ERC FUNDED PROJECTS

Pollinator declines in response to land-use intensification have raised concern about the persistence of plant species dependent on insect pollination, in particular by bees, for their reproduction. Recent empirical studies show that reduced pollinator abundance decreases densities of seedlings of insect-pollinated plants and thereby changes the composition of grassland plant communities. Cascading effects on ecosystem functioning and associated organisms are expected, but to which extent and under which conditions this is the case is yet unexplored. Here, I propose a bold, multi-year, landscape-scale experimental assessment of the extent of pollinator-driven plant community changes, their consequences for associated organisms and important ecosystem functions, and their likely contingency on other factors (soil fertility, herbivory). Specifically I will: (1) Set up a network of long-term research plots in landscapes differing in pollinator abundance to measure the changes in plant reproduction over successive years, and assessing experimentally how herbivory and soil fertility mediate these effects. (2) Explore the individual processes linking pollinators, plant communities and ecosystem functioning using long-term experiments controlling pollinator, herbivore and nutrient availability, focusing on a sample of plant species covering both the dominant species and a diversity of functional traits. (3) Assess the context-dependence of pollinator-mediated plant community determination by building and applying process-based models based on observational and experimental data, and combine with existing spatially-explicit pollinator models to demonstrate the applicability to assess agri-environmental measures. This powerful blend of complementary approaches will for the first time shed light on the cornerstone role of this major mutualism in maintaining diverse communities and the functions they support, and pinpoint the risks threatening them and the need for mitigation.

1 998 842 €

Start date: 2019-09-01, End date: 2024-08-31

Multiple Sclerosis (MS) is a leading cause of unpredictable and incurable progressive disability in young adults. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I propose that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected, spearheading the development of alternative therapies. We will exploit the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms by studying the target organ in a way that has not been possible before. This highly ambitious project comprises three synergistic facets formulated in specific aims to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting causal epigenetic states. Our unique MS biobank combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states provides a rational starting point to identify MS targets. I will complement this approach with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of robust regulators of specific MS pathways. Finally, my laboratory has extensive experience with animal models of MS and I will utilize these powerful systems to dissect molecular mechanisms of MS targets and test the therapeutic potential of targeted epigenome editing in vivo. Our findings will set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.

1 998 798 €

Start date: 2019-06-01, End date: 2024-05-31

Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.

2 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

Bacteria live in environments where resources for growth are scarce and shared with other bacteria. The ability to inhibit the growth of other bacteria is thus favourable and most bacteria use multiple systems for such antagonistic interactions, including delivery of protein toxins to other bacteria (e.g. bacteriocins, type 6 secretion and contact-dependent growth inhibition systems). In addition to their role in competition, all these toxin delivery systems frequently deliver toxins to cells of the same genotype, i.e. cells immune to the toxic activity, but a function for self-delivery of toxins has never been identified. Recent evidence from our lab suggests that self-delivery of toxins generates population heterogeneity in terms of growth at high cell densities, i.e. upon cell-cell contacts. But if this is a common feature of all toxin delivery systems is not known. Here we will investigate if toxin delivery to cells immune to the toxin creates population heterogeneity in terms of growth, mutation rates and gene expression, and if this is important for bacterial evolution and multicellularity. As homologs for many of the toxins can also be found in eukaryotes, including multicellular organisms, we will investigate if the functions of these systems are also conserved across kingdoms. We will particular characterize the role of bacterial toxin delivery systems for multicellular behaviour and adaptation to new growth environments. This research have important consequences for understanding cell-to-cell contacts and the organization of multicellular tissues in general; from how to control biofilm formation to the understanding of uncontrolled cell growth in higher eukaryotes.

1 499 765 €

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