ERC FUNDED PROJECTS

During the 20th century computer technology evolved from bulky, slow, special purpose mechanical engines to the now ubiquitous silicon chips and software that are one of the pinnacles of human ingenuity. The goal of the field of molecular programming is to take the next leap and build a new generation of matter-based computers using DNA, RNA and proteins. This will be accomplished by computer scientists, physicists and chemists designing molecules to execute ``wet'' nanoscale programs in test tubes. The workflow includes proposing theoretical models, mathematically proving their computational properties, physical modelling and implementation in the wet-lab. The past decade has seen remarkable progress at building static 2D and 3D DNA nanostructures. However, unlike biological macromolecules and complexes that are built via specified self-assembly pathways, that execute robotic-like movements, and that undergo evolution, the activity of human-engineered nanostructures is severely limited. We will need sophisticated algorithmic ideas to build structures that rival active living systems. Active-DNA, aims to address this challenge by achieving a number of objectives on computation, DNA-based self-assembly and molecular robotics. Active-DNA research work will range from defining models and proving theorems that characterise the computational and expressive capabilities of such active programmable materials to experimental work implementing active DNA nanostructures in the wet-lab.

2 349 603 €

Start date: 2018-11-01, End date: 2023-10-31

"The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia. In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes. This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."

1 998 300 €

Start date: 2014-05-01, End date: 2019-04-30

The Bantu Expansion is not only the main linguistic, cultural and demographic process in Late Holocene Africa. It is also one of the most controversial issues in African History that still has political repercussions today. It has sparked debate across the disciplines and far beyond Africanist circles in an attempt to understand how the young Bantu language family (ca. 5000 years) could spread over large parts of Central, Eastern and Southern Africa. This massive dispersal is commonly seen as the result of a single migratory macro-event driven by agriculture, but many questions about the movement and subsistence of ancestral Bantu speakers are still open. They can only be answered through real interdisciplinary collaboration. This project will unite researchers with outstanding expertise in African archaeology, archaeobotany and historical linguistics to form a unique cross-disciplinary team that will shed new light on the first Bantu-speaking village communities south of the rainforest. Fieldwork is planned in parts of the Democratic Republic of Congo, the Republic of Congo and Angola that are terra incognita for archaeologists to determine the timing, location and archaeological signature of the earliest villagers and to establish how they interacted with autochthonous hunter-gatherers. Special attention will be paid to archaeobotanical and palaeoenvironmental data to get an idea of their subsistence, diet and habitat. Historical linguistics will be pushed beyond the boundaries of vocabulary-based phylogenetics and open new pathways in lexical reconstruction, especially regarding subsistence and land use of early Bantu speakers. Through interuniversity collaboration archaeozoological, palaeoenvironmental and genetic data and phylogenetic modelling will be brought into the cross-disciplinary approach to acquire a new holistic view on the interconnections between human migration, language spread, climate change and early farming in Late Holocene Central Africa.

1 997 500 €

Start date: 2018-01-01, End date: 2022-12-31

During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth. ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date. Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.

1 837 625 €

Start date: 2016-06-01, End date: 2021-05-31

As nature’s first bioengineers, bacteriophages have evolved to modify, adapt and control their bacterial hosts through billions of years of interactions. Indeed, like modern synthetic biologists aspire to do, bacteriophages already evade bacterial silencing of their xenogeneic DNA, subvert host gene expression, and co-opt both the central and peripheral metabolisms of their hosts. Studying these key insights from a molecular systems biology perspective, inspired us to develop these evolutionary fully-adapted phage mechanisms as a next-level layer of synthetic biology tools. Thus, BIONICbacteria will provide conceptual novel synthetic biology tools that allow direct manipulation of specific protein activity, post-translational modifications, RNA stability, and metabolite concentrations. The goal of BIONICbacteria is to pioneer an unconventional way to perform synthetic biology, tapping an unlimited source of novel phage tools genetic circuits and phage modulators. To achieve these goals, we will apply and develop state-of-the-art technologies in molecular microbiology and focus on three principal aims: (1) To exploit new phage-encoded genetic circuits as synthetic biology parts and as intricate biotechnological chassis. (2) To build synthetic phage modulators (SPMs) as novel payloads to directly impact the bacterial metabolism in a targeted manner. (3) To create designer bacteria by integrating SPMs-containing circuits into bacterial strains as proof-of-concepts for applications in industrial fermentations and vaccine design. This proposed “plug-in” approach of evolutionary-adapted synthetic modules, will allow us to domesticate Pseudomonas strains in radically new ways. By building proofs-of-concept for applications in industrial fermentations and vaccine development, we address key problem in these areas with potentially high-gain solutions for society and industry.

1 998 750 €

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

"DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers. Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."

1 920 000 €

Start date: 2014-09-01, End date: 2019-08-31

Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition. The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work. To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching. Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.

1 999 660 €

Start date: 2017-06-01, End date: 2022-05-31

Adaptive behaviour is typically attributed to an executive-control system that allows people to regulate impulsive actions and to fulfil long-term goals instead. Failures to regulate impulsive actions have been associated with a variety of clinical and behavioural disorders. Therefore, establishing a good understanding of impulse-control mechanisms and how to improve them could be hugely beneficial for both individuals and society at large. Yet many fundamental questions remain unanswered. This stems from a narrow focus on reactive inhibitory control and well-practiced actions. To make significant progress, we need to develop new models that integrate different aspects of impulsive action and executive control. The proposed research program aims to answer five fundamental questions. (1) Can novel impulsive actions arise during task-preparation stages?; (2) What is the role of negative emotions in the origin and control of impulsive actions?; (3) How does learning modulate impulsive behaviour?; (4) When are impulsive actions (dys)functional?; and (5) How is variation in state impulsivity associated with trait impulsivity? To answer these questions, we will use carefully designed behavioural paradigms, cognitive neuroscience techniques (TMS & EEG), physiological measures (e.g. facial EMG), and mathematical modelling of decision-making to specify the origin and control of impulsive actions. Our ultimate goal is to transform the impulsive action field by replacing the currently dominant ‘inhibitory control’ models of impulsive action with detailed multifaceted models that can explain impulsivity and control across time and space. Developing a new behavioural model of impulsive action will also contribute to a better understanding of the causes of individual differences in impulsivity and the many disorders associated with impulse-control deficits.

1 998 438 €

Start date: 2018-06-01, End date: 2023-05-31

Evidence of a growing disengagement of citizens from politics is multiplying. Electoral turnout reaches historically low levels. Anti-establishment and populist parties are on the rise. Fewer and fewer Europeans trust their representative institutions. In response, we have observed a multiplication of institutional reforms aimed at revitalizing representative democracy. Two in particular stand out: the delegation of some political decision-making powers to (1) selected citizens and to (2) selected experts. But there is a paradox in attempting to cure the crisis of representative democracy by introducing such reforms. In representative democracy, control over political decision-making is vested in elected representatives. Delegating political decision-making to selected experts/citizens is at odds with this definition. It empowers the non-elected. If these reforms show that politics could work without elected officials, could we really expect that citizens’ support for representative democracy would be boosted and that citizens would re-engage with representative politics? In that sense, would it be a cure for the crisis of representative democracy, or rather a curse? Our central hypothesis is that there is no universal and univocal healing (or harming) effect of non-elected politics on support for representative democracy. In order to verify it, I propose to collect data across Europe on three elements: (1) a detailed study of the preferences of Europeans on how democracy should work and on institutional reforms towards non-elected politics, (2) a comprehensive inventory of all actual cases of empowerment of citizens and experts implemented across Europe since 2000, and (3) an analysis of the impact of exposure to non-elected politics on citizens’ attitudes towards representative democracy. An innovative combination of online survey experiments and of panel surveys will be used to answer this topical research question with far-reaching societal implication.

