The topic of this workshop was metabolism in general, with a special focus, although not exclusive, on parasitology. Besides an exploration of the biological, biochemical and biomedical aspects, the workshop also aimed at presenting some of the mathematical modelling, algorithmic theory and software development that have become crucial to explore such aspects.

The workshop was open to all members of these two projects but also, importantly, to the community in general.

Agenda:

Keynote lecturers:

Barbara Bakker (Faculty of Medical Sciences, University of Groningen, The Netherlands)

Title talk: Digital twins: a personalised systems medicine approach for metabolic disease.
Short abstract: Each patient is unique. Even siblings with the same pathogenic genotype may differ vastly in disease presentation and treatment response. Computational models of metabolic networks, so-called ‘digital twins’, may give insight into disease mechanisms and identify putative sources of inter-patient heterogeneity. In the talk, I will focus on the mitochondrial fatty-acid beta-oxidation (mFAO) and its interplay with vitamin and cofactor metabolism. Although the reactions and enzymes in the pathway have been known for decades, its dynamic regulation is not well understood. Deregulation of mFAO plays a pivotal role in many diseases, including age-related multifactorial diseases, such as diabetes, but also rare, inherited enzyme deficiencies. We therefore embarked on a systems biology program, combining wet-lab biochemistry, stable-isotope fluxomic, targeted proteomics, patient cell and organoid cultures, and patient-specific computational models.

Igor Cestari (Institute of Parasitology, McGill University, Montréal, Canada)

Title talk: Nuclear signaling and antigenic switching in trypanosomes.

Vassily Hatzimanikatis (École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland)

Title talk: One method does not fit all: A Hierarchy of Modelling and Computational Methods for Metabolic Analysis and Design.
Short abstract: Mathematical models are used in all fields of science and engineering to analyze and design complex and intricate systems. They have been used extensively in the study of metabolism. However, different modeling frameworks and computational methods must be tailored to study different questions and problems. Therefore, a hierarchy of models and computational methods for metabolic systems exists. We considered three main problems: (i) the reconstruction of genome-scale metabolic networks and the identification of novel pathways for the biosynthesis of non-biological chemicals; (ii) the integration of omics information for the quantitative analysis of metabolic fluxes in large-scale and genome-scale metabolic networks; and (iii) the identification of rate-limiting steps in metabolic pathways for metabolic engineering and the treatment of metabolic diseases. For each of these problems, we presented the relevant modeling and computational methods and discussed the challenges and opportunities for future developments.

Steffen Klamt (Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany)

Title talk: Network-wide thermodynamic constraints shape NAD(P)H cofactor specificity of biochemical reactions.
Short abstract: NADH and NADPH are redox cofactors coexisting in all living cells. Here, we present a computational study suggesting that evolved NAD(P)H reaction specificities in E. coli are largely shaped by metabolic network structure enabling maximal thermodynamic driving forces close to the theoretical optimum.

Ina Koch (Goethe Universität, Frankfurt am Main, Germany)

Title talk: Bipartite graphs for computational modeling in systems biology: from KEGG to Petri nets.
Short abstract: Computational modeling of biological systems at different levels of abstraction demands specific data structures. Interestingly, the use of bipartite graphs can be found as a data structure from the beginning (KEGG) until new developments in the field. We considered Petri nets as a mathematical formalism to predict the system’s properties and dynamic behavior without knowing any kinetic parameters. In the lecture, we introduced the foundations of Petri net formalism and some analysis techniques to explore specific properties. Petri nets can be applied to model metabolism, signaling transduction, and gene regulation. For illustration, we gave small case studies. Finally, we discussed new ideas for the combination of agent‐based modeling to connect signaling with metabolism.
Short bio: Ina Koch studied chemistry and did her diploma’s thesis in quantum chemistry at the University of Leipzig. She received her Ph.D. in the field of theoretical computer science with the topic “A graph-theoretical application of the pairwise and multiple alignments of protein structures”. Ina Koch has been working at different places, among them the Max Delbrück Center in the group of Jens Reich and the Max Planck Institute for Molecular Genetics in the group of Martin Vingron. Since 2010 she has held a full professorship in bioinformatics at the Goethe University Frankfurt. Her research has been dedicated to different topics, ranging from the investigation of protein structure topology using graph theory to the analysis of SNPs and alternative splicing, and, in the last years, more and more to the analysis of biochemical systems. For about 20 years, Ina Koch has been applying Petri nets to model biochemical systems, including metabolic systems, signal transduction pathways, and gene regulatory networks. Ina Koch was the spokesperson of the Fachgruppe Bioinformatik (FaBI) and is a member of the DFG review board “Foundations in Biology and Medicine”, as well as a member of several Scientific Advisory Boards.

Laura-Isobel McCall (San Diego State University, US)

Title talk: Metabolism in a 3D environment: chemical cartography of Chagas disease.
Short abstract: Chemical cartography is the spatial analysis of metabolic changes in tissue. In this talk, I discussed how chemical cartography enables insights into the determinants of cardiac and gastrointestinal Chagas disease tropism and of treatment efficacy.
Short bio: Laura-Isobel McCall, PhD, is an Associate Professor of Chemistry and Biochemistry at San Diego State University. There, she focuses on using spatially-resolved metabolomics to understand host-pathogen-microbiome interactions, to guide drug development and biomarker discovery.

Discussions on open questions

For this third edition of the workshop, besides the keynote talks, there was also two slots, one per day, for a discussion on two specific open questions. Each one was managed and moderated by two invited researchers.
For this edition, the open questions and invited researchers were:

  • Discussion 1:
    • Question: There many databases related to metabolism, and there are for a given organism, many metabolic networks that have been reconstructed that provide different and not always compatible information. How the community could address these issues?
    • Moderators: Ariel Silber, Gabriela Torres Montanaro (USP), Mariana Galvão Ferrarini (Inria), Marie-France Sagot, and Mayke Bezerra Alencar (USP)
  • Discussion 2:
    • Question: What further constraints could be integrated in stoichiometric models, going beyond mass balances, flux bounds, thermodynamic constraints and resource (including enzyme) allocation constraints.
    • Moderators: Ariel Silber, Gabriela Torres Montanaro (USP), Mariana Galvão Ferrarini (Inria), and Marie-France Sagot

Registration

Registration was free but mandatory.

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This workshop was organised by the Inria European Team Erable in the context of OLISSIPO and another project which involves a partnership with the University of São Paulo (USP), in São Paulo, Brazil, more specifically the Institute of Mathematics and Statistics (IME) and the Institute of Biomedical Sciences – Inria Associated Team Capoeira.