ERC FUNDED PROJECTS

Why is the world green? Because predators control herbivores, allowing plants to flourish. This >50 years old answer to the deceptively simple question remains controversial. After all, plants are also protected from herbivores physically and by secondary chemistry. My goal is to test novel aspects of the “green world hypothesis”: ● How the importance of top-down effects varies with forest diversity and productivity along a latitudinal gradient? ● How the key predators, birds, bats and ants, contribute to top-down effects individually and in synergy? I strive to understand this because: ● While there is evidence that predators reduce herbivore abundance and enhance plant growth, the importance of top-down control is poorly understood across a range of forests. ● The importance of key predatory groups, and their antagonistic and synergic interactions, have been rarely studied, despite their potential impact on ecosystem dynamics in changing world. I wish to achieve my goals by: ● Factorial manipulations of key insectivorous predators (birds, bats, ants) to measure their effects on lower trophic levels in forest understories and canopies, accessed by canopy cranes, along latitudinal gradient spanning 75o from Australia to Japan. ● Studying compensatory effects among predatory taxa on herbivore and plant performance. Why this has not been done before: ● Factorial experimental exclusion of predatory groups replicated on a large spatial scale is logistically difficult. ● Canopy crane network along a latitudinal gradient has only recently become available. I am in excellent position to succeed as I have experience with ● foodweb experiments along an elevation gradient in New Guinea rainforests, ● study of bird, bat and arthropod communities. If the project is successful, it will: ● Allow understanding the importance of predators from temperate to tropical forests. ● Establish a network of experimental sites along a network of canopy cranes open for follow-up research.

1 455 032 €

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

The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.

1 499 938 €

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

Plants differ strikingly from animals by the almost total absence of cell migration in their development. Plants build their bodies using a hydrostatic skeleton that consists of pressurized cells encased by a cell wall. Consequently, plant cells cannot migrate and must sculpture their bodies by orientation of cell division and precise regulation of cell growth. Cell growth depends on the balance between internal cell pressure – turgor, and strength of the cell wall. Cell growth is under a strict developmental control, which is exemplified in the Arabidopsis thaliana root tip, where massive cell elongation occurs in a defined spatio-temporal developmental window. Despite the immobility of their cells, plant organs move to optimize light and nutrient acquisition and to orient their bodies along the gravity vector. These movements depend on differential regulation of cell elongation across the organ, and on response to the phytohormone auxin. Even though the control of cell growth is in the epicenter of plant development, protein networks steering the developmental growth onset, coordination and termination remain elusive. Similarly, although auxin is the central regulator of growth, the molecular mechanism of its effect on root growth is unknown. In this project, I will establish a unique microscopy setup for high spatio-temporal resolution live-cell imaging equipped with a microfluidic lab-on-chip platform optimized for growing roots, to enable analysis and manipulation of root growth physiology. I will use developmental gradients in the root to discover genes that steer cellular growth, by correlating transcriptome profiles of individual cell types with the cell size. In parallel, I will exploit the auxin effect on root to unravel molecular mechanisms that control cell elongation. Finally, I am going to combine the live-cell imaging methodology with the gene discovery approaches to chart a dynamic spatio-temporal physiological map of a growing Arabidopsis root.

1 498 750 €

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

This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.

1 876 050 €

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

The global incidence of kidney disease is on the rise, but little progress has been made to develop novel therapies or preventative measures. New methods to generated renal tissue in vitro hold great promise for regenerative medicine and the prospect of organ replacement. Most of the strategies employed differentiate induced pluripotent stem cells (iPSCs) into kidney organoids, which can be derived from patient tissue. Direct reprogramming is an alternative approach to convert one cell type into another using cell fate specifying transcription factors. We were the first to develop a method to directly reprogram mouse and human fibroblasts to kidney cells (induced renal tubular epithelial cells - iRECs) without the need for pluripotent cells. Morphological, transcriptomic and functional analyses found that directly reprogrammed iRECs are remarkably similar to native renal tubular cells. Direct reprogramming is fast, technically simple and scalable. This proposal aims to establish direct reprogramming in nephrology and develop novel in vitro models for kidney diseases that primarily affect the renal tubules. We will unravel the mechanics of how only four transcription factors can change the morphology and function of fibroblasts towards a renal tubule cell identity. These insights will be used to identify alternative routes to directly reprogram tubule cells with increased efficiency and accuracy. We will identify cell type specifying factors for reprogramming of tubular segment specific cell types. Finally, we will use of reprogrammed kidney cells to establish new in vitro models for autosomal dominant polycystic kidney disease and nephronophthisis. Direct reprogramming holds enormous potential to deliver patient specific disease models for diagnostic and therapeutic applications in the age of personalized and targeted medicine.