1 981 589 €

Start date: 2018-09-01, End date: 2023-08-31

Deep brain stimulation (DBS) is an effective therapy for treating the symptoms of Parkinson’s disease (PD). Despite its success, the mechanisms of DBS are not understood and there is a need to improve DBS to improve long-term stimulation in a wider patient population, limit side-effects, and extend battery life. Currently DBS operates in ‘open-loop’, with stimulus parameters empirically set. Closed-loop DBS, which adjusts parameters based on the state of the system, has the potential to overcome current limitations to increase therapeutic efficacy while reducing side-effects, costs and energy. Several key questions need to be addressed before closed loop DBS can be implemented clinically. This research will develop a new multiscale model of the neuromuscular system for closed-loop DBS. The model will simulate neural sensing and stimulation on a scale not previously considered, encompassing the electric field around the electrode, the effect on individual neurons and neural networks, and generation of muscle force. This will involve integration across multiple temporal and spatial scales, in a complex system with incomplete knowledge of system variables. Experiments will be conducted to validate the model, and identify new biomarkers of neural activity that can used with signals from the brain to enable continuous symptom monitoring. The model will be used to design a new control strategy for closed-loop DBS that can accommodate the nonlinear nature of the system, and short- and long-term changes in system behavior. Though challenging, this research will provide new insights into the changes that take place in PD and the mechanisms by which DBS exerts its therapeutic influence. This knowledge will be used to design a new strategy for closed-loop DBS, ready for testing in patients, with the potential to significantly improve patient outcomes in PD and fundamentally change the way in which implanted devices utilise electrical stimulation to modulate neural activity.

1 999 474 €

Start date: 2015-08-01, End date: 2020-07-31

Dendritic cells (DCs) play a crucial role as gatekeepers of the immune system, coordinating the balance between protective immunity and tolerance to self antigens. What determines the switch between immunogenic versus tolerogenic antigen presentation remains one of the most puzzling questions in immunology. My team recently discovered an unanticipated link between a conserved stress response in the endoplasmic reticulum (ER) and tolerogenic DC maturation, thereby setting the stage for new insights in this fundamental branch in immunology. Specifically, we found that one of the branches of the unfolded protein response (UPR), the IRE1/XBP1 signaling axis, is constitutively active in murine dendritic cells (cDC1s), without any signs of an overt UPR gene signature. Based on preliminary data we hypothesize that IRE1 is activated by apoptotic cell uptake, orchestrating a metabolic response from the ER to ensure tolerogenic antigen presentation. This entirely novel physiological function for IRE1 entails a paradigm shift in the UPR field, as it reveals that IRE1’s functions might stretch far from its well-established function induced by chronic ER stress. The aim of my research program is to establish whether IRE1 in DCs is the hitherto illusive switch between tolerogenic and immunogenic maturation. To this end, we will dissect its function in vivo both in steady-state conditions and in conditions of danger (viral infection models). In line with our data, IRE1 has recently been identified as a candidate gene for autoimmune disease based on Genome Wide Association Studies (GWAS). Therefore, I envisage that my research program will not only have a large impact on the field of DC biology and apoptotic cell clearance, but will also yield new insights in diseases like autoimmunity, graft versus host disease or tumor immunology, all associated with disturbed balances between tolerogenic and immunogenic responses.

1 999 196 €

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

Duplicate genes are important in disease, are a hugely important source of evolutionary novelty, and for many years we thought we understood them. We thought that duplication relieved selective constraints. We thought that gene knockout neutrality was due to redundancy. We thought that a duplicate is a duplicate is a duplicate. Evidence is accumulating challenging each of these views. Rather than being the result of an unbiased process, the genes that tend to duplicate in our genome and others are quickly evolving, non-essential genes, irrespective of current duplication status. Conversely, genes retained after whole genome duplication (WGD) are slowly evolving, important genes. I propose that different resolution of the evolutionary constraints imposed by the demands of gene expression can explain these contrasting relationships. I propose that the opposing constraints on gene-by-gene duplications as compared to WGD channel these different sets of genes into remarkably different evolutionary trajectories. In particular, in much the same way that individual gene duplication creates an opportunity for the evolution of a new gene, the co-evolution of expression of sets of interacting genes after WGD creates an opportunity for the evolution of new biochemical pathways and protein complexes. Furthermore, I suggest a common mechanism of pathogenicity for many duplication events independent of the biochemical function of the encoded genes. With the availability of abundant high-quality genomics data, now is an opportune time to address these questions. Primarily through computational and statistical analysis I will reveal the relationship between gene duplication and expression and test a model that the indirect costs of gene expression are a major determinant of the outcome of gene duplication. I will explore the effects this has on gene and genome evolution. Finally, I will link the patterns of gene expression and duplicability to pathogenic effects.

1 824 794 €

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

One of the most ambitious goals of modern astrophysics is to characterise the physical and chemical properties of rocky planets orbiting in the habitable zone of nearby Sun-like stars. Although the observation of planetary transits could in a few limited cases be used to reach such a goal, it is widely recognised that only direct imaging techniques will enable such a feat on a statistically significant sample of planetary systems. Direct imaging of Earth-like exoplanets is however a formidable challenge due to the huge contrast and minute angular separation between such planets and their host star. The proposed EPIC project aims to enable the direct detection and characterisation of terrestrial planets located in the habitable zone of nearby stars using ground-based high-contrast imaging in the thermal infrared domain. To reach that ambitious goal, the project will focus on two main research directions: (i) the development and implementation of high-contrast imaging techniques and technologies addressing the smallest possible angular separations from bright, nearby stars, and (ii) the adaptation of state-of-the-art machine learning techniques to the problem of image processing in high-contrast imaging. While the ultimate goal of this research can likely only be reached with the advent of giant telescopes such as the Extremely Large Telescope (ELT) around 2025, the EPIC project will lay the stepping stones towards that goal and produce several high-impact results along the way, e.g. by re-assessing the occurrence rate of giant planets in direct imaging surveys at the most relevant angular separations (i.e., close to the snow line), by conducting the deepest high-contrast imaging search for rocky planets in the alpha Centauri system, by preparing the scientific exploitation of the ELT, and by providing the first open-source high-contrast image processing toolbox relying on supervised machine learning techniques.

2 178 125 €

Start date: 2019-05-01, End date: 2024-04-30

"Why do individuals vary in their cognitive abilities? This proposal takes the disciplines of cognition and evolutionary biology into a natural setting to answer this question by investigating a variety of proximate causes and population-level consequences of individual variation in cognitive ability. It represents the first large-scale integrative study of cognitive ability on any wild population. State of the art observational (remote sensing and automated self-administration trials of learning in the wild), chemical (stable isotope analysis of diet), physiological (stress, energetics, immunocompetence), molecular (DNA fingerprinting and metabarcoding) and analytical (reaction norm, quantitative genetic) techniques will be used. The chosen study system, the great tit Parus major, is one of the most widely used in Europe, but uniquely here will consist of 12 subpopulations across deciduous and conifer woodland fragments. The proposal’s broad scope is captured in three objectives: 1) To characterise proximate causes of variation in cognitive (associative/reversal learning; problem solving; brain size) and other traits (the reactive-proactive personality axis; bill morphology), all of which can influence similar ecologically important behaviour. Quantitative genetic, social, parasite-mediated, and physiological causes will be explored. 2) To examine links between these traits, and key behaviours and trade-offs, e.g., space use, niche specialization, predation, parental care and promiscuity; and 3) To examine the consequences of this variation for life histories and fitness. The research team consists of the PI, five early career biologists, and three PhD students, and will collaborate with eight researchers from Europe and further afield. The project will reveal ground-breaking insight into why individuals vary in their cognitive ability. It aims to impact a wide scientific community, to raise public interest in science, and to inform EU biodiversity policy."

