Ljubisa Miskovic

Biography

Ljubisa Miskovic earned his Ph.D. degree in Automatic Control from the Swiss Federal Institute of Technology (EPFL) under the co-supervision of Dominique Bonvin and Alireza Karimi, in 2006. He pursued his postdoctoral studies at the Centre for Systems Engineering and Applied Mechanics, Universite Catholique de Louvain with Michel Gevers before moving to the laboratory of Vassily Hatzimanikatis at the EPFL. In 2010, he became a research scientist. His research interests include systems biology, metabolic engineering, synthetic biology, data-driven control design, system identification, stochastic processes and estimation theory.

Official source

https://people.epfl.ch/ljubisa.miskovic

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Metabolism (məˈtæbəlɪzəm, from μεταβολή metabolē, "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy

The kinetic theory of gases is a simple, historically significant classical model of the thermodynamic behavior of gases, with which many principal concepts of thermodynamics were established. The

A metabolic network is the complete set of metabolic and physical processes that determine the physiological and biochemical properties of a cell. As such, these networks comprise the chemical react

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Related publications (92)

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Generative machine learning produces kinetic models that accurately characterize intracellular metabolic states

Vassily Hatzimanikatis, Ljubisa Miskovic, Michaël Roger Germain Moret

Large omics datasets are nowadays routinely generated to provide insights into cellular processes. Nevertheless, making sense of omics data and determining intracellular metabolic states remains challenging. Kinetic models of metabolism are crucial for integrating and consolidating omics data because they explicitly link metabolite concentrations, metabolic fluxes, and enzyme levels. However, the difficulties in determining kinetic parameters that govern cellular physiology prevent the broader adoption of these models by the research community. We present RENAISSANCE (REconstruction of dyNAmIc models through Stratified Sampling using Artificial Neural networks and Concepts of Evolution strategies), a generative machine learning framework for efficiently parameterizing large-scale kinetic models with dynamic properties matching experimental observations. We showcase RENAISSANCE’s capabilities through three applications: generation of kinetic models of E. coli metabolism, characterization of intracellular metabolic states, and assimilation and reconciliation of experimental kinetic data. We provide the open-access code to facilitate experimentalists and modelers applying this framework to diverse metabolic systems and integrating a broad range of available data. We anticipate that the proposed framework will be invaluable for researchers who seek to analyze metabolic variations involving changes in metabolite and enzyme levels and enzyme activity in health and biotechnological studies.

2023

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Supplementary files containing datasets needed to reproduce the results of the manuscript "Generative machine learning produces kinetic models that accurately characterize intracellular metabolic states" by S. Choudhury et al. The code to use with these data and reproduce the manuscript results is available at https://github.com/EPFL-LCSB/renaissance and https://gitlab.com/EPFL-LCSB/renaissance. The execution of parts of this code is dependent on the SkimPy toolbox (https://github.com/EPFL-LCSB/skimpy). Refer to the readme files on the RENAISSANCE code repositories for more details. The dataset contains the following files: 1. param_fixing.zip - self-explanatory (Figure 4 & 5); contains an explanatory note for this part (experiment_details.txt), and the file containing Km values fetched from the BRENDA database (Km_database.csv). 2. scripts.zip - scripts to generate figure 2-5 on toy data This work was supported by funding from the Swiss National Science Foundation grant 315230_163423, the European Union's Horizon 2020 research and innovation programme under grant agreement 814408, Swedish Research Council Vetenskapsradet grant 2016-06160, and the Ecole Polytechnique Fédérale de Lausanne (EPFL).

EPFL Infoscience2023

A genome-scale metabolic model of Saccharomyces cerevisiae that integrates expression constraints and reaction thermodynamics

Vassily Hatzimanikatis, Maria Masid Barcon, Ljubisa Miskovic, Mohammad Omid Oftadeh, Pierre Guy Rémy Salvy

Eukaryotic organisms play an important role in industrial biotechnology, from the production of fuels and commodity chemicals to therapeutic proteins. To optimize these industrial systems, a mathematical approach can be used to integrate the description of multiple biological networks into a single model for cell analysis and engineering. One of the most accurate models of biological systems include Expression and Thermodynamics FLux (ETFL), which efficiently integrates RNA and protein synthesis with traditional genome-scale metabolic models. However, ETFL is so far only applicable for E. coli. To adapt this model for Saccharomyces cerevisiae, we developed yETFL, in which we augmented the original formulation with additional considerations for biomass composition, the compartmentalized cellular expression system, and the energetic costs of biological processes. We demonstrated the ability of yETFL to predict maximum growth rate, essential genes, and the phenotype of overflow metabolism. We envision that the presented formulation can be extended to a wide range of eukaryotic organisms to the benefit of academic and industrial research. Formulating metabolic networks mathematically can help researchers study metabolic diseases and optimize the production of industrially important molecules. Here, the authors propose a framework that allows to model eukaryotic metabolism considering gene expression and thermodynamic constraints.

NATURE PORTFOLIO2021