ERC FUNDED PROJECTS

Earth's magnetic field plays a fundamental role in our planetary habitat, controlling interactions between the Earth and the solar wind. Here, I propose to use magnetic observations, made simultaneously by multiple satellites, along with numerical models of outer core dynamics, to test whether convective processes can account for ongoing changes in the field. The geomagnetic field is generated by a dynamo process within the core converting kinetic energy of the moving liquid metal into magnetic energy. Yet observations show a region of persistently weak field in the South Atlantic that has grown in size in recent decades. Pinning down the core dynamics responsible for this behaviour is essential if we are to understand the detailed time-dependence of the geodynamo, and to forecast future field changes. Global magnetic observations from the Swarm constellation mission, with three identical satellites now carrying out the most detailed ever survey of the geomagnetic field, provide an exciting opportunity to probe the dynamics of the core in exquisite detail. To exploit this wealth of data, it is urgent that contaminating magnetic sources in the lithosphere and ionosphere are better separated from the core-generated field. I propose to achieve this, and to test the hypothesis that core convection has controlled the recent field evolution in the South Atlantic, via three interlinked projects. First I will co-estimate separate models for the lithospheric and core fields, making use of prior information from crustal geology and dynamo theory. In parallel, I will develop a new scheme for isolating and removing the signature of polar ionospheric currents, better utilising ground-based data. Taking advantage of these improvements, data from Swarm and previous missions will be reprocessed and then assimilated into a purpose-built model of quasi-geostrophic core convection.

1 828 708 €

Start date: 2018-03-01, End date: 2023-08-31

The application of antimicrobial compounds produced by hosts or defensive symbionts to counter the effects of diseases has been identified in a number of organisms, but despite extensive studies on their presence, we know essentially nothing about why antimicrobials do not trigger rampant resistance evolution in target parasites. In stark contrast to virtually any other organism, fungus-farming termites have evolved a sophisticated agricultural symbiosis that pre-dates human farming by 30 million years without suffering from specialised diseases. I will capitalise on recent pioneering work in my group on proximate evidence for antimicrobial defences in the termites, their fungal crops, and their complex gut bacterial communities, by proposing to develop the farming symbiosis as a major model to test three novel concepts that may account for the evasion of resistance evolution. First, the antimicrobial compounds may have properties and evolve in ways that preclude resistance evolution in pathogens. Second, resistance is only possible towards individual compounds and not natural antimicrobial cocktails. Third, pathogens can only successfully invade and proliferate if they bypass several consecutive lines of defence, analogous to the six hallmarks of metazoan defence against cancer development. Addressing these concepts will allow fundamental insights into the remarkable success of complementary symbiont contributions to defence, and they will clarify the forces of multilevel natural selection that have allowed long-lived insect societies to evolve sustainability. Documenting and understanding these disease management principles is fundamentally important for several branches of evolutionary biology, and strategically important for adjusting human practices for future antimicrobial stewardship.

1 998 809 €

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

Atherosclerosis is considered an inflammatory disease caused by the accumulation, modification and immune cell recognition of low-density lipoproteins in the arterial wall. Plaque macrophages are held to be the main drivers of disease activity, whereas smooth muscle cells (SMCs) have traditionally been considered protective by forming fibrous tissue that stabilises plaques from undergoing rupture and causing thrombosis. In the present project, we challenge this dichotomous view of cellular villains and heroes in atherosclerosis. Using lineage tracking techniques in mice, we and others have uncovered a large population of SMCs in plaques, which has escaped detection because the cells completely lose conventional SMC phenotype. Strikingly, we have found that the entire plaque SMC population derives from only few founder SMCs that undergo massive clonal expansion and phenotypic modulation during lesion formation. We hypothesise that the balance between the different modulated SMC subtypes and the functions they carry are central to lesion progression. In EXPLOSIA we will address this hypothesis in 3 steps. First, we will conduct a comparative analysis of clonal structure in mice, minipigs, and humans. Second, we will determine links between SMC subtypes, their gene expression programs, and atherosclerotic disease activity by combining single-cell transcriptomics with novel techniques to alter atherosclerotic disease activity in gene-modified mice and minipigs. Third, we will develop techniques for manipulating genes in modulated plaque SMCs and test the causal role of perturbing SMC subtypes and function for lesion progression. The aim of the project is to answer the following key questions for a deeper understanding of atherosclerosis: - What is the clonal architecture of SMCs in human atherosclerosis? - What is the SMC gene expression signature of atherosclerotic disease activity? - Can interventions targeting SMCs prevent dangerous lesion development?

1 998 875 €

Start date: 2020-08-01, End date: 2025-07-31

Glycans decorate most proteins, cover cell membranes, and represent one of the four building blocks of life, together with nucleic acids, lipids, and amino acids. Yet, our understanding of how glycans influence the life of cells and organisms is limited, and only few functions have been molecularly dissected. Glycans present a huge structural diversity with species and cell- type specificity that underlie specific biological functions. However, more than half a century of research has been severely hampered by the complexity and technical difficulties with analyzing glycans. While, the glycome (all glycans in a cell or organism) is a difficult entry point for discovery, the glycogenome (all genes involved in glycosylation) in contrast is a feasible entry point, because most of the genes controlling glycosylation are now known, and there are fewer technical barriers especially with the emergence of gene editing technologies. Our research group has pioneered the “glycogenome entry” to functional glycomics using gene editing to simplify glycosylation in cells. My research group has pioneered a next generation approach using organotypic tissue models in combination with sophisticated mass spectrometry to decipher glycan functions. The tissue model has provided the first evidence that aberrant glycosylation in cancer directly induce oncogenic features, and that glycosylation of Herpes virus is essential for viral propagation. In this proposal, I will use step-by-step genetic deconstruction of glycosylation capacities in organotypic tissue models for broad discovery and dissection of specific structure-function relationships driving normal epithelial formation, transformation and interaction with the microbiome. Specifically, I will address: 1. How glycosylation affect and shape epithelial homeostasis and transformation 2. How regulation of glycosylation fine-tunes protein functions 3. How glycans influence host-pathogen interactions in “real” epithelial tissue models

1 995 199 €

Start date: 2018-03-01, End date: 2023-02-28