1 993 189 €

Start date: 2015-03-01, End date: 2020-12-31

With this research programme, inspired by open problems within noncommutative algebraic geometry (NCAG) as well as by actual developments in algebraic topology, it is our aim to lay out new foundations for NCAG. On the one hand, the categorical approach to geometry put forth in NCAG has seen a wide range of applications both in mathematics and in theoretical physics. On the other hand, algebraic topology has received a vast impetus from the development of higher topos theory by Lurie and others. The current project is aimed at cross-fertilisation between the two subjects, in particular through the development of “higher linear topos theory”. We will approach the higher structure on Hochschild type complexes from two angles. Firstly, focusing on intrinsic incarnations of spaces as large categories, we will use the tensor products developed jointly with Ramos González and Shoikhet to obtain a “large version” of the Deligne conjecture. Secondly, focusing on concrete representations, we will develop new operadic techniques in order to endow complexes like the Gerstenhaber-Schack complex for prestacks (due to Dinh Van-Lowen) and the deformation complexes for monoidal categories and pasting diagrams (due to Shrestha and Yetter) with new combinatorial structure. In another direction, we will move from Hochschild cohomology of abelian categories (in the sense of Lowen-Van den Bergh) to Mac Lane cohomology for exact categories (in the sense of Kaledin-Lowen), extending the scope of NCAG to “non-linear deformations”. One of the mysteries in algebraic deformation theory is the curvature problem: in the process of deformation we are brought to the boundaries of NCAG territory through the introduction of a curvature component which disables the standard approaches to cohomology. Eventually, it is our goal to set up a new framework for NCAG which incorporates curved objects, drawing inspiration from the realm of higher categories.

1 171 360 €

Start date: 2019-06-01, End date: 2024-05-31

"Linear programming has proved to be an invaluable tool both in theory and practice. Semidefinite programming surpasses linear programming in terms of expressivity while remaining tractable. This project proposal investigates the modeling power of linear and semidefinite programming, in the context of combinatorial optimization. Within the emerging framework of extended formulations (EFs), I seek a decisive answer to the following question: Which problems can be modeled by a linear or semidefinite program, when the number of constraints and variables are limited? EFs are based on the idea that one should choose the ""right"" variables to model a problem. By extending the set of variables of a problem by a few carefully chosen variables, the number of constraints can in some cases dramatically decrease, making the problem easier to solve. Despite previous high-quality research, the theory of EFs is still on square one. This project proposal aims at (i) transforming our current zero-dimensional state of knowledge to a truly three-dimensional state of knowledge by pushing the boundaries of EFs in three directions (models, types and problems); (ii) using EFs as a lens on complexity by proving strong consequences of important conjectures such as P != NP, and leveraging strong connections to geometry to make progress on the log-rank conjecture. The proposed methodology is: (i) experiment-aided; (ii) interdisciplinary; (iii) constructive."

1 455 479 €

Start date: 2014-09-01, End date: 2019-08-31

Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.

1 987 860 €

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

Most biotechnological therapeutics used in the clinic today and under current development, are of protein nature. Eukaryotic expression systems (such as yeasts and mammalian cells) for these therapeutic proteins add carbohydrate moieties (glycans) to the proteins, and these glycans strongly modulate the protein's in vivo biodistribution and therapeutic efficacy. Until recently, no adequate tools were available to accurately control glycosylation structure in these expression systems, but bio-engineering research in our lab and elsewhere has now largely overcome this problem. In the GlycoTarget ERC Consolidator grant project, we aim at exploring the relation between the structure of the glycans on therapeutic proteins and the in vivo targeting properties of these modified proteins to different tissues/cells/subcellular organelles. As highly medically relevant test cases for this exploration, we have selected three diseases with strong unmet therapeutic need, that could potentially be treated with glyco-targeted biopharmaceuticals through three different routes of protein delivery: progressive liver disease (intravenous), allergic asthma (subcutaneous immunization) and active tuberculosis (intrapulmonary delivery).

1 994 760 €

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

The current theory of cosmic inflation is largely based on classical physics. This undermines its predictivity in a world that is fundamentally quantum mechanical. With this project we will develop a novel approach towards a quantum theory of inflation. We will do this by introducing holographic techniques in cosmology. The notion of holography is the most profound conceptual breakthrough that has emerged form fundamental high-energy physics in recent years. It postulates that (quantum) gravitational systems such as the universe as a whole have a precise `holographic’ description in terms of quantum field theories defined on their boundary. Our aim is to develop a holographic framework for quantum cosmology. We will then apply this to three areas of theoretical cosmology where a quantum approach is of critical importance. First, we will put forward a holographic description of inflation that clarifies its microphysical origin and is rigorously predictive. Using this we will derive the distinct observational signatures of novel, truly holographic models of the early universe where inflation has no description in terms of classical cosmic evolution. Second, we will apply holographic cosmology to improve our understanding of eternal inflation. This is a phase deep into inflation where quantum effects dominate the evolution and affect the universe’s global structure. Finally we will work towards generalizing our holographic models of the primordial universe to include the radiation, matter and vacuum eras. The resulting unification of cosmic history in terms of a single holographic boundary theory may lead to intriguing predictions of correlations between early and late time observables, tying together the universe’s origin with its ultimate fate. Our project has the potential to revolutionize our perspective on cosmology and to further deepen the fruitful interaction between cosmology and high-energy physics.

1 995 900 €

Start date: 2014-08-01, End date: 2019-07-31

This ERC program addresses an unsettled political science problem, namely how does the shifting of policymaking competencies to higher levels of government affect the opportunities of societal interests to seek representation. On this issue two completely different theoretical expectations exist. One the one hand, the Madisonian view entails that shifting competencies upwards is a healthy antidote to the powers of specific interests that may dominate smaller polities. Multi-levelness may also provide political opportunities as it enables actors to make strategic venue shifts when they are unable to attract the necessary attention at one venue. On the other hand, shifting policymaking upwards may seriously restrict the opportunities for diffuse interests, undermine encompassing forms of interest representation, and increase the barriers for local groups to gain attention. Instead of creating opportunities for all, multi-layered systems may decrease opportunities and reproduce or reinforce representational bias. One of the reasons why the implications of multi-layeredness are so poorly understood is the fact that political science has not developed a proper understanding of what representational bias means; some scholars see bias in terms of mobilization, while others conceive it in terms of the strategic interactions between organized interests and policymakers. This ERC program will integrate theoretically, methodologically and empirically these different aspects of group politics, by taking explicitly into account the nature of multi-layered systems. The innovative character of it lies in the theoretical combination of mapping interest group community dynamics, with a more nuanced characterization of organizational form and an in-depth investigation of bias in terms of strategies.

1 655 263 €

Start date: 2014-09-01, End date: 2019-08-31

Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.

2 000 000 €

Start date: 2019-04-01, End date: 2024-03-31

Tissue Engineering (TE) refers to the branch of medicine that aims to replace or regenerate functional tissue or organs using man-made living implants. As the field is moving towards more complex TE constructs with sophisticated functionalities, there is a lack of dedicated in vitro devices that allow testing the response of the complex construct as a whole, prior to implantation. Additionally, the knowledge accumulated from mechanistic and empirical in vitro and in vivo studies is often underused in the development of novel constructs due to a lack of integration of all the data in a single, in silico, platform. The INSITE project aims to address both challenges by developing a new mesofluidics set-up for in vitro testing of TE constructs and by developing dedicated multiscale and multiphysics models that aggregate the available data and use these to design complex constructs and proper mesofluidics settings for in vitro testing. The combination of these in silico and in vitro approaches will lead to an integrated knowledge-rich mesofluidics system that provides an in vivo-like time-varying in vitro environment. The system will emulate the in vivo environment present at the (early) stages of bone regeneration including the vascularization process and the innate immune response. A proof of concept will be delivered for complex TE constructs for large bone defects and infected fractures. To realize this project, the applicant can draw on her well-published track record and extensive network in the fields of in silico medicine and skeletal TE. If successful, INSITE will generate a shift from in vivo to in vitro work and hence a transformation of the classical R&D pipeline. Using this system will allow for a maximum of relevant in vitro research prior to the in vivo phase, which is highly needed in academia and industry with the increasing ethical (3R), financial and regulatory constraints.

