Assemblages génétiquement encodés en cellules vivantes pour contrôler les processus biochimiques

1. Summary

This PhD project aims to engineer genetically encoded self-assemblies in living cells to

implement new cellular functions. Our approach involves designing protein-based building blocks that

undergo phase separation through multivalent, low-affinity interactions, mimicking biomolecular

condensates. These condensates organize important chemistry in space and time and are key

regulators of cellular functions. The project integrates expertise in protein engineering (de novo design

versus rational approaches), biophysics, cell biology, quantitative microscopy, and data analysis.

2. Background and Scientific Context

Cells contain millions of biomolecules that interact to drive essential functions such as energy

production and waste recycling. A key question is how these molecules assemble at the right time and

place for these processes. Recent evidence highlights biomolecular condensates, liquid-like droplets

formed via phase separation, as central to cellular organization. This project aims to engineer artificial

condensates using physical chemistry principles, providing a strategy to control molecular organization

at the organelle scale.

3. Goals and Methodology

3.1 Task 1: Engineered Protein Scaffolds to Induce Intracellular Phase Separation : Rational versus

De novo design

The first goal is to develop protein scaffolds that enable controlled assembly and disassembly

of condensates with tunable properties. Previous designs successfully induced condensates in cells for

biochemical studies [1-5] but lacked precise temporal control and relied on a limited set of multivalent

scaffolds. To overcome these challenges, we will introduce novel dimerization strategies for rapid

(minute-scale) induction and enhance multivalency to tune condensate properties such as exchange

rates, viscosity, and phase behavior. A key innovation is benchmarking de novo designs generated via

machine learning against those derived from rational approaches.

3.2 Task 2: Reversible Perturbation of Cell Metabolism

The second goal focuses on using engineered condensates to manipulate lipid metabolism by

reversibly trapping key organelles like lipid droplets (LDs) and mitochondria. These condensates will

disrupt organelle dynamics, redirect lipid flux, and alter metabolism. We will assess metabolic changes

linked to LD and mitochondria perturbations, particularly investigating vulnerabilities in cancer cells

(such as ferroptosis). This approach could uncover new strategies for targeting metabolic pathways

during disease development.

Our laboratory, located in the heart of Paris, engages in interdisciplinary research, fostering a collaborative environment where biologists, physical chemists, and biophysicists work together. We benefit from a rich academic setting, close to renowned institutes such as ENS, Curie Institute, and Collège de France.

Profile: Interested applicants should hold a master's degree in Quantitative Biology, Biophysics, Chemical Biology, or a related field and demonstrate a strong interest in interdisciplinary work.