ERC FUNDED PROJECTS

Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed. An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue. The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.

1 499 975 €

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

The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.

1 225 000 €

Start date: 2008-09-01, End date: 2013-08-31

Antibiotics have contributed to a tremendous increase in human well-being, saving many millions of lives. However, antibiotics become obsolete the more they are used as selection pressure promotes the development of resistant bacteria. The World Health Organization has proclaimed antibiotic resistance as a major global threat to public health. Today, 700,000 deaths per year are due to untreatable infections. To win the battle against antibiotic resistance, new policies affecting the supply and demand of existing and new drugs must be designed. I propose new research to identify and evaluate feasible and effective demand-side policy interventions targeting the relevant decision makers: physicians and patients. ABRSEIST will make use of a broad econometric toolset to identify mechanisms linking antibiotic resistance and consumption exploiting a unique combination of physician-patient-level antibiotic resistance, treatment, and socio-economic data. Using machine learning methods adapted for causal inference, theory-driven structural econometric analysis, and randomization in the field it will provide rigorous evidence on effective intervention designs. This research will improve our understanding of how prescribing, resistance, and the effect of antibiotic use on resistance, are distributed in the general population which has important implications for the design of targeted interventions. It will then estimate a structural model of general practitioners’ acquisition and use of information under uncertainty about resistance in prescription choice, allowing counterfactual analysis of information-improving policies such as mandatory diagnostic testing. The large-scale and structural econometric analyses allow flexible identification of physician heterogeneity, which ABRSEIST will exploit to design and evaluate targeted, randomized information nudges in the field. The result will be improved rational use and a toolset applicable in contexts of antibiotic prescribing.

1 498 920 €

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

Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and metabolites that influence WAT inflammation are entirely unknown. We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity. Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may generate a platform for microbiome-based personalized therapy against obesity and its complications.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29

A half century since it came into existence, the discipline of Film and Screen Studies remains mostly Eurocentric in its historical, theoretical and critical frameworks. Although “world cinema” and “transnational cinema” scholars have attempted to broaden its canon and frameworks, several major problems persist. Films and scholarship by Africans in particular, and by people of colour in general, are frequently marginalised if not altogether excluded. This prevents exciting exchanges that could help to re-envision Film and Screen Studies for the twenty-first century, in an era in which greater access to the technological means of making films, and circulating them on a range of screens, means that dynamic “screen worlds” are developing at a rapid rate. AFRISCREENWORLDS will study these “screen worlds” (in both their textual forms and industrial structures), with a focus on Africa, as a way of centring the most marginalised regional cinema. We will also elaborate comparative studies of global “screen worlds” – and, in particular, “screen worlds” in the Global South – exploring their similarities, differences, and parallel developments. We will respond to the exclusions of Film and Screen Studies not only in scholarly ways – through conferences and publications – but also in creative and activist ways – through drawing on cutting-edge creative research methodologies (such as audiovisual criticism and filmmaking) and through helping to decolonise Film and Screen Studies (through the production of ‘toolkits’ on how to make curricula, syllabi, and teaching more globally representative and inclusive). On a theoretical level, we will make an intervention through considering how the concept of “screen worlds” is better equipped than “world cinema” or “transnational cinema” to explore the complexities of audiovisual narratives, and their production and circulation in our contemporary moment, in diverse contexts throughout the globe.

1 985 578 €

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

This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.

1 195 385 €

Start date: 2008-05-01, End date: 2013-10-31

"Recent developments in image-making techniques have resulted in a drastic blurring of the threshold between the world of the image and the real world. Immersive and interactive virtual environments have enabled the production of pictures that elicit in the perceiver a strong feeling of being incorporated in a quasi-real world. In doing so such pictures conceal their mediateness (their being based on a material support), their referentiality (their pointing to an extra-iconic dimension), and their separateness (normally assured by framing devices), paradoxically challenging their status as images, as icons: they are veritable “an-icons”. This kind of pictures undermines the mainstream paradigm of Western image theories, shared by major models such as the doctrine of mimesis, the phenomenological account of image-consciousness, the analytic theories of depiction, the semiotic and iconological methods. These approaches miss the key counter-properties regarding an-icons as ""environmental"" images: their immediateness, unframedness, and presentness. Subjects relating to an-icons are no longer visual observers of images; they are experiencers living in a quasi-real environment that allows multisensory affordances and embodied agencies. AN-ICON aims to develop “an-iconology” as a new methodological approach able to address this challenging iconoscape. Such an approach needs to be articulated in a transdisciplinary and transmedial way: 1) HISTORY – a media-archaeological reconstruction will provide a taxonomy of the manifold an-iconic strategies (e.g. illusionistic painting, pre-cinematic dispositifs, 3D films, video games, head mounted displays); 2) THEORY – an experiential account (drawing on phenomenology, visual culture and media studies) will identify the an-iconic key concepts; 3) PRACTICES – a socio-cultural section will explore the multifaceted impact of an-iconic images, environments and technologies on contemporary professional domains as well as on everyday life. "

