ERC FUNDED PROJECTS

Life is fundamentally characterised by order, compartmentalisation and biochemical reactions, which occurs at the right place right time – within, on the surface and between cells. Only a proportion of life processes can be addressed with contemporary approaches like liquid encapsulations (e.g. droplets) or engineering compartments (e.g. scaffolds). I believe these approaches are severely limited. I am convinced that a technique to study, work and locally probe adherent cells & tissues at micrometer distances from cell surfaces in “open space” would represent a major advance for the biology of biointerfaces. I therefore propose a non-contact, scanning technology, which spatially confines nanoliter volumes of chemicals for interacting with cells at the µm-length scale. This technology called the vertical microfluidic probe (vMFP) – that I developed at IBM-Zurich – shapes liquid on surfaces hydrodynamically and is compatible with samples on Petri dishes & microtiter plates. The project is organized in 4 themes: (1) Advancing the vMFP by understanding the interaction of liquid flows with biointerfaces, integrating functional elements (e.g. heaters/electrodes, cell traps) & precision control. (2) Developing a higher resolution method to stain tissue sections for multiple markers & better quality information. (3) Retrieving rare elements such as circulating tumor cells from biologically diverse libraries. (4) Patterning cells for applications in regenerative medicine. Since cells & tissues will no longer be limited by closed systems, the vMFP will enable a completely new range of experiments to be performed in a highly interactive, versatile & precise manner – this approach departs from classical “closed” microfluidics. It is very likely that such a tool by providing multifunctional capabilities akin to the proverbial ‘Swiss army knife’ will be a unique facilitator for investigations of previously unapproachable problems in cell biology & the life science.

1 488 600 €

Start date: 2013-01-01, End date: 2017-12-31

The detection of primordial gravity waves created during the Big Bang ranks among the greatest potential intellectual achievements in modern science. During the last few decades, the instrumental progress necessary to achieve this has been nothing short of breathtaking, and we today are able to measure the microwave sky with better than one-in-a-million precision. However, from the latest ultra-sensitive experiments such as BICEP2 and Planck, it is clear that instrumental sensitivity alone will not be sufficient to make a robust detection of gravitational waves. Contamination in the form of astrophysical radiation from the Milky Way, for instance thermal dust and synchrotron radiation, obscures the cosmological signal by orders of magnitude. Even more critically, though, are second-order interactions between this radiation and the instrument characterization itself that lead to a highly non-linear and complicated problem. I propose a ground-breaking solution to this problem that allows for joint estimation of cosmological parameters, astrophysical components, and instrument specifications. The engine of this method is called Gibbs sampling, which I have already applied extremely successfully to basic CMB component separation. The new and ciritical step is to apply this method to raw time-ordered observations observed directly by the instrument, as opposed to pre-processed frequency maps. While representing a ~100-fold increase in input data volume, this step is unavoidable in order to break through the current foreground-induced systematics floor. I will apply this method to the best currently available and future data sets (WMAP, Planck, SPIDER and LiteBIRD), and thereby derive the world's tightest constraint on the amplitude of inflationary gravitational waves. Additionally, the resulting ancillary science in the form of robust cosmological parameters and astrophysical component maps will represent the state-of-the-art in observational cosmology in years to come.

1 999 205 €

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

"Atmospheric aerosol particles have been shown to impact the earth's climate because they scatter and absorb solar radiation (direct effect) and because they can modify the microphysical properties of clouds by acting as cloud condensation nuclei or ice nuclei (indirect effects). Radiative forcing by anthropogenic aerosols remains poorly quantified, thus leading to considerable uncertainty in our understanding of the earth’s climate response to the radiative forcing by greenhouse gases. Black carbon (BC), mostly emitted by anthropogenic combustion processes and biomass burning, is an important component of atmospheric aerosols. Estimates show that BC may be the second strongest contributor (after CO2) to global warming. Adverse health effects due to particulate air pollution have also been associated with traffic-related BC particles. These climate and health effects brought BC emission reductions into the political focus of possible mitigation strategies with immediate and multiple benefits for human well-being. Laboratory experiments aim at the physical and chemical characterisation of BC emissions from diesel engines and biomass burning under controlled conditions. A mobile laboratory equipped with state-of-the-art aerosol sensors will be used to determine the contribution of different BC sources to atmospheric BC loadings, and to investigate the evolution of the relevant BC properties with atmospheric aging during transport from sources to remote areas. The interactions of BC particles with clouds as a function of BC properties will be investigated with in-situ measurements by operating quantitative single particle instruments behind a novel sampling inlet, which makes selective sampling of interstitial, cloud droplet residual or ice crystal residual particles possible. Above experimental studies aim at improving our understanding of BC’s atmospheric life cycle and will be used in model simulations for quantitatively assessing the atmospheric impacts of BC."

