ERC FUNDED PROJECTS

The current trend in biophotonics is to try and replicate the same ease and precision that our hands, eyes and ears offer at the macroscopic level, e.g. to hold, observe, squeeze and pull, rotate, cut and probe biological specimens in microfluidic environments. The bidding to get closer and closer to the object of interest has prompted the development of extremely advanced manipulation techniques at scales comparable to that of the wavelength of light. However, the fact that the optical beam can only access the microfluidic chip from the narrow aperture of a microscopic objective limits the versatility of the photonic function that can be realized. With this project, the applicant proposes to introduce a new biophotonic platform based on the all optical manipulation of flexible photonic metasurfaces. These artificial two-dimensional materials have virtually arbitrary photonic responses and have an intrinsic exceptional mechanical stability. This cross-disciplinary project, bridging photonics, material sciences and biology, will enable the adoption of the most modern and advanced photonic designs in microfluidic environments, with transformative benefits for microscopy and biophotonic applications at the interface of molecular and cell biology.

1 999 524 €

Start date: 2019-02-01, End date: 2024-01-31

The development of longer lasting, higher energy density and cheaper rechargeable batteries represents one of the major technological challenges of our society, batteries representing the limiting components in the shift from gasoline-powered to electric vehicles. They are also required to enable the use of more (typically intermittent) renewable energy, to balance demand with generation. This proposal seeks to develop and apply new NMR metrologies to determine the structure and dynamics of the multiple electrode-electrolyte interfaces and interphases that are present in these batteries, and how they evolve during battery cycling. New dynamic nuclear polarization (DNP) techniques will be exploited to extract structural information about the interface between the battery electrode and the passivating layers that grow on the electrode materials (the solid electrolyte interphase, SEI) and that are inherent to the stability of the batteries. The role of the SEI (and ceramic interfaces) in controlling lithium metal dendrite growth will be determined in liquid based and all solid state batteries. New DNP approaches will be developed that are compatible with the heterogeneous and reactive species that are present in conventional, all-solid state, Li-air and redox flow batteries. Method development will run in parallel with the use of DNP approaches to determine the structures of the various battery interfaces and interphases, testing the stability of conventional biradicals in these harsh oxidizing and reducing conditions, modifying the experimental approaches where appropriate. The final result will be a significantly improved understanding of the structures of these phases and how they evolve on cycling, coupled with strategies for designing improved SEI structures. The nature of the interface between a lithium metal dendrite and ceramic composite will be determined, providing much needed insight into how these (unwanted) dendrites grow in all solid state batteries. DNP approaches coupled with electron spin resonance will be use, where possible in situ, to determine the reaction mechanisms of organic molecules such as quinones in organic-based redox flow batteries in order to help prevent degradation of the electrochemically active species. This proposal involves NMR method development specifically designed to explore a variety of battery chemistries. Thus, this proposal is interdisciplinary, containing both a strong emphasis on materials characterization, electrochemistry and electronic structures of materials, interfaces and nanoparticles, and on analytical and physical chemistry. Some of the methodology will be applicable to other materials and systems including (for example) other electrochemical technologies such as fuel cells and solar fuels and the study of catalysts (to probe surface structure).

3 498 219 €

Start date: 2019-10-01, End date: 2024-09-30

Many significant global challenges in catalysis for energy and sustainable chemistry have already been solved in nature. Metalloenzymes within microorganisms catalyse the transformation of carbon dioxide into simple carbon building blocks or fuels, the reduction of dinitrogen to ammonia under ambient conditions and the production and utilisation of dihydrogen. Catalytic sites for these reactions are necessarily based on metals that are abundant in the environment, including iron, nickel and molybdenum. However, attempts to generate biomimetic catalysts have largely failed to reproduce the high activity, stability and selectivity of enzymes. Proton and electron transfer and substrate binding are all finely choreographed, and we do not yet understand how this is achieved. This project develops a suite of new experimental infrared (IR) spectroscopy tools to probe and understand mechanisms of redox metalloenzymes in situ during electrochemically-controlled steady state turnover, and during electron-transfer-triggered transient studies. The ability of IR spectroscopy to report on the nature and strength of chemical bonds makes it ideally suited to follow the activation and transformation of small molecule reactants at metalloenzyme catalytic sites, binding of inhibitors, and protonation of specific sites. By extending to the far-IR, or introducing mid-IR-active probe amino acids, redox and structural changes in biological electron relay chains also become accessible. Taking as models the enzymes nitrogenase, hydrogenase, carbon monoxide dehydrogenase and formate dehydrogenase, the project sets out to establish a unified understanding of central concepts in small molecule activation in biology. It will reveal precise ways in which chemical events are coordinated inside complex multicentre metalloenzymes, propelling a new generation of bio-inspired catalysts and uncovering new chemistry of enzymes.