2 328 736 €

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

AncientAdhesives addresses the most crucial problem in Palaeolithic archaeology: How to reliably infer cognitively complex behaviour in the deep past. To study the evolution of Neandertal and modern human cognitive capacities, certain find categories are taken to reflect behavioural and thus cognitive complexitye.g. Among these are art objects, personal ornaments and complex technology. Of these technology is best-suited to trace changing behavioural complexity, because 1) it is the least vulnerable to differential preservation, and 2) technological behaviours are present throughout the history of our genus. Adhesives are the oldest examples of highly complex technology. They are also known earlier from Neandertal than from modern human contexts. Understanding their technological complexity is thus essential to resolve debates on differences in cognitive complexity of both species. However, currently, there is no agreed-upon method to measure technological complexity. The aim of AncientAdhesives is to create the first reliable method to compare the complexity of Neandertal and modern human technologies. This is achieved through three main objectives: 1. Collate the first comprehensive body of knowledge on adhesives, including ethnography, archaeology and (experimental) material properties (e.g. preservation, production). 2. Develop a new archaeological methodology by modifying industrial process modelling for archaeological applications. 3. Evaluate the development of adhesive technological complexity through time and across species using a range of explicit complexity measures. By analysing adhesives, it is possible to measure technological complexity, to identify idiosyncratic behaviours and to track adoption and loss of complex technological know-how. This represents a step-change in debates about the development of behavioural complexity and differences/similarities between Neanderthals and modern humans.

1 499 926 €

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

Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?

1 500 000 €

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

One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.

500 000 €

Start date: 2008-09-01, End date: 2011-08-31

Arboviruses infect millions of people each year, however, mechanisms that drive viral emergence and maintenance remain largely unknown. A combination of host factors (e.g., human mobility), mosquito factors (e.g., abundance) and viral factors (e.g., transmissibility) interconnect to drive spread. Further, for endemic arboviruses, complex patterns of population immunity, built up over many years, appear key to the emergence of particular lineages. To disentangle the contribution of these different drivers, we need detailed data from the same pathogen system over a long time period from the same location. In addition, we need new methods, which can integrate these different data sources and allow appropriate mechanistic inferences. In this project, I will use the most globally prevalent arbovirus, dengue virus, as a case study. I will focus on Thailand where all four dengue serotypes have circulated endemically for decades and excellent long-term data and isolates exist, to address two fundamental questions: i) How do population-level patterns of immunity evolve over time and what is their impact on strain dynamics? I will use mechanistic models applied to historic serotype-specific case data to reconstruct the evolving immune profile of the population and explore the impact of immunity on viral diversity using sequences from archived isolates from each year over a 50-year period. ii) How do human behaviors, vector densities interact with immunity to dictate spread? I will work with geolocated full genome sequences from across Thailand and use detailed data on how people move, their contact patterns, their immunity profiles and mosquito distributions to study competing hypotheses of how arboviruses spread. I will compare the key drivers of dengue spread with that found for outbreaks of Zika and chikungunya. This proposal addresses fundamental questions about the mechanisms that drive arboviral emergence and spread that will be relevant across disease systems.

1 499 896 €

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

This project leads to one of the most dynamic regions in prehistory: the Caucasus of the 4th and early 3rd mill. BC. During this vibrant time, basic innovations emerged, which were crucial until the 19th century: wheel and wagon, copper alloys, the potter’s wheel, new breeds of woolly sheep, domestication of the horse, and others. At the same time, massive migrations from the East European steppe during the early 3rd mill. BC changed the European gene pool. The project challenges the still predominant narrative that all technical achievements stemmed from urban centres in Mesopotamia. New studies have created space for alternative hypotheses: possibly it was not the development of new techniques, but instead their adaptation from different ‘peripheries’ and their re-combination and re-configuration that formed the basis for the success of these ‘civilisations’. The Caucasus, linking Mesopotamia to the Eurasia and Europe, is for the first time in the focus of a study on innovation transfer. The study will make a major contribution by investigation of four axial innovations: wheel and wagon, metal alloys, silver metallurgy and woolly sheep. 40 wheels will be analysed by computer tomography and strontium isotopes. Some 300 copper alloys artefacts and 200 silver objects will be examined using mass spectrometry with laser ablation. 400 aDNA genom-wide analyses of humans from burials in the North Caucasus will offer the unique chance of elucidating the role of migrations for the spread of innovations. The pottery in the region, often linked to Mesopotamia, will be studied under technical aspects and is a complementary path to shed light on migration and the transfer of knowledge. Excavations in settlements will allow building up a chronology using 400 AMS 14C analyses. The project is multidisciplinary, making use of the most up-to-date analytical methods. Our long experience and reputation on both sides of the Caucasus is the ideal background for cutting-edge research.