1 992 015 €

Start date: 2014-03-01, End date: 2019-02-28

While the crisis of the territorial nation-state in the Middle East has once again been brought to a head by the wars in Iraq and Syria, it cannot be simply understood as the logical consequence of an imported political construction. Based on two epistemological notions – borderlands as histoire-problème (history-as-problem) and the co-production of borders between state and society – this research project proposes to rethink the classical historical narrative about the emergence of the post-Ottoman Middle East. Taking its cue from trans-border phenomena and thus paying attention to the circulation of people, goods and ideas as well as to everyday encounters between local actors and state representatives, the project will be guided by four principle objectives to offer: • A socio-historical analysis of state violence in the borderlands of the Middle East; • An examination of the capacity of border populations to create the history of the borderlands, nation-states, and the region as a whole; • A study of the frontier effects based around the notions of subjectivity, space and time, and involving various levels of observation (macro, meso and micro) in order to identify the ruptures and continuities evoked by the delineation of new borderlines; and • A historical lens through which to make sense of current events in Syria and Iraq, and possibly orient conflict-resolution practitioners. Through the exploitation of a wide range of sources (diplomatic, administrative and military records, missionary documents, newspapers) and by looking at the social construction of international frontiers at the borderlands located between Turkey, Iraq and Syria in the interwar era, the research project will provide a much more holistic yet finely-grained understanding of the formation of the territorial state in the region in the aftermath of the First World War as well as a historical perspective on the on-going armed conflicts.

1 997 675 €

Start date: 2017-09-01, End date: 2022-08-31

Plate tectonics characterises the complex and dynamic evolution of the outer shell of the Earth in terms of rigid plates. These tectonic plates overlie and interact with the Earth's mantle, which is slowly convecting owing to energy released by the decay of radioactive nuclides in the Earth's interior. Even though links between mantle convection and plate tectonics are becoming more evident, notably through subsurface tomographic images, advances in mineral physics and improved absolute plate motion reference frames, there is still no generally accepted mechanism that consistently explains plate tectonics and mantle convection in one framework. We will integrate plate tectonics into mantle dynamics and develop a theory that explains plate motions quantitatively and dynamically. This requires consistent and detailed reconstructions of plate motions through time (Objective 1). A new model of plate kinematics will be linked to the mantle with the aid of a new global reference frame based on moving hotspots and on palaeomagnetic data. The global reference frame will be corrected for true polar wander in order to develop a global plate motion reference frame with respect to the mantle back to Pangea (ca. 320 million years) and possibly Gondwana assembly (ca. 550 million years). The resulting plate reconstructions will constitute the input to subduction models that are meant to test the consistency between the reference frame and subduction histories. The final outcome will be a novel global subduction reference frame, to be used to unravel links between the surface and deep Earth (Objective 2).

2 499 010 €

Start date: 2011-05-01, End date: 2016-04-30

Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

2 498 915 €

Start date: 2016-02-01, End date: 2021-01-31

My goal is to study several important open mathematical problems in non-equilibrium (NEQ) systems and to build a bridge between these problems and NEQ aspects of soft sciences, in particular biological questions. Traffic on this bridge is going to be two-way, the mathematics carrying a long history as a language of science towards the soft sciences, and the soft sciences fruitfully asking new questions and building new paradigms for mathematical research. Out-of-equilibrium systems pose several fascinating problems: The Fourier law which says that resistance of a wire is proportional to its length is still presenting hard problems for research, and even the existence and the convergence to a NEQ steady state are continuously posing new puzzles, as do questions of smoothness and correlations of such states. These will be addressed with stochastic differential equations, and with particlescatterer systems, both canonical and grand-canonical. The latter are extensions of the well-known Lorentz gas and the study of hyperbolic billiards. Another field where NEQ plays an important role is the study of glassy systems. They were studied with molecular dynamics (MD) but I have used a topological variant, which mimics astonishingly well what happens in MD simulations. The aim is to extend this to 3 dimensions, where new problems appear. Finally, I will apply the NEQ studies to biological systems: How a system copes with the varying environment,adapting in this way to a novel type of NEQ. I will study networks of communication among neurons,which are like random graphs with the additional property of being embedded, and the arrangement of genes on chromosomes in such a way as to optimize the adaptation to the different cell types which must be produced using the same genetic information. I will answer such questions with students and collaborators, who will specialize in the subprojects but will interact with my help across the common bridge.

2 135 385 €

Start date: 2012-04-01, End date: 2017-07-31

The overall goal of this project is to understand the molecular mechanisms that lead to the generation of potent and broadly neutralizing antibodies against medically relevant pathogens, and to identify the factors that limit their production in response to infection or vaccination with current vaccines. We will use high-throughput cellular screens to isolate from immune donors clonally related antibodies to different sites of influenza hemagglutinin, which will be fully characterized and sequenced in order to reconstruct their developmental pathways. Using this approach, we will ask fundamental questions with regards to the role of somatic mutations in affinity maturation and intraclonal diversification, which in some cases may lead to the generation of autoantibodies. We will combine crystallography and long time-scale molecular dynamics simulation to understand how mutations can increase affinity and broaden antibody specificity. By mapping the B and T cell response to all sites and conformations of influenza hemagglutinin, we will uncover the factors, such as insufficient T cell help or the instability of the pre-fusion hemagglutinin, that may limit the generation of broadly neutralizing antibodies. We will also perform a broad analysis of the antibody response to erythrocytes infected by P. falciparum to identify conserved epitopes on the parasite and to unravel the role of an enigmatic V gene that appears to be involved in response to blood-stage parasites. The hypotheses tested are strongly supported by preliminary observations from our own laboratory. While these studies will contribute to our understanding of B cell biology, the results obtained will also have translational implications for the development of potent and broad-spectrum antibodies, for the definition of correlates of protection, and for improving vaccine design.

1 867 500 €

Start date: 2015-10-01, End date: 2020-09-30

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