Title: Workshop Metabolism and mathematical models: Two for a tango – 1st Edition
Dates: November 18-19, 2021
Location: This workshop will be held in a virtual way
The topic of this workshop is metabolism in general, with a special focus, although not exclusive, on parasitology. Besides an exploration of the biological, biochemical and biomedical aspects, the workshop will also aim at presenting some of the mathematical modelling, algorithmic theory and software development that have become crucial to explore such aspects.
This workshop is being organised in the context of two projects, both with the Inria European Team Erable. One of the projects 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 – and the other involves the Inesc-ID/IST in Portugal, ETH in Zürich and EMBL in Heidelberg – H2020 Twinning Project Olissipo.
The workshop is open to all members of these two projects but also, importantly, to the community in general.
Michael Barrett (University of Glasgow, Scotland)
Title talk: Metabolomics of drug response in trypanosomes and leishmania.
Short abstract: Many drugs act through inhibition of metabolic enzymes. Moreover, resistance to drugs can be brought about through changes in the metabolic homeostasis of cells. Here, I will discuss how metabolomics has been useful in identifying targets for a number of drugs and drug candidates that are active against trypanosomes and leishmania, and also how changes in metabolism underpin resistance to some key anti-parasitic drugs.
Frédéric Bringaud (University of Bordeaux, France)
Short abstract: Trypanosoma brucei is a unicellular eukaryote that causes Human African Trypanosomiasis, also known as sleeping sickness. Parasite transmission between mammals is ensured by a haematophagous insect vector of the genus Glossina, also called the tsetse fly. Trypanosomes adapt to their natural hosts, in particular to the available carbon sources required to fuel central metabolism and to produce ATP. In the digestive tract of the insect vector, procyclic forms (PCF) of T. brucei use proline abundantly present in the glucose-depleted environment of the insect, although they prefer to consume glucose in vitro. Recent data highlighted that in the presence of physiological amounts of proline, PCF use TCA cycle intermediates (succinate, malate or α-ketoglutarate) to stimulate the parasite growth. Glycerol can also fuel the central carbon metabolism of the parasite, which developed an absolute preference for glycerol over glucose. T. brucei is the only unicellular eukaryote to date reported to prefer a non-glycolytic carbon source to glucose. The relevance of these unexpected biochemical characteristics will be discussed in light of the trypanosome particularities and interactions with its hosts..
Fabien Jourdan (Inrae Toxalim MetaboHUB, Toulouse, France)
Title talk: Making sense of metabolic profiles using network science and knowledge graphs.
Short abstract: Metabolic modulation is a cornerstone cellular response to genetic or environmental stresses. This plasticity is going beyond central metabolism and may involve complex processes spanning several metabolic pathways. Hence, it is a key challenge to be able to decipher metabolic modulations in a systemic and global perspective.
The aim of the computational methods and tools which will be presented is thus to consider the full complexity of metabolism. To do so, all metabolic reactions the cell is able to achieve are gathered in a single mathematical model call “genome scale metabolic network”. Based on this model, it is then possible to identify metabolic modulations associated to metabolic fingerprints or suggest metabolites of interest to enrich biochemical interpretation.
Even if metabolic profiles and associated metabolic network modulations are very informative, their biological and physiological interpretation remain a challenge, requiring researchers to gather and connect various pieces of knowledge from a large range of resources. To aid in this task, we introduce FORUM: a Knowledge Graph (KG) providing a semantic representation of relations between chemicals and biomedical concepts, built from a large-scale federation of life science databases and scientific literature repositories. These associations allow to derivate new hypothesis from observed metabolites or anticipate which metabolites could be expected to be measured for a given disease.
Daniel Merkle (University of Southern Denmark, Denmark)
Short abstract: The well-defined formalism of graph transformation provides a rule-based generative system, well grounded in category theory, for the analysis of large and complex reaction networks on an atomic level. Integer hyperflows on hypergraphs generated by such rule-based approach enable the identification and design of complex reaction patterns, including catalysis and autocatalysis. The compositionality of rules is key for automated coarse-graining approaches. In this presentation the before-mentioned mathematical formalisms and its accompanying computational framework will be presented. Application examples will be given for metabolic engineering, for the design of hypothetical catalytic mechanisms in enzymes, and for atom tracing and isotope labelling experiment design. A discussion on future research directions will include the model-based analysis of microbial communities.