1 997 286 €

Start date: 2019-03-01, End date: 2024-02-29

Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.

1 552 948 €

Start date: 2018-12-01, End date: 2023-11-30

In the epoch of Gaia, fundamental stellar properties will be made widely available for large numbers of stars. These properties are expected to unleash a new wave of discovery in the field of astrophysics. But while many properties of stars are measurable, meaningful Helium abundances (Y) remain elusive and as a result fundamental properties are not accurate. Helium enrichment laws, which underpin most stellar properties, link initial Y to initial metallicity, but these relations are very uncertain with gradients (dY/dZ) spanning the range 1 to 3. This uncertainty is the initial Y problem and this is a bottleneck that must be overcome to unleash the true potential of Gaia. Without measurements of initial Y for all stars we need to find alternative observables that trace out the evolution of initial Y. We will search for better tracers using the power of asteroseismology as a calibrator. Asteroseismic measures of Helium will be used to construct a map from observable properties (fundamental, chemical or even dynamical) back to initial Helium. This is a challenge that can only be solved through the use of the latest asteroseismic techniques coupled to a rigorous yet flexible statistical scheme. I am uniquely qualified in the cutting edge methods of asteroseismology and the application of advanced multi-level statistical models. The intersection of these two skill sets will allow me to solve the initial Helium problem. The motivation for a timely solution to this problem could not be stronger. We have just entered an age of large asteroseismic datasets, vast spectroscopic surveys, and the billion star program of Gaia. The next wave of scientific breakthroughs in stellar physics, exoplanetary science, and Galactic archeology will be held back unless accurate fundamental stellar properties are available. We can only produce these accurate properties with a reliable map of stellar Helium.

1 496 203 €

Start date: 2019-04-01, End date: 2024-03-31

All organisms in nature are targets for parasite attack. Over a century ago, it was first observed that symbiotic species living in hosts can provide a strong barrier against infection, beyond the host’s own defence responses. We now know that ‘protective’ microbial symbiont species are key components of plant, animal, and human microbiota, shaping host health in the face of parasite infection. I have shown that microbes can evolve within days to protect, providing the possibility that microbe-mediated defences can take-over from hosts in fighting with parasites over evolutionary time. This new discovery of an evolvable microbe-mediated defence challenges our fundamental understanding of the host-parasite relationship. Here, I will use a novel nematode-microbe interaction, an experimental evolution approach, and assays of phenotypic and genomic changes (the latter using state-of-the-art sequencing and CRISPR-Cas9 technologies) to generate new insights into the drivers and consequences of coevolving protective symbioses. Specifically, the objectives are to test: (i) the ability of microbe-mediated protection to evolve more rapidly than host-encoded resistance, (ii) the impacts of evolvable protective microbes on host-parasite coevolution, and the effect of community complexity, in the form of (iii) parasite and (iv) within-host microbial heterogeneity, in shaping host-protective microbe coevolution from scratch. Together, these objectives will generate a new, synthetic understanding of how protective symbioses evolve and influence host resistance and parasite infectivity, with far-reaching implications for tackling coevolution in communities.