2 161 750 €

Start date: 2018-09-01, End date: 2023-08-31

Osteoarthritis (OA) is a serious disease of the joints affecting nearly 10% of the population worldwide. Realising an efficacious therapeutic solution for treating OA remains one of the greatest challenges in the field of orthopaedic medicine. This proposal envisions a future where 3D bioprinting systems located in hospitals will provide ‘off-the-shelf’, patient-specific biological implants to treat diseases such as OA. To realise this vision, this project will use 3D bioprinting to generate anatomically accurate, biomimetic constructs that can be used to regenerate both the cartilage and bone in a diseased joint. The first aim of this proposal is to print a mesenchymal stem cell laden biomaterial that is both immediately load bearing and can facilitate the regeneration of articular cartilage in vivo, such that the bioprinted construct will not require in vitro maturation prior to implantation. Mechanical function will be realised by integrating an interpenetrating network hydrogel into a 3D printed polymeric scaffold, while chondro-inductivity will be enhanced by the spatially-defined incorporation of cartilage extracellular matrix components and chondrogenic growth factors into the bioprinted construct. The second aim of the proposal is to use 3D bioprinting to create a cell-free, composite construct to facilitate regeneration of the bony region of a large osteochondral defect, where vascularization will be accelerated by immobilizing spatial gradients of vascular endothelial growth factor into the implant. The third aim of the proposal is to scale-up the proposed 3D bioprinted construct to enable whole joint regeneration. Finite element modelling will be used determine the optimal structural characteristics of the scaled-up implant for it to fulfil its required mechanical function. If successful, such an implant would form the basis of a truly transformative therapy for treating degenerative joint disease.

1 999 700 €

Start date: 2015-09-01, End date: 2020-08-31

Over the past decade, redshift surveys and multi-wavelength imaging campaigns have drawn up an empirical picture of how many stars had formed in which types of galaxies over the history of the universe. However, we have yet to unravel the individual pathways along which galaxies evolve, and the physical processes that drive them. Continuing with the previous approach -- larger and deeper photometric samples -- is not adequate to achieve this goal. A change of focus is required. In this ERC project I will embark on a new way to address the question of galaxy evolution. I will do so as Principle Investigator of the recently approved LEGA-C observing program that has been allocated 128 nights of observation time over the next 4 years with ESO's flagship facility the Very Large Telescope. This new survey will produce for 2500 distant (at z~1) galaxies with, for the first time, sufficient resolution and S/N to measure ages and chemical compositions of their stellar populations as well as internal velocity dispersions and dynamical masses. This will provide an entirely new physical description of the galaxy population 7 Gyr ago, with which I will finally be able solve long-standing questions in galaxy formation that were out of reach before: what is the star-formation history of individual galaxies, why and how is star-formation ``quenched'' in many galaxies, and to what extent do galaxies grow subsequently through merging afterward? LEGA-C is worldwide the largest spectroscopic survey of distant galaxies to date, and ERC funding will be absolutely critical in harvesting this unparallelled database. I am seeking to extend my research group to realize the scientific potential of this substantial investment (6.5M Eur) of observational resources by the European astronomy community. Timing of the execution of the VLT program is perfectly matched with the timeline of this ERC program.

1 884 875 €

Start date: 2016-04-01, End date: 2021-03-31

Amyloid-like protein aggregation is a process of protein assembly via the formation of intermolecular β-structures by short aggregation prone sequence regions. This occurs as an unwanted side-reaction of impaired protein folding in disease, but also for the construction of natural nanomaterials. Aggregates appear to be strongly enriched in particular proteins, suggesting that the assembly process itself is specific, but the cross-seeding of the aggregation of one protein by aggregates of another protein has also been reported. The key question that I aim to address in this proposal is how the beta-interactions of the amino acids in the aggregate spine determine the trade-off between the specificity of aggregation versus cross-seeding. To this end, I will determine the energy difference between homotypic versus heterotypic interactions and how differences in sequence translate into energy gaps. Moreover, I will analyse the sequence variations of aggregation prone stretches in natural proteomes to understand the danger of widespread co-aggregation. To achieve these outcomes, I will study the interactions and cross-seeding of aggregating proteins and model peptides in vitro and in cells. I will extract the sequence and structural determinants of co-aggregation, and employ these to construct novel bioinformatics algorithm that can accurately predict co-aggregation and cross-seeding. I will use these to analyse co-aggregation cascades in natural proteomes looking for mechanisms that protect them from wide-spread cross-seeding. This work will have a significant impact on the understanding of the downstream effects of protein aggregates and may reveal co-aggregation networks in human diseases such as the major neurodegenerative diseases or cancer, potentially opening up new research lines on the mechanisms underlying these pathologies and thus identify targets for novel therapies.

1 995 523 €

Start date: 2015-06-01, End date: 2020-05-31

Metastatic growth of cancer cells requires extracellular matrix (ECM) production. The current understanding is that transcription factors regulate ECM production and thus metastatic growth by increasing the expression of collagen prolyl 4-hydroxylase (CP4H). In contrast, we recently discovered that metabolism regulates CP4H activity independently of the known transcription factors. Specifically, we found that loss of pyruvate metabolism inhibits CP4H activity and consequently ECM–dependent breast cancer cell growth. Based on this discovery we propose the novel concept that metabolism regulates metastatic growth by increasing ECM production. In this project we will investigate the following questions: 1) What is the mechanism by which pyruvate regulates CP4H activity in breast cancer cells? To address this question we will investigate pyruvate metabolism and ECM production in 3D cultures of various breast cancer cell lines using 13C tracer analysis, metabolomics, and two-photon microscopy based ECM visualization. 2) How can this novel metabolic regulation be exploited to inhibit breast cancer-derived lung metastases growth? To address this question we will inhibit pyruvate metabolism in metastatic breast cancer mouse models using genetically modified cells and small molecules in combination with immuno- and chemotherapy. 3) How can this novel regulation be translated to different metastatic sites and cancers of different origin? To address this question we will determine the in vivo metabolism of breast cancer-, lung cancer-, and melanoma-derived liver and lung metastases (using metabolomics and 13C tracer analysis), and link it to ECM production (using two-photon microscopy based ECM visualization). With this project we will deliver a novel concept by which metabolism regulates metastatic growth. In a long-term perspective we expect that targeting this novel metabolic regulation will pave the way for an unexplored approach to treat cancer metastases.

2 000 000 €

Start date: 2018-06-01, End date: 2023-05-31

MMS-II pursues the hypothesis that the Mamluk sultanate was a cultural product constructed in the interaction between state formation and historiography. MMS-II follows up from the ERC-project MMS' focus on the social production of power networks in the Syro-Egyptian sultanate between the 1410s and 1460s, but it does so by directing the themes of political history and Arabic historiography towards entirely new, unexplored horizons. Current understanding of the late medieval Middle East continues to rely heavily on the rich Arabic historiographical production of the period. However, the particular nature, impact and value of this highly politicized historiography remains hugely underexplored and underestimated. MMS-II aims to remedy this, by arguing with and beyond instead of against or outside of this historiography’s subjectivities. It wants to understand its texts as products of particular socio-cultural practices and, at the same time, as a particular type of actors in such practices. Analytically, state formation will be prioritised as one extremely relevant patterned set of effects of such practices. Heuristically, the project will focus on practices related to claims of historical truth and order, asking how Arabic historiographical texts written between the 1410s and the 1460s related to the regularly changing social orders that were produced around the different sultans of these decades. My main hypothesis is that of these texts' active participation in the construction of a particular social memory of one longstanding sultanate of military slaves (‘Mamlukisation’). MMS-II has three specific objectives: the creation of a reference tool for Arabic historiographical texts from the period 1410-1470; the in-depth study of particular sets of these texts; the analysis of political vocabularies in these texts. By thus exploring the inter-subjective re/production of Arabic historiography MMS-II will generate a welcome cultural turn in late medieval Islamic history.

