ERC FUNDED PROJECTS

The evolutionary pressures exerted by viruses on their host cells constitute a major force that drives the evolution of cellular antiviral mechanisms. The proposed research is motivated by our interest in the roles of protein-RNA interactions in both prokaryotic and eukaryotic antiviral pathways and will proceed in two directions. The first project stems from our current work on the CRISPR pathway, a recently discovered RNA-guided adaptive defense mechanism in bacteria and archaea that silences mobile genetic elements such as viruses (bacteriophages) and plasmids. CRISPR systems rely on short RNAs (crRNAs) that associate with CRISPR-associated (Cas) proteins and function as sequence-specific guides in the detection and destruction of invading nucleic acids. To obtain molecular insights into the mechanisms of crRNA-guided interference, we will pursue structural and functional studies of DNA-targeting ribonuceoprotein complexes from type II and III CRISPR systems. Our work will shed light on the function of these systems in microbial pathogenesis and provide a framework for the informed engineering of RNA-guided gene targeting technologies. The second proposed research direction centres on RNA-targeting antiviral strategies employed by the human innate immune system. Here, our work will focus on structural studies of major interferon-induced effector proteins, initially examining the allosteric activation mechanism of RNase L and subsequently focusing on other antiviral nucleases and RNA helicases, as well as mechanisms by which RNA viruses evade the innate immune response of the host. In our investigations, we plan to approach these questions using an integrated strategy combining structural biology, biochemistry and biophysics with cell-based functional studies. Together, our studies will provide fundamental molecular insights into RNA-centred antiviral mechanisms and their impact on human health and disease.

1 467 180 €

Start date: 2013-11-01, End date: 2018-10-31

BACKGROUND Ancient DNA research has recently entered the genomics era. Performing “ancient population genomics” is now technically possible. Utilizing the temporal aspect of this new data, we can address fundamental evolutionary questions such as the amount of selection acting on the genome or the mode and tempo of the colonization of the world. AIMS The overall goal of the proposed research is to (i) generate and analyse data to answer two long standing questions in human evolution: understanding the molecular basis of human adaptation to high altitude and investigating the timing of the Polynesian-South American contact, (ii) develop statistical approaches that combine ancient and modern genetic data to estimate the timing and the intensity of a selective sweep and an admixture event. METHODOLOGY Application: We will collect, date and DNA sequence human remains. Combining the ancient genetic data, 14C dates with existing modern genomic data will allow us to increase the resolution as to the timing of the adaptive and the admixture event, respectively, while generating unique datasets. Theory: We will build on existing methods based on one-locus classical population genetic models to develop tools to analyse whole genome time serial data. RELEVANCE Ecological: The results will address the fundamental question of how much of the human genome is undergoing selection, better characterize one of the textbook examples of adaptation in humans and contribute to our understanding of the peopling of the Americas. Medical: We will gain insights into the fundamental stress physiology experienced at high altitude and therefore into altitude-related illnesses. Methodological: The methods developed in this project will not only benefit the growing field of ancient genomics but also other fields where data is collected in a temporal manner, such as experimental evolution and epidemiology

1 498 478 €

Start date: 2016-08-01, End date: 2021-07-31

"Throughout evolution both intestinal helminths and commensal bacteria have inhabited our intestines. This ""ménage à trois"" situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Such pressures remain in developing countries, whilst the eradication of helminths in industrialized countries has shifted this evolutionary balance—possibly underlying the increased development of chronic inflammatory diseases. We hypothesize that helminth-bacterial interactions are a key determinant of healthy homeostasis. Preliminary findings from our laboratory indicate that helminth infection of mice alters the abundance and diversity of intestinal bacteria and impacts on the availability of immuno-modulatory metabolites; this altered environment correlates with a direct health advantage, protecting against inflammatory diseases such as asthma and rheumatoid arthritis. We intend to validate and extend these data in humans by performing bacterial phlyogenetic and metabolic analysis of stool samples collected from a large cohort of children living in a helminth endemic region of Ecuador. We further propose to test our hypothesis that helminth-bacterial interactions contribute to disease modulation using experimental models of infection and disease. We plan to develop and utilize mouse models to elucidate the mechanisms through which bacterial dysbiosis and helminth infection influence the development of chronic inflammatory diseases. These models will be utilized for germ-free and recolonization experiments, investigating the relative contribution of bacteria versus helminthes to host immunity, co-metabolism and disease modulation. Taking a trans-disciplinary approach, this research will break new ground in our understanding of the crosstalk and pressures between intestinal helminth infection and commensal bacterial communities, and the implications this has for human health."

1 480 612 €

Start date: 2013-04-01, End date: 2018-03-31

The developments of Statistical Mechanics and Quantum Field Theory are among the major achievements of the 20th century's science. During the second half of the century, these two subjects started to converge. In two dimensions, this resulted in a most remarkable chapter of mathematical physics: Conformal Field Theory (CFT) reveals deep structures allowing for extremely precise investigations, making such theories powerful building blocks of many subjects of mathematics and physics. Unfortunately, this convergence has remained non-rigorous, leaving most of the spectacular field-theoretic applications to Statistical Mechanics conjectural. About 15 years ago, several mathematical breakthroughs shed new light on this picture. The development of SLE curves and discrete complex analysis has enabled one to connect various statistical mechanics models with conformally symmetric processes. Recently, major progress was made on a key statistical mechanics model, the Ising model: the connection with SLE was established, and many formulae predicted by CFT were proven. Important advances towards connecting Statistical Mechanics and CFT now appear possible. This is the goal of this proposal, which is organized in three objectives: (I) Build a deep correspondence between the Ising model and CFT: reveal clear links between the objects and structures arising in the Ising and CFT frameworks. (II) Gather the insights of (I) to study new connections to CFT, particularly for minimal models, current algebras and parafermions. (III) Combine (I) and (II) to go beyond conformal symmetry: link the Ising model with massive integrable field theories. The aim is to build one of the first rigorous bridges between Statistical Mechanics and CFT. It will help to close the gap between physical derivations and mathematical theorems. By linking the deep structures of CFT to concrete models that are applicable in many subjects, it will be potentially useful to theoretical and applied scientists.

998 005 €

Start date: 2017-03-01, End date: 2022-02-28