ERC FUNDED PROJECTS

This project investigates the two-way relationship between spatio-temporal genome organization and coordinated gene regulation, through an approach at the interface between physics, computer science and biology. In the nucleus, preferred positions are observed from chromosomes to single genes, in relation to normal and pathological cellular states. Evidence indicates a complex spatio-temporal coupling between co-regulated genes: e.g. certain genes cluster spatially when responding to similar factors and transcriptional noise patterns suggest domain-wide mechanisms. Yet, no individual experiment allows probing transcriptional coordination in 4 dimensions (FISH, live locus tracking, Hi-C...). Interpreting such data also critically requires theory (stochastic processes, statistical physics…). A lack of appropriate experimental/analytical approaches is impairing our understanding of the 4D genome. Our proposal combines cutting-edge single-molecule imaging, signal-theory data analysis and physical modeling to study how genes coordinate in space and time in a single nucleus. Our objectives are to understand (a) competition/recycling of shared resources between genes within subnuclear compartments, (b) how enhancers communicate with genes domain-wide, and (c) the role of local conformational dynamics and supercoiling in gene co-regulation. Our organizing hypothesis is that, by acting on their microenvironment, genes shape their co-expression with other genes. Building upon my expertise, we will use dual-color MS2/PP7 RNA labeling to visualize for the first time transcription and motion of pairs of hormone-responsive genes in real time. With our innovative signal analysis tools, we will extract spatio-temporal signatures of underlying processes, which we will investigate with stochastic modeling and validate through experimental perturbations. We expect to uncover how the functional organization of the linear genome relates to its physical properties and dynamics in 4D.

1 499 750 €

Start date: 2018-04-01, End date: 2023-03-31

The emergence of life is one of the most fascinating and yet largely unsolved questions in the natural sciences, and thus a significant challenge for scientists from many disciplines. There is growing evidence that ribonucleic acid (RNA) polymers, which are capable of genetic information storage and self-catalysis, were involved in the early forms of life. But despite recent progress, RNA synthesis without biological machineries is very challenging. The current project aims at understanding how to synthesize RNA in abiotic conditions. I will solve problems associated with three critical aspects of RNA formation that I will rationalize at a molecular level: (i) accumulation of precursors, (ii) formation of a chemical bond between RNA monomers, and (iii) tolerance for alternative backbone sugars or linkages. Because I will study problems ranging from the formation of chemical bonds up to the stability of large biopolymers, I propose an original computational multi-scale approach combining techniques that range from quantum calculations to large-scale all-atom simulations, employed together with efficient enhanced-sampling algorithms, forcefield improvement, cutting-edge analysis methods and model development. My objectives are the following: 1 • To explain why the poorly-understood thermally-driven process of thermophoresis can contribute to the accumulation of dilute precursors. 2 • To understand why linking RNA monomers with phosphoester bonds is so difficult, to understand the molecular mechanism of possible catalysts and to suggest key improvements. 3 • To rationalize the molecular basis for RNA tolerance for alternative backbone sugars or linkages that have probably been incorporated in abiotic conditions. This unique in-silico laboratory setup should significantly impact our comprehension of life’s origin by overcoming major obstacles to RNA abiotic formation, and in addition will reveal significant orthogonal outcomes for (bio)technological applications.

1 497 031 €

Start date: 2018-02-01, End date: 2023-01-31

Applied electrochemistry plays a key role in many technologies, such as batteries, fuel cells, supercapacitors or solar cells. It is therefore at the core of many research programs all over the world. Yet, fundamental electrochemical investigations remain scarce. In particular, electrochemistry is among the fields for which the gap between theory and experiment is the largest. From the computational point of view, there is no molecular dynamics (MD) software devoted to the simulation of electrochemical systems while other fields such as biochemistry (GROMACS) or material science (LAMMPS) have dedicated tools. This is due to the difficulty of accounting for complex effects arising from (i) the degree of metallicity of the electrode (i.e. from semimetals to perfect conductors), (ii) the mutual polarization occurring at the electrode/electrolyte interface and (iii) the redox reactivity through explicit electron transfers. Current understanding therefore relies on standard theories that derive from an inaccurate molecular-scale picture. My objective is to fill this gap by introducing a whole set of new methods for simulating electrochemical systems. They will be provided to the computational electrochemistry community as a cutting-edge MD software adapted to supercomputers. First applications will aim at the discovery of new electrolytes for energy storage. Here I will focus on (1) ‘‘water-in-salts’’ to understand why these revolutionary liquids enable much higher voltage than conventional solutions (2) redox reactions inside a nanoporous electrode to support the development of future capacitive energy storage devices. These selected applications are timely and rely on collaborations with leading experimental partners. The results are expected to shed an unprecedented light on the importance of polarization effects on the structure and the reactivity of electrode/electrolyte interfaces, establishing MD as a prominent tool for solving complex electrochemistry problems.

