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On the path to an artificial cell

In his book ’What is life’, the physicist Erwin Schroedinger defines metabolism in the following way : ’How does a living organism avoid its decay ? The obvious answer is : by eating, drinking, breathing and (in the case of plants) by assimilating. The technical term is metabolism’. Metabolism is therefore an essential ingredient of living systems. Metabolism distinguishes a living cell from a simple (micro) chemical reactor : whereas the chemical reactions occurring in a simple reactor spontaneously drive the system to the minimum of its free energy, the metabolism maintains the compartment in a state out of equilibrium, far from its minimum of energy. This state is maintained in the cell as long as nutrient sources are available and these nutrients can be degraded leading to energy dissipation.

The construction of an artificial living cell therefore requires assembling and controlling the metabolism within microcompartments. In a "bottom-up" synthetic biology approach, the goal is to build a cell from controlled ingredients, known and characterized and then assembled in a modular way [2]. The long-term idea is to obtain a living complex system but not functioning as a black box such as a cell. The control and the possible programmability of its objects will eventually be interesting systems at the industrial level to overcome the defects of living systems in the transformation of resources and raw materials or for transformations involving compounds not present in nature. Bottom-up Synthetic biology is based on a minimal vision of the cell with the objective of reproducing one or more functions of life by allowing the use of modules of biological origins or not. In this approach, the elementary modules come potentially from various fields. Soft matter chemistry allows for the formulation of compartments, soft matter physics allows the description and control of interactions between active elements, biochemistry provides enzymes as specific catalysts of reactions, and cell biology provides organelles having specific functions.

Here, the authors address the question of the modular integration of a metabolic function in an assembly of micro-compartments in the form of drops of water-in-oil. The production of these micro-compartments is performed in microfluidic, which allows a fine control of the size of its compartments, but also a control of the composition of these compartments. The assembled metabolism is minimal, based on a single reaction catalyzed by an enzyme. This reaction requires a co-factor, NADH an essential ingredient in cellular processes consumed by the reaction. This sole reaction occuring in the compartment, the system reaches its equilibrium rapidly by consuming the substrate until the reaction substrate or NADH has completely disappeared. The drops are then simple micro-reactors. Yet, when a NADH regeneration module is added to the system, the reaction is self-sustained and a constant level of NADH is obtained inside the compartment. The system is in a steady state but permanently dissipates the chemical energy of the reaction : the system is thus kept out of equilibrium. A key to the system is therefore the regeneration module of NADH which is obtained here by extraction of the vesicles involved in the respiratory chain of Escherichia coli bacteria. By modulating the amount of substrate or the amount of these vesicles, the off-balance state is maintained for varying times. The use of microfluidics then makes it possible to produce controlled populations of these out-of-equilibrium systems, as elementary bricks making it possible to set up more complex functions or to test hypotheses on the emergence of life.

This project was carried out within the framework of the Max Syn Bio Network [3], which brings together ten Max Planck Institutes in Germany and the group of Jean-Christophe Baret at the Paul Pascal Research Center. The project also benefited from the support of the ERC (FP7/2007-2013/ERC Grant agreement 306385–SofI), of the ’Région Aquitaine’ and of the Programme University of Bordeaux Initiative of Excellence (IDEX Bordeaux) (ANR-10-IDEX-03-02).

Publications

Out-of-equilibrium microcompartments for the bottom-up integration of metabolic functions, T. Beneyton, D. Krafft, C. Bednarz, C. Kleineberg, C. Woelfer, I. Ivanov, T. Vidakovic-Koch, K. Sundmacher & J.-C. Baret, Nature Communications, In press 2018.
DOI : 10.1038/s41467-018-04825-1

References

[1] What is life ? The Physical Aspect of the Living Cell. Erwin Schroedinger (1944)

[2] Sequential bottom-up assembly of mechanically stabilized synthetic cells by microfluidics, M. Weiss, J. P. Frohnmayer, L. T. Benk, B. Haller, J.-W. Janiesch, T. Heitkamp, M. Boersch, R. B. Lira, R. Dimova, R. Lipowsky, E. Bodenschatz, J.-C. Baret, T. Vidakovic-Koch, K. Sundmacher, I. Platzman & J. P. Spatz, Nature Materials, 17, 89-96 (2018)

[3] MaxSynBio ‐ Avenues towards creating cells from the bottom up, P. Schwille, J. Spatz, K. Landfester, E. Bodenschatz, S. Herminghaus, V. Sourjik, T. Erb, P. Bastiaens, R. Lipowsky, A. Hyman, P. Dabrock, J.-C. Baret, T. Vidakovic-Koch, P. Bieling, R. Dimova, H. Mutschler, T. Robinson, D. Tang, S. Wegner & K. Sundmacher, Angewandte Chemie Int. Ed., in press 2018
http://dx.doi.org/10.1002/anie.201802288

Article published in Max-Planck-Gesellschaft Science Magazine

Article paru sur le site de l’Institut de Chimie

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Jean-Christophe Baret