1 499 917 €

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

Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatment has been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, and for direct and localized modifications of these circuits. We propose minimally invasive technologies for measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to correct the abnormal behavioural phenotypes (in rodents with potential scalability to non-human primates and humans). First, we present a proof-of-principle study on mutant zebrafish, in which we correct whole-brain level abnormal activity patterns and behaviours by using large-scale single-neuron resolution measurements, and by simultaneously modulating multiple sub-networks via neuromodulator cocktails. Next, we present strong preliminary data in rodents and our plan: (1) For manipulating brain circuits in rodents/primates noninvasively, we will develop technologies that can deliver receptive-specific neuromodulators to spatially precise brain targets without opening/damaging the blood brain barrier. These methods will employ engineered ultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits in rodents/primates, we will develop flexible low-power neuromorphic μECoG circuits that can detect single neuron signals from superficial cortical layers of many cortical areas simultaneously. (3) Finally, these novel technologies will be comprehensively evaluated on a mouse model of obsessive compulsivity and anxiety using a battery of behavioural tasks to reverse the pathological symptoms (beyond what is achievable by existing approaches). This project constitutes a major step towards the development and testing of minimallyinvasive and high-precision technologies for manipulating brain activity patterns, which can impact both our understanding of the brain and treatment of intractable brain disorders.

1 998 984 €

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

"Complex life on Earth is powered by bioenergetic organelles -- mitochondria and chloroplasts. Originally independent organisms, these organelles have retained their own genomes (mtDNA and cpDNA), which have been dramatically reduced through evolutionary history. Organelle genomes form dynamic populations within present-day eukaryotic cells, akin to individuals co-evolving in a ""cellular ecosystem"". The structure of these populations is central to eukaryotic life. However, the processes shaping the content of these genomes through history, and maintaining their integrity in modern organisms, are poorly understood. This challenges our understanding of eukaryotic evolution and our ability to design rational strategies to engineer bioenergetic performance. EvoConBiO will address these questions using a unique and unprecedented interdisciplinary approach, combining experimental characterisation and manipulation of organelle genomes with mathematical modelling and cutting-edge statistics. This highly novel combination of experiment and theory will drive the field in a new direction, for the first time uncovering the universal principles underlying the evolution and cellular control of mitochondria and chloroplasts. Our groundbreaking recent work on mtDNA suggests a common tension underlying organelle evolution, between genetic robustness (transferring genes to the nucleus) and the control and maintenance of organelles (retaining genes in organelles). EvoConBiO will reveal the pathways underlying organelle evolution, why organisms adapt to different points on these pathways, and how they resolve this underlying tension. In addition to these ""blue sky"" scientific insights into a process of central evolutionary importance, we will harness our findings to ""learn from evolution"" in high-risk high-reward development of new experimental strategies to engineer chloroplast performance in plants and algae of importance in EU agriculture, biofuel production, and bioengineering."

1 417 862 €

Start date: 2019-07-01, End date: 2024-06-30

Antibodies play an important role ensuring successful protection after vaccination. Upon injection, antigen-binding antibodies are generated to prime the host’s immune system for future encounters with the threat. These responses are highly heterogeneous, with each cell contributing with a single antibody variant to the complexity. Each antibody variant furthermore can recognize a different antigen/epitope with varying specificity and affinity. The immunological function induced is related to those parameters. Depending on the nature of the threat, required protective functional antibodies vary. Therefore, also each vaccination against those threads needs to trigger a specific functional antibody repertoire. Presently, induced functional antibody repertoires have not yet been studied sufficiently, mostly due to the lack of technologies that enable analysing these repertoires with high enough throughput and resolution. Consequently, the mechanisms behind the evolution of these functional repertoires, and the influence of vaccination on these repertoires remain poorly understood. An innovative technology combined with a methodical approach to vaccinations will enable the FuncMab research team to generate data sets needed for the understanding of immunological processes that result in different functional antibody repertoires. Herein, antibodies are analysed on the individual cell level in high-throughput using specific bioassays that target various antibody functions and their biophysical parameters, generating high-resolution data. These functional repertoires are followed over time and evolutionary changes can be linked to introduced vaccine variations, allowing a quantitative approach to study the changes within the repertoires. These in-depth data sets will not only allow understanding interactions between vaccine components and their generated immune responses, but also propels this project to the forefront of creating a new generation of successful vaccines

1 500 000 €

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

Pregnancy complications such as preeclampsia and preterm birth are known to affect infant health, but their influence on mothers’ long-term health is not well understood. Most previous studies are seriously limited by their reliance on information from the first pregnancy. Often they lack the data to study women’s complete reproductive histories. Without a complete reproductive history, the relationship between pregnancy complications and women’s long-term health cannot be reliably studied. The Medical Birth Registry of Norway, covering all births from 1967-, includes information on more than 3 million births and 1.5 million sibships. Linking this to population based death and cancer registries provides a worldwide unique source of population-based data which can be analysed to identify heterogeneities in risk by lifetime parity and the cumulative experience of pregnancy complications. Having worked in this field of research for many years, I see many erroneous conclusions in studies based on insufficient data. For instance, both after preeclampsia and after a stillbirth, the high risk of heart disease observed in one-child mothers is strongly attenuated in women with subsequent pregnancies. I will study different patterns of pregnancy complications that occur alone or in combination across pregnancies, and analyse their associations with cause specific maternal mortality. Using this unique methodology, I will challenge the idea that placental dysfunction is the origin of preeclampsia and test the hypothesis that pregnancy complications may cause direct long-term effects on maternal health. The findings of this research have the potential to advance our understanding of how pregnancy complications affect the long-term maternal health and help to develop more effective chronic disease prevention strategies.

2 500 000 €

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