1 588 769 €

Start date: 2018-04-01, End date: 2023-03-31

Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses. ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify. In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen. Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.

1 499 794 €

Start date: 2017-12-01, End date: 2022-11-30

Single-photon sources (SPSs) are systems capable of emitting photons one by one. These sources are of major importance for quantum-information science and applications. SPSs experiments generally rely on the optical excitation of two level systems of atomic-scale dimensions (single-molecules, vacancies in diamond…). Many fundamental questions related to the nature of these sources and the impact of their environment remain to be explored: Can SPSs be addressed with atomic-scale spatial accuracy? How do the nanometer-scale distance or the orientation between two (or more) SPSs affect their emission properties? Does coherence emerge from the proximity between the sources? Do these structures still behave as SPSs or do they lead to the emission of correlated photons? How can we then control the degree of entanglement between the sources? Can we remotely excite the emission of these sources by using molecular chains as charge-carrying wires? Can we couple SPSs embodied in one or two-dimensional arrays? How does mechanical stress or localised plasmons affect the properties of an electrically-driven SPS? Answering these questions requires probing, manipulating and exciting SPSs with an atomic-scale precision. This is beyond what is attainable with an all-optical method. Since they can be confined to atomic-scale pathways we propose to use electrons rather than photons to excite the SPSs. This unconventional approach provides a direct access to the atomic-scale physics of SPSs and is relevant for the implementation of these sources in hybrid devices combining electronic and photonic components. To this end, a scanning probe microscope will be developed that provides simultaneous spatial, chemical, spectral, and temporal resolutions. Single-molecules and defects in monolayer transition metal dichalcogenides are SPSs that will be studied in the project, and which are respectively of interest for fundamental and more applied issues.

1 996 848 €

Start date: 2018-06-01, End date: 2023-05-31

Somatosensation encompass a wide range of processes, from feeling touch to temperature, as well as experiencing pleasure and pain. When afferent inputs are degraded or removed, such as in neuropathies or amputation, exploring the world becomes extremely difficult. Chronic pain is a major health issue that greatly diminishes quality of life and is one of the most disabling and costly conditions in Europe. The loss of a body part is common due to accidents, tumours, or peripheral diseases, and it has instantaneous effects on somatosensory functioning. Treating such disorders entails detailed knowledge about how somatosensory signals are encoded. Understanding these processes will enable the restoration of healthy function, such as providing real-time, naturalistic feedback in prostheses. To date, no prosthesis currently provides long-term sensory feedback, yet accomplishing this will lead to great quality of life improvements. The present proposal aims to uncover how basic tactile processes are encoded and represented centrally, as well as how more complex somatosensation is generated (e.g. wetness, pleasantness). Novel investigations will be conducted in humans to probe these mechanisms, including peripheral in vivo recording (microneurography) and neural stimulation, combined with advanced brain imaging and behavioural experiments. Preliminary work has shown the feasibility of the approach, where it is possible to visualise the activation of single mechanoreceptive afferents in the human brain. The multi-disciplinary approach unites detailed, high-resolution, functional investigations with actual sensations generated. The results will elucidate how basic and complex somatosensory processes are encoded, providing insights into the recovery of such signals. The knowledge gained aims to provide pain-free, efficient diagnostic capabilities for detecting and quantifying a range of somatosensory disorders, as well as identifying new potential therapeutic targets.