2 000 000 €

Start date: 2017-01-01, End date: 2021-12-31

With stellar masses in the range of eight to several hundreds of solar masses, massive stars are among the most important cosmic engines, each individual object strongly impacting its local environment and populations of massive stars driving the evolution of galaxies throughout the history of the universe. Recently, I have shown that stars more massive than 15 Msun rarely, if at all, form and live in isolation but rather as part of a binary or higher-order multiple system. Understanding the life cycle of massive multiple systems, from their birth to their death as supernovae and long-duration gamma ray bursts, is one of the most pressing scientific questions in modern astrophysics. To obtain the key observational breakthroughs needed to revolutionize our understanding of high-mass stars, my research program is developed along three themes: (i) investigate the physical processes that set the multiplicity properties of massive stars, (ii) establish the multiplicity properties of unevolved massive stars across the entire mass range, (iii) identify and uniquely characterize post-interaction products. The implementation of the MULTIPLES program involves ambitious time-resolved observational campaigns targeting large populations of massive stars at key stages of their pre-supernova evolution and in different metallicity environments. These campaigns will combine state-of-the-art spectroscopy and high-angular resolution techniques with novel multiplicity and atmosphere analysis methods appropriate for multiple systems. Upon completion, the observational constraints that will be obtained in this project will have implications that extend well beyond the sole domain of stellar astrophysics.

1 991 243 €

Start date: 2018-10-01, End date: 2023-09-30

NeoplAT offers a fresh and thoroughly documented account of the impact of Pagan Neoplatonism on the Abrahamic traditions. It focuses mainly, but not exclusively, on the Elements of Theology of Proclus (fifth century) which occupies a unique place in the history of thought. Together with its ninth-century Arabic adaptation, the Book of Causes, it has been translated, adapted, refuted and commented upon by Muslim, Jewish and Christian thinkers across centuries, up to the dawn of modernity. Despite a renewed interest in Proclus’ legacy in recent years, one still observes a tendency to repeat conventional hypotheses focused on a limited range of well-studied authors. This project radically challenges these conservative narratives both by analysing invaluable, previously ignored resources and by developing an innovative comparative approach that embraces a variety of research methods and disciplines. Specialists in Arabic, Greek and Latin history of ideas, philology, palaeography and lexicography develop an intense interdisciplinary research laboratory investigating the influence of Proclus on the mutual exchanges between the scriptural monotheisms from the ninth to the sixteenth centuries. Based on fundamental archival examinations in underused library collections, NeoplAT aims (1) to identify new Arabic and Latin manuscripts and to continue to explore a corpus of texts recently discovered by the PI, representing a largely unknown intellectual heritage; (2) to retrace the scholarly networks by which Neoplatonism was transmitted between the Middle East, Byzantium and the Latin West, with particular attention to the dynamics of exchange within each cultural milieu; (3) to analyse the impact of Proclus on the history of metaphysics and on the relations between philosophy and theology within the Abrahamic traditions. NeoplAT achieves these goals through a collaborative, adapted methodology; its specific outputs will provide research tools for the broader academic community.

1 992 590 €

Start date: 2018-05-01, End date: 2023-04-30

This project offers the first comprehensive reconstruction and interpretation of receptions of ancient novels (1st-4th cent. AD) in (Greek, Arabic and western vernacular) secular narrative from Late Antiquity and the early Middle Ages. Novel Echoes follows up from the ERC Starting Grant project Novel Saints (on hagiography). It does so by taking ancient novelistic receptions towards entirely new, unexplored horizons. Our knowledge about the early history of the novel is incomplete. Receptions of ancient novels have been studied for periods from the 11th and 12th cent. onwards but not systematically examined for preceding eras – much to the detriment of the study of both narrative (then and later) and the history of fiction. This project pursues the hypothesis that different secular, narrative traditions in this period were impacted (directly or indirectly) by ancient novelistic influences of different kinds and adopted (and adapted) them to various degrees and purposes; and that, since the ancient novel is a genre defined by its own fictionality, its reception in later narrative impacts notions of truth and authentication in ways that other (often more authoritative) literary models (e.g. Homer and the Bible) do not. Novel Echoes strikes a balance between breath and depth by envisaging three objectives: 1. the creation of a reference tool charting all types of novelistic influence in secular narrative from the 4th to the 12th cent.; 2. the in-depth study of particular sets of texts and the analysis of their implicit conceptualizations of truth, authentication, fiction and narrative; 3. the reconstruction of routes of transmission in both the West and the East. Given the project’s innovative focus, it will enhance our understanding of both the corpus texts and the early history of the novel; place the study of corpus texts on an improved methodological footing; and contribute to the theoretical study of the much-vexed question of how to conceptualize fiction.

1 999 375 €

Start date: 2019-05-01, End date: 2024-04-30

This research explores the impact of property regimes on experiences of citizenship across five democratic countries: Greece, The Netherlands, Spain, the United Kingdom and the United States. Property rights are a foundational element of democracy, but the right to private property exists in tension with values of equality and a right to shelter. An investigation of property is urgent given the recent normalisation of economic models that have resulted in millions of evictions every year. Through an ethnographic study of eviction this research provides a comparative analysis of the benefits and limitations of contemporary property regimes for democratic citizenship. A property regime is defined as the combination of moral discourses about real landed property with the regulatory policies and market mechanisms that shape the use, sale and purchase of property. The selected countries represent a diverse set of property regimes, but all five are experiencing a housing and eviction crisis that has created new geographies of disadvantage, exacerbated inequalities of race, gender, age and income, and led to social unrest. Building on the PI's previous research into citizen-driven democratic innovation, this research critically examines the concept of property through a novel methodology dubbed 'conflictive context construction' that employs a qualitative approach centred on moments of conflict resulting from the use, sale or purchase of specific properties to answer: how do property regimes shape people's experience of citizenship and what can this tell us about the role of property in contemporary models of democratic governance? The high gain of this research lies in the opportunity to rethink the role of property within democracy based on extensive empirical data about how moral assumptions combine with particular ways of regulating and marketing property to exacerbate, alleviate or create inequalities within contemporary experiences of democratic citizenship.

1 970 688 €

Start date: 2018-09-01, End date: 2023-08-31

In PhotonICSWARM, I will use silicon photonics technology to build general-purpose, programmable optical chips that rely on topologies of distributed waveguide circuits governed by distributed control algorithms. In silicon photonics, optical signals are transported along waveguides on photonic integrated circuits and processed by elements that filter specific wavelengths or modulate signals. Silicon photonics is the choice technology for high-speed communication links, but also for different types of sensors. However, photonic circuits are still very simple compared to today's electronics, because they use connectivity topologies where light follows a single path. The optical chip concepts I propose in PhotonICSWARM start from radically different topologies, which will allow 1-2 orders of magnitude scaling in complexity. They are based on tightly interconnected, distributed optical signal paths. This high connectivity will enable much more complex optical functions, and to realise these I will apply adaptive, distributed control algorithms. I will explore different optical waveguide concepts: waveguide meshes, phased arrays, lattices of resonators, lateral leakage and 2-D holographic gratings. These will be fabricated on existing state-of-the-art technology platforms, so PhotonICSWARM will rather revolve around the theory, simulation, design and characterisation methodologies. With these distributed photonic circuits I will create programmable photonics that can be applied for many applications, as the optical equivalent of electronic field-programmable gate arrays (FPGA). They can enable on-chip parallel optical signal processing for pattern recognition or real-time encryption of high-bitrate optical data streams. Programmable circuits can speed up the research cycle, taking much less time to test new photonic chip concepts, and over time make integrated photonics accessible to the 'Maker community'.