1 499 275 €

Start date: 2019-02-01, End date: 2024-01-31

In eukaryotic cells, DNA replication is tightly regulated to ensure that the genome is duplicated only once per cell cycle. Errors in the control mechanisms that regulate chromosome ploidy cause genomic instability, which is linked to the development of cellular abnormalities, genetic disease and the onset of cancer. Recent reconstitution experiments performed with purified proteins revealed that initiation of eukaryotic genome duplication requires three distinct steps. First, DNA replication start sites are identified and targeted for the loading of an inactive MCM helicase motor, which encircles the double helix. Second, MCM activators are recruited, causing duplex-DNA untwisting. Third, upon interaction with a firing factor, the MCM ring opens to eject one DNA strand, leading to unwinding of the replication fork and duplication by dedicated replicative polymerases. These three events are not understood at a molecular level. Structural investigations so far aimed at imaging artificially isolated replication steps and used simplified templates, such as linear duplex DNA to study helicase loading or pre-formed forks to understand unwinding. However, the natural substrate of the eukaryotic replication machinery is not DNA but rather chromatin, formed of nucleosome arrays that compact the genome. Chromatin plays important regulatory roles in all steps of DNA replication, by dictating origin start-site selection and stimulating replication fork progression. Only by studying chromatin replication, we argue, will we understand the molecular basis of genome propagation. To this end, we have developed new protocols to perform visual biochemistry experiments under the cryo-electron microscope, to image chromatin duplication at high resolution, frozen as it is being catalysed. Using these strategies we want to generate a molecular movie of the entire replication reaction. Our achievements will change the way we think about genome stability in eukaryotic cells.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29

This programme aims to convert carbon dioxide into high value hydrocarbon products using carbon neutral electrochemical methods. High value products are materials that may be used as carbon based chemical feedstocks and as synthetic fuels, reducing the ever-present demand on oil and natural gas to fulfil these needs. The project is within the remit of an international ambition to valorise carbon dioxide waste and reduce environmentally harmful greenhouse gas generation, as opposed to stopping at carbon capture and sequestration. This proposal outlines an alternative route to carbon dioxide utilisation (CDU), in which a mediated approach that decouples the electrochemical reduction from the catalytic process is explored. Novel bimetallic catalysts will be synthesised and studied, meditating electron donating solutions will be generated, and a robust and comprehensive analytical arrangement will be implemented to allow total identification and quantification of the wide range of possible products. Electrocatalytic CO2 reduction is one of the key approaches to CDU, as it has a direct pathway to carbon neutral renewable electricity. Nonetheless it is a field that has shown minimal progress in the past 30 years. A paradigm shift is necessary in the approach to electrochemical CO2 reduction, where conventional heterogeneous interfacial catalysis is limited by mass transport, passivation, and CO2 solubility. This proposal outlines the use of electron donating mediators generated separately to the catalysed chemical reduction of CO2, such that the electrolyte becomes the electrode. This opens a whole new avenue for catalyst research, and here target bimetallic catalysts that suppress side reactions and promote high value product synthesis are described.

1 499 994 €

Start date: 2018-10-01, End date: 2023-09-30

Group-living has been predicted to have opposing effects on disease risk and immune strategies. First, since repeated contacts between individuals facilitate pathogen transmission, sociality may favour high investment in personal immunity. Alternatively, because social animals can limit disease spread through collective sanitary actions (e.g., mutual grooming) or organisational features (e.g., division of the group’s social network into distinct subsets), sociality may instead favour low investment in personal immunity. The overall goal of this project is to experimentally test these conflicting predictions in ants using advanced data collection and analytical tools. I will first quantify the effect of social organisation on disease transmission using a combination of automated behavioural tracking, social network analysis, and empirical tracking of transmission markers (fluorescent beads). Experimental network manipulations and controlled disease seeding by a robotic ant will allow key predictions from network epidemiology to be tested, with broad implications for disease management strategies. I will then study the effect of colony size on social network structure and disease transmission, and how this in turn affects investment in personal immunity. This will shed light on far-reaching hypotheses about the effect of group size on social organisation ('size-complexity’ hypothesis) and immune investment (‘density-dependent prophylaxis’). Finally, I will explore whether prolonged pathogen pressure induces colonies to reinforce the transmission-inhibiting aspects of their social organisation (e.g., colony fragmentation) or to invest more in personal immunity. This project will represent the first empirical investigation of the role of social organisation in disease risk management, and allow its importance to be compared with other immune strategies. This will constitute a significant advance in our understanding of the complex feedback between sociality and health.

1 499 995 €

Start date: 2019-04-01, End date: 2024-03-31