1 223 639 €

Start date: 2019-01-01, End date: 2023-12-31

Which molecules are present in the atmosphere of exoplanets? What are their mass, radius and age? Do they have clouds, convection (atmospheric turbulence), fingering convection, or a circulation induced by irradiation? These questions are fundamental in exoplanetology in order to study issues such as planet formation and exoplanet habitability. Yet, the impact of fingering convection and circulation induced by irradiation remain poorly understood: - Fingering convection (triggered by gradients of mean-molecular-weight) has already been suggested to happen in stars (accumulation of heavy elements) and in brown dwarfs and exoplanets (chemical transition e.g. CO/CH4). A large-scale efficient turbulent transport of energy through the fingering instability can reduce the temperature gradient in the atmosphere and explain many observed spectral properties of brown dwarfs and exoplanets. Nonetheless, this large-scale efficiency is not yet characterized and standard approximations (Boussinesq) cannot be used to achieve this goal. - The interaction between atmospheric circulation and the fingering instability is an open question in the case of irradiated exoplanets. Fingering convection can change the location and magnitude of the hot spot induced by irradiation, whereas the hot deep atmosphere induced by irradiation can change the location of the chemical transitions that trigger the fingering instability. This project will characterize the impact of fingering convection in the atmosphere of stars, brown dwarfs, and exoplanets and its interaction with the circulation in the case of irradiated planets. By developing innovative numerical models, we will characterize the reduction of the temperature gradient of the atmosphere induced by the instability and study the impact of the circulation. We will then predict and interpret the mass, radius, and chemical composition of exoplanets that will be observed with future missions such as the James Webb Space Telescope (JWST).

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31

The role of experience in language acquisition has been the focus of heated theoretical debates, between proponents of nativist views according to whom experience plays a minimal role and advocates of empiricist positions holding that experience, be it linguistic, social or other, is sufficient to account for language acquisition. Despite more than a half century of dedicated research efforts, the problem is not solved. The present project brings a novel perspective to this debate, combining hitherto unconnected research in language acquisition with recent advances in the neurophysiology of hearing and speech processing. Specifically, it claims that prenatal experience with speech, which mainly consists of prosody due to the filtering effects of the womb, is what shapes the speech perception system, laying the foundations of subsequent language learning. Prosody is thus the cue that links genetically endowed predispositions present in the initial state with language experience. The proposal links the behavioral and neural levels, arguing that the hierarchy of the neural oscillations corresponds to a unique developmental chronology in human infants’ experience with speech and language. The project uses state-of-the-art brain imaging techniques, EEG & NIRS, with monolingual full term newborns, as well as full-term bilingual, preterm and deaf newborns to investigate the link between prenatal experience and subsequent language acquisition. It proposes to follow the developmental trajectories of these four populations from birth to 6 and 9 months of age.

1 621 250 €

Start date: 2018-06-01, End date: 2023-05-31

Distributed systems underlie many modern technologies, a prime example being the Internet. The ever-increasing abundance of distributed systems necessitates their design and usage to be backed by strong theoretical foundations. A major challenge that distributed systems face is the lack of a central authority, which brings many aspects of uncertainty into the environment, in the form of unknown network topology or unpredictable dynamic behavior. A practical restriction of distributed systems, which is at the heart of this proposal, is the limited bandwidth available for communication between the network components. A central family of distributed tasks is that of local tasks, which are informally described as tasks which are possible to solve by sending information through only a relatively small number of hops. A cornerstone example is the need to break symmetry and provide a better utilization of resources, which can be obtained by the task of producing a valid coloring of the nodes given some small number of colors. Amazingly, there are still huge gaps between the known upper and lower bounds for the complexity of many local tasks. This holds even if one allows powerful assumptions of unlimited bandwidth. While some known algorithms indeed use small messages, the complexity gaps are even larger compared to the unlimited bandwidth case. This is not a mere coincidence, and in fact the existing theoretical infrastructure is provably incapable of giving stronger lower bounds for many local tasks under limited bandwidth. This proposal zooms in on this crucial blind spot in the current literature on the theory of distributed computing, namely, the study of local tasks under limited bandwidth. The goal of this research is to produce fast algorithms for fundamental distributed local tasks under restricted bandwidth, as well as understand their limitations by providing lower bounds.

1 486 480 €

Start date: 2018-06-01, End date: 2023-05-31