ERC FUNDED PROJECTS

The actin cytoskeleton of the cell is critical for the complex, integrated processes associated with development, operation and sustainability of the human body. The Arp2/3 complex consisting of seven protein subunits is essential to stimulate dynamic branched actin networks needed for multiple cellular processes. The Arp2/3 complex has always been considered as a single entity, but in humans and other mammals, three of the Arp2/3 complex subunits are encoded by two isoforms, thus allowing the formation of eight distinct Arp2/3 complexes. The Way lab has shown that Arp2/3 subunit composition dramatically affects the formation and stability of branched actin networks. The Way and Gomes labs have shown how specific Arp2/3 isoforms are essential for muscle development. Our synergistic, high-risk, high-gain goal is to define the role of Arp2/3 complex diversity at three hierarchies of biology: 1. Molecular basis of Arp2/3 diversification With purified isoform-specific complexes we will perform cryo-electron microscopy and single molecule fluorescence microscopy to reveal the structural variations and influence of Arp2/3 diversity on actin networks in vitro. 2. Cellular function of different Arp2/3 complexes With cells expressing specific Arp2/3 isoforms, we will use quantitative live cell imaging and cryoelectron tomography to reveal the dependence of cellular actin networks on Arp2/3 diversity and its functional consequences. 3. Developmental and physiological role of individual Arp2/3 complexes. With genetically modified cultured myofibers and transgenic mice, we will use an array of imaging approaches to reveal the contribution of different Arp2/3 family members to muscle development, structure and physiology. Our interdisciplinary plan builds on the strengths of our three labs, takes advantage of unique reagents and powerful model systems, and will allow us to determine how Arp2/3 diversity contributes to biological complexity at multiple scales.

10 715 153 €

Start date: 2019-07-01, End date: 2025-06-30

"X-ray crystallography yields atomic-resolution 3D images of the whole spectrum of molecules ranging from small inorganic clusters to large protein complexes constituting the macromolecular machinery of life. Life is not static, and many of the most important reactions in chemistry and biology are light induced and occur on ultrafast timescales. These have been studied with high time resolution primarily by ultrafast laser spectroscopy, but they reduce the vast complexity of the process to a few reaction coordinates. Here we develop attosecond serial crystallography and spectroscopy, to give a full description of ultrafast processes atomically resolved in real space and on the electronic energy landscape, from co-measurement of X-ray and optical spectra, and X-ray diffraction. This technique will revolutionize our understanding of structure and function at the atomic and molecular level and thereby unravel fundamental processes in chemistry and biology. We apply a fully coherent attosecond X-ray source based on coherent inverse Compton scattering off a free-electron crystal, developed in this project, to outrun radiation damage effects due to the necessary high X-ray irradiance required to acquire diffraction signals [A. Cho, ""Breakthrough of the year"", Science 388, 1530 (2012)]. Our synergistic project will optimize the entire instrumentation towards fundamental measurements of the mechanism of light absorption and excitation energy transfer. The multidisciplinary team optimizes X-ray pulse parameters, in tandem with sample delivery, crystal size, and advanced X-ray detectors. We will apply our new capabilities to one of the most important problems in structural biology, which is to elucidate the dynamics of light reactions, electron transfer and protein structure in photosynthesis. Also, the attosecond source can provide a coherent seed and will help to overcome peak flux limitations of X-ray FELs by introducing chirped pulse amplification to FEL technology."

13 884 200 €

Start date: 2014-08-01, End date: 2020-07-31

Our goal is to uncover the learning algorithms that subserve biological intelligence and to discover how they are implemented in the brain. We take for granted that biological intelligence results from neural information processing, that neural information processing is based on the transmission of action potentials through synapses, and that learning is realized through synaptic plasticity. We are inspired by two key observations: Firstly, we know that biological learning unfolds in ways different from mainstream machine learning that relies on learning from large labeled datasets. Second, we discovered that the engagement of the brain during play can result in unexpected and profound cognitive benefits. This proposal describes an untravelled route to the learning algorithms of the brain that runs through the no-man’s-land between synaptic physiology, systems neuroscience, cognitive neuroscience, theoretical neuroscience and machine learning. Our approach focuses on the self-teaching abilities of the mammalian brain and covers and connects four major topics: (1) the objective functions that govern synaptic plasticity, (2) the teaching signals through which learning is steered, (3) behavioral mechanisms of self-teaching, in particular play behaviors, (4) the brain states that engage self-teaching behaviors, in particular the brain state of play. The BrainPlay grant will study self-teaching abilities from synapses to brains, from computational theory to action video games. As gaming has been shown to be highly beneficial for human brain function, we are intrigued by how little we know about what is going on in playing brains and how the brain state of play shapes learning. Engaging the latest theoretical and technological breakthroughs, BrainPlay will reach far beyond mainstream neuroscience and embrace and elucidate playfulness and self-teaching as important components of the brain's learning algorithms.

9 781 250 €

Start date: 2019-08-01, End date: 2025-07-31

The evolutionary success of multicellular organisms is based on the division of labor between cells. While some of the molecular determinants for cell fate specification have been identified, a fundamental understanding of which genetic activities are required in each cell of a developing tissue is still outstanding. The DECODE project will develop and apply leading-edge system genetics methods to Arabidopsis and Drosophila, two major model systems from the plant and animal kingdoms to decode context-dependent genetic networks in vivo. To achieve this, DECODE will bring together experimental and theoretical groups with complementary expertise in model organism genetics and cellular phenotyping, single-cell genomics, statistics and computational biology. Building on our combined expertise, we will create functional genetic maps using conditional CRISPR/Cas9-based single- and higher order knockout perturbations in vivo combined with single-cell expression profiling and imaging. Coupled with powerful computational analysis, this project will not only define, predict and rigorously test the unique genetic repertoire of each cell, but also unravel how genetic networks adapt their topology and function across cell types and external stimuli. With more than thousand conditional knockouts, characterized by several million single-cell transcriptome profiles and high-resolution imaging this project will create the largest single-cell perturbation map in any model organism and will provide fundamental insights into the genetic architecture of complex tissues. Analyzing two tissues with divergent organization and regulatory repertoire will enable us to uncover general principles in the genetic circuits controlling context dependent cell behavior. Consequently, we expect that the DECODE project in model organisms will lay the conceptual and methodological foundation for perturbation-based functional atlases in other tissues or species.

10 625 000 €

Start date: 2019-07-01, End date: 2025-06-30