1 990 000 €

Start date: 2017-04-01, End date: 2022-03-31

Generalist (polyphagous) herbivores can feed and reproduce on many different plant species and include some of the most pesticide resistant and notorious pests in agriculture. An evolutionary link between host plant range and the development of pesticide resistance has been suggested. Although crucial for devising efficient crop protection strategies, the mechanisms underlying rapid adaptation are not well understood, especially in generalists. The spider mite Tetranychus urticae is a global pest known to feed on 1,100 different hosts from 140 plant families, including most major crops. With experimental advances and new tools developed for T. urticae, we are now poised for fundamental advances in understanding the molecular genetic make-up of adaption in generalist pests. We will generate a large collection of fully inbred and resistant mite strains and describe the sampled genomic variation in the context of selection and adaptation. We will study gene regulation mechanisms and quantify cis versus trans regulation of gene expression on a genome wide scale. We will then create a unique population resource that will allow us to map master regulators of gene expression and construct a gene-regulatory network of adaptation responsive genes. In a highly replicated experimental evolution study, combined with Bulk Segregant Analysis (BSA), we will uncover, without a prior hypothesis, the genomic loci that underlie complex cases of resistance and plant adaptation. A core set of adaptation genes will be validated by functional expression and high-throughput interaction assays. Further validation will come from the development of genome editing tools. In summary, POLYADAPT will exploit the genomic tools now available for spider mites to elucidate regulatory and causal variants underlying the extreme adaptation potential of polyphagous pests. This will in the long term lead to innovative methods of pest management.

1 926 250 €

Start date: 2018-06-01, End date: 2023-05-31

Programmed cell death is essential for homeostasis, and its deregulation contributes to human disease. Inflammasome-induced pyroptosis of infected macrophages contributes to host defense against infections, but the concomitant release of inflammatory danger signals and leaderless cytokines is detrimental in chronic inflammatory diseases. The central hypothesis of the PyroPop ERC Consolidator project is that inflammasomes are cytosolic platforms that couple pathogen sensing to multiple programmed cell death modes. This is based on our preliminary data showing that inflammasomes can be triggered to switch from inflammatory pyroptosis to programmed necrosis and non-inflammatory apoptosis. This suggests that the (patho)physiological outcomes of inflammasome activation may be modulated for therapeutic purposes. However, the molecular machinery and effector mechanisms of pyroptosis, inflammasome-induced apoptosis and programmed necrosis are virtually unknown. My objectives are (i) to explore the cleavage events and subcellular dynamics of pyroptosis by proteomics and high-resolution time-lapse microscopy; (ii) to clarify the molecular mechanisms of pyroptosis and inflammasome-controlled cell death switching; and (iii) to address how inflammasome-associated cell death modes impact on anti-bacterial host defense and chronic inflammatory pathology in vivo through the identification of pyroptosis-selective biomarkers and clinical analysis of pyroptosis-deficient mouse models. The central hypothesis in this regard is that inflammasome-mediated secretion of leaderless cytokines (such as IL-1β and IL-18) and danger signals may be mechanistically coupled to pyroptosis, but not apoptosis induction. By clarifying the mechanisms of inflammasome-controlled programmed cell death, this project may set the path for the development of an entirely novel class of inflammation-modulating therapies that are based on converting inflammatory pyroptosis into non-inflammatory apoptosis.

1 997 915 €

Start date: 2017-01-01, End date: 2021-12-31

REAL opens up new perspectives in moral and political philosophy by closing the rift between analytical theories of rights and egalitarian theories of distributive justice. There is a perception in both the academic and public discourse that pursuing egalitarian economic policies is incompatible with a commitment to rights. Socialist thinkers have traditionally been sceptical of rights, and contemporary egalitarian theories are often silent about them. At the same time, theories that take rights seriously either neglect the distributive dimension or suggest that egalitarian redistribution may infringe on individual rights. Egalitarianism and rights thus appear to be inhospitable to each other. This project seeks first, to understand what explains this divide and second, to demonstrate that it can be bridged. REAL is motivated by the thought that a theory of justice, including economic justice, would be more action-guiding if it could translate its recommendations into moral and subsequently legal rights. It thus aims to show that egalitarianism is not only compatible with a commitment to rights but that they are mutually supportive. The project has three main objectives: - to refute the idea that the concept of rights rules out egalitarian commitments - to uncover the reasons why egalitarianism is inhospitable to rights and show that they are inconclusive - to propose a rights-friendly egalitarian theory of justice The project will critically examine theories of rights and egalitarian theories of justice and adopts an analytical approach that blends arguments from political and legal philosophy, normative ethics and axiology in order to provide a novel and solid framework that integrates the two and advances current debates in these areas.

1 319 355 €

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

"This project will produce a large-scale, quantitative analysis of the ways in which women’s writing was received and circulated in the early modern period. By exploring the phenomenon of early modern literary reception in a rigorous and comprehensive way, the project will allow us to see more clearly the importance and function of reception; specifically how the field of reception articulates and develops critical and aesthetic engagements, how it reveals the extent to which gender shapes ideas about authorship, and how it historicizes our current debates about intellectual impact and gender. Existing reception scholarship has focused on qualitative case studies and tended to prioritize print culture; the field requires a quantitative approach that takes full account of the realities of textual transmission in a period when manuscript circulation retained its broad appeal. RECIRC overcomes the logistical challenges by focusing on the category of the manuscript miscellany and on networks as centres of textual circulation, producing new knowledge about transmission and book ownership. The project will test the hypothesis that the attribution of texts to anonymous, pseudonymous and gender-designated authors is revelatory regarding how gender determined reception. RECIRC’s specific objectives are: to challenge assumptions that women’s penetration of the literary field in this period was limited by focusing on textual reception rather than production; to transform current thinking on the nature of impact and the quality of reception by classifying and analysing the modes of textual engagement in new ways; to provoke a new understanding of the invention of the author in this period by approaching the question via reception, grounding it in a gendered understanding of the complex constructions of authorship that includes the exploitation of anonymity and pseudonymity; and to advance current discourses about scholarly impact by opening up and critiquing their historical contexts."

1 823 928 €

Start date: 2014-07-01, End date: 2019-06-30

Why sexual reproduction is overwhelmingly predominant among the metazoans remains unclear. Ancient asexual taxa are interesting model systems to gain general insights into the adaptive values of sex. The most notorious and the highest taxonomic rank within the metazoans to reproduce asexually is the bdelloid rotifers. While studies suggest that most asexuals arose recently, the published genome of the bdelloid rotifer Adineta vaga provided the first positive evidence for the long-term ameiotic evolution of this group, confirming its ancient asexuality. How bdelloid rotifers have been able to persist despite the expected negative consequences of asexuality is the focus of this ERC proposal. I will study the mechanisms that prevent genome deterioration and promote diversification in the absence of meiotic recombination. I will include sexual rotifer sister clades in the comparison and study all components of the bdelloid lifestyle that may foster their evolution. One of the key components could be their desiccation resistance and the associated DNA double-strand breaks that appear upon prolonged desiccation. To this end, I plan to (i) sequence genomes of sexual rotifers and distinct bdelloid species that diverged a long time ago, including lineages that never experience desiccation; (ii) apply contact genomics, cellular and molecular assays, as well as targeted mutagenesis to uncover their DNA repair mechanisms; (iii) use whole-genome and RAD sequencing to perform a population genomic study of genetic exchanges among bdelloids; and (iv) investigate the function of the meiosis-specific Spo11 gene in bdelloids through targeted mutagenesis and complementation experiments. Using a computational simulation I will generate theoretical predictions on the impact of the mechanisms promoting genome evolution in asexuals. This proposal should revolutionize the field of asexual evolution and provide a new biological model system to study fundamental processes such as DNA repair.