2 487 875 €

Start date: 2019-07-01, End date: 2024-06-30

Our project proposes a fragmentary account of the art histories produced in present-day Poland, Hungary, Slovakia, Romania, Bulgaria and Serbia between 1850 and 1950, from an entangled histories perspective. We will look at the relationships between the art histories produced in these countries and the art histories produced in Western Europe. But, more importantly, we will investigate how the art histories written in the countries mentioned above resonate with each other, either proposing conflicting interpretations of the past, or ignoring uncomfortable competing discourses. We will investigate the art histories written between 1850 and 1950 because we are interested in how art history contributed to nation building discourses. Therefore, we will focus on those art histories that concur to nationalising the past. Our project is articulated around three crucial concepts – periodisation, style and influence – set in the context of relevant contemporary historiographies produced in Western Europe, and analysing the entanglements with competing historiographies in each of the countries considered. We will focus on two main issues: 1. How did Central and Eastern European art historians adopt, adapt and respond to theoretical and methodological issues developed elsewhere, and 2. What are the periodisations of art produced on the territory of Central and Eastern European countries; what are the theoretical and methodological strategies for conceptualising local styles; and how was the concept of influence used in establishing hierarchical relationships. Researching the conceptualisation of a theoretical framework that would accommodate the artistic production of the past will show the difficulties in dealing with a complex reality without simplifying and essentializing it along ideological lines. The research will also show that the three concepts that we focus on are not neutral or strictly descriptive, and that their use in art history needs to be reconsidered.

1 192 250 €

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

Spider silk is Nature’s high performance material that has the potential to revolutionize the materials industry. However, production and spinning of artificial spider silk fibers are challenging, and current methods to produce silk fibers include denaturing conditions which prevent the silk proteins from assembling into fibers in the same complex way as native silk proteins do. In order to fulfill the potential of spider silk we need to increase our understanding of the silk formation process and decipher how protein folding and interactions relate to mechanical properties of the resulting silk fiber. Recent insights into the physiology and molecular mechanisms of the spinning process has made it possible to develop a biomimetic artificial spider silk spinning device (see our publications Andersson et al. Nat Chem Biol. 2017; Otikovs et al. Angew Chemie Int Engl Ed. 2017). We are, for the first time, able to spin artificial silk fibers in which the proteins adopt correct secondary, tertiary and quaternary structures. The overall objective of ARTSILK is to build on these recent technical leaps and use state-of-the-art technologies to generate artificial silk fibers that are equal or superior to native spider silk in terms of toughness and tensile strength. To reach the overall objective we will use the recently mapped spider genome, protein engineering and single cell RNA (ScRNA) sequencing to design novel silk proteins for fiber production. We will also study the relationship between protein secondary structure formation and fiber mechanical properties in order to decipher the ques that determine mechanical properties of the fiber. This knowledge will be important also for the basic understanding of how soluble proteins covert into b-sheet rich fibrils in, e.g., Alzheimer’s disease. Finally, we will use microfluidic chips to engineer the next generation spinning device and 3D-printing techniques to make reproducible three-dimensional structures of spider silk.