Daniel Segrè (Boston University, US)
Title talk: Using computational models to help design synthetic microbial communities.
Short abstract: Metabolism operates as a multiscale process that induces interactions between microbial species and leads to division of labor and cross-feeding in complex microbial communities. By combining spatio-temporal dynamic flux balance modeling with convection-diffusion equations we model the metabolic activity of communities in complex environments, starting from the genomes of individual species. We envisage that these approaches will be increasingly valuable for understanding natural communities (e.g. plant-associated consortia), and for guiding targeted synthetic ecology experiments with artificial communities that can be used both as benchmark for our models and as valuable avenues for multi-species metabolic engineering.
Alena Ziková (Institute of Parasitology, Czech Academy of Sciences, Czech Republic)
Title talk: Unexpected metabolic flexibility of mammalian forms of trypanosomes.
Short abstract: Human African Trypanosomiasis and Animal African Trypanosomiasis are serious diseases of humans and livestock, respectively, caused by the protozoan parasites of the genus Trypanosoma. The infectious form of these extravascular parasites resides primarily in the bloodstream of their mammalian host, but may also infect other tissues (central nervous system, adipose tissue, skin). Highly efficient glycolysis is the predominant source of cellular ATP, which is why the parasite mitochondrion lacks an active oxidative phosphorylation and has been falsely accused of being simple and dormant with no important metabolic role. In my talk, I will revise this claim and show that the mitochondrion of the mammalian form is an essential organelle that plays critical roles in cellular respiration, redox balance, carbon metabolism, and ATP production. I will present a map of putative metabolic pathways that provide the parasite with the metabolic flexibility and adaptability it needs when encountering different niches in its mammalian host. Our findings may aid future drug development, provide insights into mechanisms of drug resistance, and reveal the link between the parasite’s metabolism and the host environment.
In order to cover a larger audience, the workshop will take place in the afternoon, CET time (French time), on both days.
|Thursday 18||Friday 19|
|14h00-14h10 CET time||Introduction to the workshop||Introduction to the second day|
|14h10-14h50 CET time||Talk 1: Fabien Jourdan||Talk 4: Alena Ziková|
|14h50-15h05 CET time||Questions and discussion on Talk 1||Questions and discussion on Talk 4|
|15h05-15h15 CET time||Short break||Short break|
|15h15-15h55 CET time||Talk 2: Michael Barrett||Talk 5: Daniel Merkle|
|15h55-16h10 CET time||Questions and discussion on Talk 2||Questions and discussion on Talk 5|
|16h10-16h20 CET time||Short break||Short break|
|16h20-17h00 CET time||Talk 3: Daniel Segrè||Talk 6: Frédéric Bringaud|
|17h00-17h15 CET time||Questions and discussion on Talk 3||Questions and discussion on Talk 6|
|17h15-17h30 CET time||Final discussion and conclusion of the first day||Final discussion and conclusion of the workshop|
Registration is now closed. It actually had to close before the end of the deadline of November 16 midnight as before that, we reached the maximum number of participants that we could have with the Zoom system we will be using. The Zoom link has already been sent to all those who registered.
However, we set up a parallel YouTube system where those not registered and thus without the Zoom link will be able to connect to follow a live broadcast of the Workshop. Actually, there are two links, one for each day. These YouTube links are:
Marie-France Sagot, Inria, CNRS and University of Lyon 1 UMR 5558, France
Ariel M. Silber, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
Sara Tanqueiro, Project Manager of the H2020 Twinning project Olissipo
Susana Vinga, Instituto Superior Técnico and INESC-ID, Lisbon, Portugal, and coordinator of the H2020 Twinning project Olissipo
The Workshop reached its limit allowed by the Zoom system used. The Workshop will also be broadcast by YouTube. We will indicate later the total number of participants. These came from a broad range of countries worldwide.
The Inria Associated Team Capoeira has received funding from Fapesp in Brazil and from Inria in France.
The H2020 Twinning Project Olissipo has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 951970.
One of the organisers of the workshop, Ariel M. Silber, is also supported by the project “A Global Network fo Neglected Tropical Diseases” of the GCRF-UKRI research programme.