1 908 375 €

Start date: 2017-10-01, End date: 2022-09-30

Neurodegeneration is characterized by misfolded proteins and dysfunctional synapses. Synapses are often located very far away from their cell bodies and they must therefore largely independently cope with the unfolded, dysfunctional proteins that form as a result of synaptic activity and stress. My hypothesis is that synaptic terminals have adopted specific mechanisms to maintain robustness over their long lives and that these may become disrupted in neurodegenerative diseases. Recent evidence indicates an intriguing relationship between several Parkinson disease genes, synaptic vesicle trafficking and autophagy, providing an excellent entry point to study key molecular mechanisms and interactions in synaptic membrane trafficking and synaptic autophagy. We will use novel genome editing methodologies enabling fast in vivo structure-function studies in fruit flies and we will use differentiated human neurons to assess the conservation of mechanisms across evolution. In a complementary approach I also propose to capitalize on innovative in vitro liposome-based proteome-wide screening methods as well as in vivo genetic screens in fruit flies to find novel membrane-associated machines that mediate synaptic autophagy with the ultimate aim to reveal how these mechanisms regulate the maintenance of synaptic health. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic autophagy and function, but it will also reveal mechanisms of synaptic dysfunction in models of neuronal demise and open new research lines on mechanisms of synaptic plasticity.

1 999 025 €

Start date: 2016-01-01, End date: 2020-12-31

With planetary urbanization fast approaching there is growing clarity regarding the unsustainability of cities, not least with respect to food consumption. Sharing, including food sharing, is increasingly being identified as one transformative mechanism for sustainable cities: reducing consumption; conserving resources, preventing waste and providing new forms of socio-economic relations. However, such claims currently rest on thin conceptual and empirical foundations. SHARECITY will identify and examine diverse practices of city-based food sharing economies, first determining their form, function and governance and then identifying their impact and potential to reorient eating practices. The research has four objectives: to advance theoretical understanding of contemporary food sharing economies in cities; to generate a significant body of comparative and novel international empirical knowledge about food sharing economies and their governance within global cities; to design and test an assessment framework for establishing the impact of city-based food sharing economies on societal relations, economic vitality and the environment; and to develop and implement a novel variant of backcasting to explore how food sharing economies within cities might evolve in the future. Providing conceptual insights that bridge sharing, social practice and urban transitions theories, SHARECITY will generate a typology of food sharing economies; a database of food sharing activities in 100 global cities; in-depth food sharing profiles of 7 cities from the contrasting contexts of USA, Brazil and Germany, Greece, Portugal, Ireland and Australia; a sustainability impact toolkit to enable examination of city-based food sharing initiatives; and scenarios for future food sharing in cities. Conducting such frontier science SHARECITY will open new research horizons to substantively improve understanding of how, why and to what end people share food within cities in the 21st Century.

1 860 009 €

Start date: 2015-10-01, End date: 2021-07-31

The SONORA project aims to increase the general understanding of how complex sound scenes are impacted by the spatial dynamics of room acoustics. This knowledge is crucial in the design of signal processing algorithms for audio acquisition and reproduction problems in real-life situations, where moving sound sources and observers interact with room acoustics in a complicated manner. A major part of the project will be devoted to the development of novel room acoustics models and to the unification of existing models. The room acoustics models developed in this project will be data-driven models with a physically motivated structure, and are expected to fill the existing gap between geometric and wave-based models. This will be achieved by formulating existing and novel models in a dictionary-based mathematical framework and introducing a new concept coined as the equivalent boundary model, aimed at relaxing the prior knowledge required on the physical room boundary. A second part of the project will focus on the development of a protocol for measuring spatiotemporal sound fields. This protocol will be rooted in a novel sound field sampling theory which exploits the spatial sparsity of sound sources by invoking the compressed sensing paradigm. Thirdly, novel signal processing algorithms capable of handling spatiotemporal sound fields will be designed. By employing recent advances in large-scale optimization and multidimensional scaling, fast and matrix-free algorithms will be obtained that do not require prior knowledge of the sound scene geometry. The SONORA research results are anticipated to have a notable impact in various audio acquisition and reproduction problems, including acoustic signal enhancement, audio analysis, room inference, virtual acoustics, and spatial audio reproduction. These problems have many applications in speech, audio, and hearing technology, hence a significant benefit for industry and for technology end users is expected in the long run.

1 999 825 €

Start date: 2018-05-01, End date: 2023-04-30

When I am looking at my coffee machine that makes funny noises, this is an instance of multisensory perception – I perceive this event by means of both vision and audition. But very often we only receive sensory stimulation from a multisensory event by means of one sense modality. If I hear the noisy coffee machine in the next room (without seeing it), then how do I represent the visual aspects of this multisensory event? The aim of this research project is to bring together empirical findings about multimodal perception and empirical findings about (visual, auditory, tactile) mental imagery and argue that on occasions like the one described in the last paragraph, we have multimodal mental imagery: perceptual processing in one sense modality (here: vision) that is triggered by sensory stimulation in another sense modality (here: audition). Multimodal mental imagery is rife. The vast majority of what we perceive are multisensory events: events that can be perceived in more than one sense modality – like the noisy coffee machine. And most of the time we are only acquainted with these multisensory events via a subset of the sense modalities involved – all the other aspects of these events are represented by means of multisensory mental imagery. This means that multisensory mental imagery is a crucial element of almost all instances of everyday perception, which has wider implications to philosophy of perception and beyond, to epistemological questions about whether we can trust our senses. Focusing on multimodal mental imagery can help us to understand a number of puzzling perceptual phenomena, like sensory substitution and synaesthesia. Further, manipulating mental imagery has recently become an important clinical procedure in various branches of psychiatry as well as in counteracting implicit bias – using multimodal mental imagery rather than voluntarily and consciously conjured up mental imagery can lead to real progress in these experimental paradigms.

1 966 530 €

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

Cryptographic implementations are traditionally evaluated based on a trade-off between security and efficiency. However, when it comes to physical security against attacks exploiting side-channel leakages or fault insertions, this approach is limited by the difficulty to define the adversaries (e.g. their knowledge about the target implementation) and to specify sound physical assumptions. Quite naturally, the problem becomes even more challenging in contexts where implementations can be maliciously modified during design or fabrication via so-called hardware Trojans. To a large extent, these vulnerabilities echo the general challenge of restoring trust that is faced by cryptographic research in view of the recent Snowden revelations. In this context, we believe that the design of small components able to perform secure computations locally will be an important building block of future information systems. For this purpose, the SWORD project envisions a paradigm shift in embedded security, by adding trust as an essential element in the evaluation of physically secure objects. Our two main ingredients to reach this ambitious goal are a good separation between mathematics and physics, and improved transparency in security evaluations. That is, we want cryptographic implementations to rely on physical assumptions that can be empirically verified, in order to obtain sound security guarantees based on mathematical proofs or arguments. And we want to make the empirical verification of physical assumptions more transparent, by considering open source hardware and software. By allowing adversaries and evaluators to know implementation details, we expect to enable a better understanding of the fundamentals of physical security, therefore leading to improved security, efficiency and trust in the longer term. That is, we hope to establish security guarantees based on a good understanding of the physics, rather than the (relative) misunderstanding caused by closed systems.