2 000 000 €

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

Since the invention of the spinning frame, automation has been one of the drivers of economic growth. Yet, workers, economist or the general public have been concerned that automation may destroy jobs or create inequality. This concern is particularly prevalent today with the sustained rise in economic inequality and fast technological progress in IT, robotics or self-driving cars. The empirical literature has showed the impact of automation on income distribution. Yet, the level of wages itself should also affect the incentives to undertake automation innovations. Understanding this feedback is key to assess the long-term effect of policies. My project aims to provide the first quantitative account of the two-way relationship between automation and the income distribution. It is articulated around three parts. First, I will use patent data to study empirically the causal effect of wages on automation innovations. To do so, I will build firm-level variation in the wages of the customers of innovating firms by exploiting variations in firms’ exposure to international markets. Second, I will study empirically the causal effect of automation innovations on wages. There, I will focus on local labour market and use the patent data to build exogenous variations in local knowledge. Third, I will calibrate an endogenous growth model with firm dynamics and automation using Danish firm-level data. The model will replicate stylized facts on the labour share distribution across firms. It will be used to compute the contribution of automation to economic growth or the decline of the labour share. Moreover, as a whole, the project will use two different methods (regression analysis and calibrated model) and two different types of data, to answer questions of crucial policy importance such as: Taking into account the response of automation, what are the long-term effects on wages of an increase in the minimum wage, a reduction in labour costs, or a robot tax?

1 295 890 €

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

Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics. Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo. We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus. Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.

1 475 475 €

Start date: 2018-12-01, End date: 2023-11-30

When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.

1 630 000 €

Start date: 2008-10-01, End date: 2013-09-30

Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.

1 499 869 €

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

Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes. The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD. In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery. I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.

1 499 354 €

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

As an onco-hematologist with a strong expertise in genomics, I significantly contributed to the understanding of multiple myeloma (MM) heterogeneity and its evolution over time, driven by genotypic and phenotypic features carried by different subpopulations of cells. MM is preceded by prevalent, asymptomatic stages that may evolve with variable frequency, not accurately captured by current clinical prognostic scores. Supported by preliminary data, my hypothesis is that the same heterogeneity is present early on the disease course, and identification of the biological determinants of evolution at this stage will allow better prediction of its evolutionary trajectory, if not its control. In this proposal I will therefore make a sharp change from conventional approaches and move to early stages of MM using unique retrospective sample cohorts and ambitious prospective sampling. To identify clonal MM cells in the elderly before a monoclonal gammopathy can be detected, I will collect bone marrow (BM) from hundreds of hip replacement specimens, and analyze archive peripheral blood samples of thousands of healthy individuals with years of annotated clinical follow-up. This will identify early genomic alterations that are permissive to disease initiation/evolution and may serve as biomarkers for clinical screening. Through innovative, integrated single-cell genotyping and phenotyping of hundreds of asymptomatic MMs, I will functionally dissect heterogeneity and characterize the BM microenvironment to look for determinants of disease progression. Correlation with clinical outcome and mini-invasive serial sampling of circulating cell-free DNA will identify candidate biological markers to better predict evolution. Last, aggressive modelling of candidate early lesions and modifier screens will offer a list of vulnerabilities that could be exploited for rationale therapies. These methodologies will deliver a paradigm for the use of molecularly-driven precision medicine in cancer.

1 998 781 €

Start date: 2019-03-01, End date: 2024-02-29

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

Uncertainty is everywhere, as the saying goes, but rarely considered in ethical reflections. This project aims to reinterpret ethical discussions on current advances in biomedicine: instead of understanding bioethical positions as extensions of classical normative views in ethics (consequentialism, deontologism, contractualism etc.), my project interprets them more accurately as involving various normative approaches to decision making under uncertainty. The following hard cases in bioethics provide the motivation for research: 1) Regulating scientific research under uncertainty about the ontological/moral status (e.g. parthenogenetic stem cells derived from human parthenotes) in the context of meta-reasoning under normative uncertainty. 2) The value of preventive medicine in healthcare (e.g. vaccinations) in the context of decision-making under metaphysical indeterminacy. 3) Population or reproductive decisions (e.g. preimplantation genetic diagnosis) in the context of valuing mere existence. The main drive behind this project is the rapid progress in biomedical research combined with new kinds of uncertainties. These new and “deep” uncertainties trigger specific forms of emotions and cognitions that influence normative judgments and decisions. The main research questions that will be addressed by conceptual analysis, new psychological experiments, and case studies are the following: how do the heuristics and biases (H&B) documented by behavioral scientists influence the formation of normative judgments in bioethical contexts; how to demarcate between distorted and undistorted value judgments; to what extent is it permissible for individuals or policy makers to yield to H&B. The hypothesis is that many existing bioethical rules, regulations, practices seem to have emerged from unreliable reactions, rather than by means of deliberation on the possible justifications for alternative ways to decide about them under several layers and types of uncertainty.

1 499 625 €

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

How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

909 850 €

Start date: 2008-12-01, End date: 2013-11-30

Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies). The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo. The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.

1 999 875 €

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