ERC FUNDED PROJECTS

During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.

2 323 468 €

Start date: 2016-07-01, End date: 2021-06-30

Individuals of the same species vary widely in size, but their organs have reproducible proportions and patterns of cell types. How cell fate specification and tissue growth are coordinated during embryonic development to achieve this reproducibility is a fundamental question in biology. Yet, surprisingly little is known about the underlying mechanisms. A major challenge has been to obtain the quantitative data required to assess the dynamics and variability in growth, pattern and signalling by morphogens – molecules that regulate both cell fate specification and tissue growth. I recently established experimental and theoretical approaches that allowed me to reconstruct with unprecedented resolution the three-dimensional growth and pattern of mouse and chick spinal cord. My data revealed a previously unanticipated role of tissue growth dynamics in controlling pattern reproducibility. This quantitative framework provides an exciting opportunity to elucidate the biophysical and molecular mechanisms of growth and pattern coordination. I will use this unique position to understand: 1) how signalling by multiple morphogens is integrated to control pattern, 2) how morphogens control cell cycle kinetics, 3) how morphogen source and target tissue are coupled to achieve pattern reproducibility. To address these issues, I will build on my experience with quantitative analyses to design novel assays where signalling, cell cycle dynamics and transcriptomes can be precisely measured and manipulated with single cell resolution. I will exploit state-of-the-art genome editing techniques to uncouple the critical feedback links and gain a novel perspective on pattern reproducibility and morphogen function. The project will advance our fundamental understanding of tissue morphogenesis and provide novel insights relevant to understanding information processing by signal transduction cascades, morphogen gradient activity, tissue engineering, and cancer biology.

1 499 119 €

Start date: 2016-07-01, End date: 2021-06-30

How do extreme electromagnetic fields modify the dynamics of matter? Will quantum electrodynamics effects be important at the focus of an ultra intense laser? How are the magnetospheres of compact stellar remnants formed, and can we capture the physics of these environments in the laboratory? These are all longstanding questions with an overarching connection to extreme plasma physics. Electron-positron pair plasmas are pervasive in all these scenarios. Highly nonlinear phenomena such as QED processes, magnetogenesis, radiation, field dynamics in complex geometries, and particle acceleration, are all linked with the collective dynamics of pair plasmas through mechanisms that remain poorly understood. Building on our state-of-the-art models, on the availability of enormous computational power, and on our recent transformative discoveries on ab initio modelling of plasmas under extreme conditions, the time is ripe to answer these questions in silico. InPairs aims to understand the multidimensional dynamics of electron-positron plasmas under extreme laboratory and astrophysical fields, to determine the signatures of the radiative processes on pair plasmas, and to identify the physics of the magnetospheres of compact stellar remnants, focusing on the electrodynamics of pulsars, that can be mimicked in laboratory experiments using ultra high intensity lasers and charged particle beams. This proposal relies on massively parallel simulations to bridge the gap, for the first time, between the pair plasma creation mechanisms, the collective multidimensional microphysics, and their global dynamics in complex geometries associated with laboratory and astrophysical systems. Emphasis will be given to detectable signatures e.g. radiation and accelerated particles, with the ultimate goal of solving some of the central questions in extreme plasma physics, thus opening new connections between computational studies, laboratory experiments, and relativistic plasma astrophysics.

1 951 124 €

Start date: 2016-09-01, End date: 2021-08-31

"China’s success story of the past three decades is seen as an anomaly. Market-based reforms have generated an economic system that can hardly be described as socialist anymore, but the Communist Party of China remains in power. Although social unrest is on the rise, the CCP enjoys the consent of the overwhelming majority of its people. Most agree that China’s economic performance is the key to solving this apparent puzzle, but how can extraordinary high rates of public support be maintained in a country where income inequality is so extreme? We believe that the answer to this question lies in the responsiveness of China’s authoritarian one-party regime to popular demands and grievances, a capability that has so far been attributed only to democratic regimes. We further believe that the rapid improvement of e-participation, the opportunity to evaluate public services on the Internet, has greatly facilitated regime responsiveness - China’s score in the United Nations e-participation index is higher than the European average. We suggest, however, that as the government increasingly calibrates public policy towards satisfying the demand of China’s netizens, the ""technologically illiterate"" are forced to express their demands in public protests and other forms of social unrest. The proposed project sheds light on the intended and unintended consequences of enhanced e-participation in China by exploring which social interests China’s rulers incorporate into public policy making, and how these decisions influence the propensity of particular social groups to voice their demands by either participating online or taking to the streets. By exploring the “complex system” in which online complaints, social unrest and public policy interact, the project provides insights into the micro-foundations of regime responsiveness in China. It thereby increases our knowledge of how the CCP seeks to defer the antagonism that prompted the revolutions in Egypt, Tunisia and Syria."

1 292 440 €

Start date: 2016-05-01, End date: 2021-10-31