1 997 661 €

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

Cells communicate with the outside world through proteins anchored in their plasma membrane and hereto constantly adjust their plasma membrane (PM) proteome. In this adjustment process, removing proteins from the PM mainly occurs through clathrin-mediated endocytosis (CME). Mechanistically however, this process remains poorly understood in plants. A recent study from my group has shown that, in contrast to other model systems, plant CME involves two early endocytic adaptor protein complexes: the evolutionary conserved Adaptor Protein 2 complex (AP-2) and the newly identified TPLATE complex (TPC). In the same study, we also show that both complexes have overlapping but also independent functions in driving CME in plants, implying that plants use additional ways to recognize membrane proteins (cargo) for internalization. In this project I will use an integrative approach to unravel the early steps of CME in plants. Specifically, I will address the following biological questions: - Is the evolutionary retention of the TPC in plants causal to specific cargo recognition? (WP1) - What are the spatio-temporal dynamics of TPC and CME effectors at the plasma membrane? (WP2) - How does acute removal of TPC subunits affect complex recruitment and CME? (WP3) - How is the TPC organized at the structural level? (WP4) - Which interactions occur and can we couple subunit/domain structures to functionality? (WP5) To answer these questions, I will combine state-of-the art proteomics with highly dynamic multi-color live cell imaging and structural biology. The overall objective is to gain a deep mechanistic insight into the developmentally essential process of CME in plants. This will enable me to specifically specifically modulate the abundance of plasma membrane proteins involved in nutrient uptake, toxin avoidance, cell wall formation and hormone and defence responses. Understanding TPC-dependent CME will also provide insight into evolutionary aspects of endocytosis.

1 998 813 €

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

TEXTEVOLVE will study the Targums. Targums are Jewish Aramaic paraphrases of the Hebrew Bible. They are important because they provide a unique insight into what Jews believed God was saying to them through their sacred texts at transformative moments in Jewish history, particularly the aftermath of the First Jewish-Roman War (66–74 CE). The state of the art in the study of the Targums is defined by 1) methodology, and 2) the primary sources that are available. TEXTEVOLVE will go beyond the state of the art in both areas. Methodology — We do not possess the author’s original copy of any Targum. Rather, in most cases we have multiple copies preserved in much later manuscripts, all of which differ one from another. Existing methodology aims to reconstruct the earliest possible form of the text. But changes made by later copyists also yield important insights into evolving Jewish culture, theology, and praxis. Therefore TEXTEVOLVE reframes the dominant research question in the field so that neither the importance of the original wording nor the significance of subsequent changes is neglected. It asks: How did the text of the Targums evolve over time and why? TEXTEVOLVE will develop a new methodology, called Evolutionary Philology, that is capable of addressing this core question. It will use techniques from evolutionary biology that have not previously been applied to texts to achieve this. This will have implications across disciplines that work with historical texts. Primary Sources — To ensure the most robust possible dataset, TEXTEVOLVE will expand the pool of primary sources available for analysis. TEXTEVOLVE will find Targum manuscripts that have been ‘lost’ in un-catalogued or poorly catalogued collections, and will analyse for the first time recently discovered manuscripts from the ‘European Genizah’. Since the available primary sources define the boundaries of any discipline, this is the second major way in which TEXTEVOLVE goes beyond the state of the art.

1 966 259 €

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

Protein synthesis and degradation, energy metabolism, signalling, processing of information-encoding polymers (RNA and DNA) are facilitated and regulated by molecular machines, protein complexes that undergo significant conformational changes in time as they facilitate their function. To be able to control the biological processes rationally and with high precision it is essential to understand their mechanism at atomic level. A powerful way to gain detailed insight onto function of these proteins is to see these molecules at atomic resolution while they function. The high-resolution structures of biological macromolecules obtained by X-ray crystallography, NMR and more recently single particle electron cryogenic microscopy (cryo-EM) have provided insights onto the way many molecular machines are constructed. These methods generally provide snapshots of discrete long-lived states, visualizing the conformational changes along the reaction trajectory at high-resolution often remains an elusive objective. The aim of my proposal is to develop methods for visualizing transient conformations of protein complexes by time-resolved single particle cryo-EM. Time-resolved cryo-EM combines structural study with kinetics by freeze-trapping kinetic intermediates in a biological reaction and has potential to provide atomic-resolution ‘movies’ of functioning biological complexes. Technical limitations however so far restricted widespread use and utilization of the complete potential of this technique. Main part of this project is dedicated to development of microfluidic instruments for cryo-EM sample preparation. If successful, our approaches will allow trapping kinetic intermediates of molecular machines with millisecond time-resolution using picogram amounts of protein sample. The developed method will be applied to resolve key functional conformations of respiratory complex I and observe regulatory trajectories of ligand-gated ion channels.

1 777 157 €

Start date: 2017-06-01, End date: 2022-05-31

The RAS pathway is the most frequently activated signaling node in human disease. Despite intensive efforts, effective therapeutic strategies for RAS-driven disease remain daunting. Elucidation of the mechanisms of RAS activation promises to lead toward novel therapeutic approaches to inhibit RAS activity, and may permit identification of patients who might benefit from RAS pathway inhibitors. Our preliminary studies show that reversible ubiquitylation controls RAS activity by altering its interaction network, thus representing a conceptually novel mechanism of RAS regulation. Our initial steps towards the understanding of the RAS ubiquitylation machinery have shown that positive regulators of RAS ubiquitylation are frequently mutated or down-regulated in RAS-driven diseases, whereas negative regulators are commonly up-regulated. These striking initial results suggest that dysregulation of RAS ubiquitylation may be an alternative mechanism that drives RAS activation in human disease. Here, we aim to elucidate the role of the ubiquitin system in RAS-driven disease. We will unravel the molecular machinery controlling RAS ubiquitylation and ascertain alterations of the identified machinery in RAS-driven disease. To assess the functional impact of these alterations, we will create genetically modified mouse models and CRISPR-engineered human cell models. We will employ cutting-edge proteomic approaches to determine how disease-associated dysregulation of RAS ubiquitylation perturbs RAS interactions and signalling. Using a synthetic biologic approach, we will obtain insights into mechanisms by which ubiquitylation modulates RAS interactions. It is significant that, in contrast to the majority of known RAS regulators, the ubiquitin enzymes are “druggable”, which implicates them as promising targets for inhibiting RAS activity. Thus, our studies could lead to new ways of defeating RAS-driven disease.

1 999 796 €

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

Can fear memories be erased from the brain? While it sounds like science fiction, recent findings suggest that fear memories can be undone upon their retrieval, through either pharmacological or behavioural interventions. Still, whether such reconsolidation interference techniques genuinely result in permanent erasure of the original fear memory is a topic of considerable controversy. Purely behavioural work may never settle the debate, as it cannot be excluded that an apparent loss of fear memory reflects a long-lasting failure to retrieve the fear memory rather than its permanent erasure. We argue that a careful look at the brain memory circuits that control the reduced expression of fear after reconsolidation interference, through imaging studies in humans and inactivation studies in rats, does have the potential to resolve the controversy and decide between erasure and retrieval failure as mechanisms underlying reconsolidation interference [WP1]. To open up a memory trace for reconsolidation interference, it is important that retrieval of the memory is accompanied by surprise or prediction error (PE; a discrepancy between the memory and what actually happens), as we demonstrated in a break-through study in Science (Sevenster, Beckers, & Kindt, 2013). Here, we propose that subtle differences in the degree of PE generated during fear memory retrieval may be what demarcates memory erasure from impaired retrieval. To investigate that claim, we will pioneer an objective neural marker of PE in humans [WP2] and use optogenetics to directly trigger dopamine-based PE signals in the rat brain in order to establish the causal role of PE in enabling fear memory erasure. Along the way, we will investigate the generalization of fear to novel cues as both a problem and a potential target for fear memory modification [WP3] and test an innovative method to interfere with reconsolidation that circumvents limitations of current pharmacological and behavioural techniques [WP4].

2 000 000 €

Start date: 2015-09-01, End date: 2020-08-31