rule-based modelling approach to define particle-based models that can be flexibly parallelised on either CPU or GPU-architecture. In comparison with an established particle-based simulator, we achieve speed ups of >650-fold on modern GPUs whilst maintaining robust simulation. Additionally, we will demonstrate how we apply stochastic hybrid approaches to model the activity of multi-protein complexes and their contribution to cell signalling outcomes. In introducing these approaches, we will simultaneously present specific examples where we have successfully applied these approaches to help us understand fundamental biological processes, predict outcomes in biologically relevant scenarios and in the design of targeted therapeutics.
 

Video:

*April 6, 2022. Multi-scale modelling. Martin Falcke, Lutz Brusch. >>>including video<<<

Multi-scale modelling

Dr. Martin Falcke, Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Dr. Lutz Brusch, Research Group Leader,Center for Information Services and High Performance Computing (ZIH), Technische Universität Dresden

Location: ZOOM

Abstract

Biological systems comprise many structural levels represented by molecules, cell organelles, cells, tissues, organs, organisms, populations and ecological levels. Each structural levels has its typical time and length scale from fs and nm on molecular level to km and years on ecological level. Multiscale modelling refers to mathematical models describing dynamics on different structural levels. Here, several structural levels and several scales may be accounted for either by a single equation or by multiple coupled equations each comprising only one scale. We present examples of both approaches.
In the first case, we present reaction diffusion systems for cardiac myocytes taking behaviour of individual ion channels into account and simulating whole cells at the same time. The mathematical problems and methods addressing them will be explained. For the second case, we introduce coupling of processes between intracellular, cellular and tissue scales. Such coupling requires that parameters of model processes on one scale get driven by the dynamical variables of model components at another scale. We demonstrate such model integration across multiple scales in the software framework Morpheus (https://morpheus.gitlab.io) and discuss the emergence of complex 'morphodynamic' behaviour that cannot be addressed by simpler models at a single scale.

 

Video:

*March 2, 2022. Response-Time Modelling of Cell-Cell Interaction Dynamics . Kevin Thurley >>>including video<<<

Prof. Kevin Thurley, Biomathematik, Institut für Experimentelle Onkologie, Universitätsklinikum Bonn, https://www.thurleylab.org 

Location: Zoom 
 

Abstract

Response-Time Modelling of Cell-Cell Interaction Dynamics

Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. In this talk, I will introduce a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships (Thurley K, Wu LF, Altschuler SJ, Cell Systems 2018, DOI: 10.1016/j.cels.2018.01.016). The approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps. Here, response-time modeling will be presented in the context of data-driven analysis of T cell differentiation and expansion in chronic viral infections. 
 

Video:

*February 2, 2022. Large-scale pathway models for biomedical research. Jan Hasenauer >>>including video<<<

Prof. Dr. Jan Hasenauer, LIMES Institute, Universität Bonn

Target audience: PhD and master students, postdocs, group leaders in the modelling field.

Location: Zoom

Abstract

Large-scale pathway models for biomedical research.

Pathway models are powerful tools in modern life sciences. They are based on knowledge of individual biological pathways and can be integrated into large-scale models to capture crosstalk. In this seminar, I will briefly introduce the modeling approach and methods used to create large-scale models. I will then present a large-scale model of cancer signal transduction with thousands of biochemical species and reactions as an example application. Variants of this model have been used for multi-omics analyses in murine model systems and human cell lines. We have developed workflows for parameterization and analysis of these models. I hope to discuss these approaches and future directions. 

 

Video:

January 12, 2022. Using Disease Maps in Biomedical Research. Olaf Wolkenhauer, Shailendra Gupta, Matti Hoch

Prof. Dr. Olaf Wolkenhauer, Dept of Systems Biology & Bioinformatics, University of Rostock

Dr. Shailendra Gupta, Systems Biology & Bioinformatics, University of Rostock

Matti Hoch, Systems Biology & Bioinformatics, University of Rostock

Location: online ZOOM

Abstract

Using Disease Maps in Biomedical Research

Olaf Wolkenhauer, Shailendra Gupta, Matti Hoch (Systems Biology & Bioinformatics, University of Rostock)
Disease maps are interactive, web-based representations of the phenotypic, cellular, and molecular processes underlying complex diseases in the form of knowledgebase. Disease maps provide a platform to integrate heterogeneous clinical and experimental data for formulating hypotheses on diagnostic, prognostic, and/or therapeutic markers using systems biology and bioinformatics-based methods.  In the seminar, we shall contrast the disease map approach with small-scale pathway modelling efforts and present examples from cancer systems biology and demoing the Atlas of Inflammation Resolution (AIR) (https://air.bio.informatik.uni-rostock.de) The AIR contains 40 manually curated submaps including > 6T elements each of which are manually annotated. In addition, the AIR is enriched with regulatory layers of microRNAs, lncRNAs, and transcription factors that form a large molecular interaction map (MIM) with >23,000 molecular interactions. We developed workflows that facilitate the integration and analyses of multi-omics data directly on the disease maps and enable users to perform in silico perturbation experiments for formulating data-driven hypotheses. In the seminar, we hope for a discussion in which we compare the “disease map approach” with other pathway and network modelling approaches.
 

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