ERC FUNDED PROJECTS

What does the fossil record tell us about the evolution of colour in animals through deep time? Evidence of colour in fossils can inform on the visual signalling strategies used by ancient animals. Research to date often has a narrow focus, lacks a broad phylogenetic and temporal context, and rarely incorporates information on taphonomy. This proposal represents a bold new holistic approach to the study of fossil colour: it will couple powerful imaging- and chemical analytical techniques with a rigorous programme of fossilisation experiments simulating decay, burial, and transport, and analysis of fossils and their sedimentary context, to construct the first robust models for the evolution of colour in animals through deep time. The research will resolve the original integumentary colours of fossil higher vertebrates, and the original colours of fossil hair; the fossil record of non-melanin pigments in feathers and insects; the biological significance of monotonal patterning in fossil insects; and the evolutionary history of scales and 3D photonic crystals in insects. Critically, the research will test, for the first time, whether evidence of fossil colour can solve broader evolutionary questions, e.g. the true affinities of enigmatic Cambrian chordate-like metazoans, and feather-like integumentary filaments in dinosaurs. The proposal entails construction of a dedicated experimental maturation laboratory for simulating the impact of burial on tissues. This laboratory will form the core of the world’s first integrated ‘experimental fossilisation facility’, consolidating the PI’s team as the global hub for fossil colour research. The research team comprises the PI, three postdoctoral researchers, and three PhD students, and will form an extensive research network via collaborations with 13 researchers from Europe and beyond. The project will reach out to diverse scientists and will inspire a positive attitude to science among the general public and policymakers alike.

1 562 000 €

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

Over the next 35 years, antibiotic resistant bacteria are expected to kill more than 300 million people. The need to find alternative strategies for antimicrobial therapies remains a global challenge with several bottlenecks in the antibiotic discovery process. Using Staphylococcus aureus, the most common multidrug-resistant bacterium in the European Union and an excellent model organism for cell division in cocci, we propose: (i) to find new pathways to re-sensitize resistant bacteria. Bacteria undergo major morphology changes during the cell cycle. We hypothesize that these changes generate windows of opportunity during which bacteria are more susceptible or more tolerant to the action of antibiotics. We will identify key regulators of the cell cycle in order to manipulate the duration of windows of opportunity for the action of existing antibiotics. (ii) to develop new fluorescence-based reporters for whole-cell screenings of antimicrobial compounds with new modes of action, including compounds that arrest or delay the cell cycle; compounds that target non-essential pathways that are required for expression of resistance against existing antibiotics and therefore can be used as synergistic drugs for combination therapies; compounds that inhibit the production of virulence factors and compounds that revert persister states that are phenotypically resistant to antibiotics. (iii) to unravel new modes of action of antibiotics by using the constructed reporter strains as powerful tools to learn how antibiotics act at the single cell level. Over the past years, my group has become expert on the biology of S. aureus, has constructed powerful biological tools to study cell division and synthesis of the cell surface and has studied mechanisms of action of various antimicrobial compounds. We are therefore in a privileged position to quickly unravel the function of new players in the bacterial cell cycle and simultaneously contribute to accelerate antibiotic discovery.

2 533 500 €

Start date: 2018-03-01, End date: 2023-02-28

Interspecific competition is arguably the best interaction to address how individual trait variation and eco-evolutionary feedbacks shape species distributions and trait evolution, due to its indirect effects via the shared resource. However, a clear understanding of such feedbacks is only possible if each contributing factor can be manipulated independently. With COMPCON, we will address how individual variation, niche width, niche construction and the presence of competitors shape species distributions and trait evolution, using a system amenable to manipulation of all these variables. The system is composed of two spider mite species, Tetranychus urticae and T. ludeni, that up- and down-regulate plant defences (i.e., negative and positive niche construction, respectively). Tomato mutant plants with low defences will be used as an environment in which niche construction is not expressed. Furthermore, tomato plants will be grown under different cadmium concentrations, allowing quantitative variation of available niches. Using isogenic lines, we will measure individual variation in niche width, niche construction and competitive ability. Different combinations of lines will then be used to test key predictions of recent theory on how such variation affects coexistence with competitors. Subsequently, mite populations will evolve in environments with either one or more potential niches, in plants where niche construction is possible or not, and in presence or absence of competitors (coevolving or not). We will test how these selection pressures affect niche width, niche construction and competitive ability, as well as plant damage. Finally, we will re-derive isogenic lines from these treatments, to test how evolution under different scenarios affects individual variation in niche width. COMPCON will shed new light on the role of competition in shaping eco-evolutionary communities, with bearings on disciplines ranging from macro-ecology to evolutionary genetics

1 999 275 €

Start date: 2017-05-01, End date: 2022-04-30

A new immunoregulatory axis has emerged in recent years demonstrating that cellular metabolism is crucial in controlling immune responses. This regulatory axis is acutely sensitive to nutrients that fuel metabolic pathways and support nutrient sensitive signalling pathways. My recent research demonstrates that nutrients are dynamically controlled and are not equally available to all immune cells. The data shows that activated T cells, clustered around a dendritic cell (DC), can consume the available nutrients, leaving the DC nutrient deprived in vitro. This local regulation of the DC nutrient microenvironment by neighbouring cells has profound effects on DC function and T cell responses. Nutrient deprived DC have altered signalling (decreased mTORC1 activity), increased pro-inflammatory functions (IL12 and costimulatory molecule expression) and induce enhanced T cell responses (proliferation, IFNγ production). However, proving this, particularly in vivo, is a major challenge as the tools to investigate nutrient dynamics within complex microenvironments have not yet been developed. This research programme will generate innovative new technologies to measure the local distribution of glucose, glutamine and leucine (all of which control mTORC1 signalling) to be visualised and quantified. These technologies will pioneer a new era of in vivo nutrient analysis. Nutrient deprivation of antigen presenting DC will then be investigated (using our new technologies) in response to various stimuli within the inflammatory lymph node and correlated to CD8 T cell responses. We will generate state-of-the-art transgenic mice to specifically knock-down nutrient transporters for glucose, glutamine, or leucine in DC to definitively prove that the availability of these nutrients to antigen presenting DC is a key mechanism for controlling CD8 T cells responses. This would be a paradigm shifting discovery that would open new horizons for the study of nutrient-regulated immune responses.

1 995 861 €

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

Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity. In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci. Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease. This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.

1 358 534 €

Start date: 2013-01-01, End date: 2018-12-31

All natural populations are constantly subject to new mutations, and frequently face new environments, to which they adapt. Knowledge of the genetics of adaptation should provide the centerpiece of a unified theory of evolution. Despite its extreme importance, the process of adaptation is far from being understood. How does the shape of distribution of fitness effects of mutations depend on the environment? What is the importance of epistasis in adaptive evolution? are still open questions. While empirical observations on advantageous mutations are extremely difficult, recent technical advances allow us to start tackling these questions with an unprecedented accuracy. Here we will combine different methods in a novel powerful marker system to track adaptive mutations as they become incorporated into bacterial populations adapting to different environments and as they fix. Interestingly theory suggest that some generalities may underlie the process of adaptation and that ecology may be important in the dynamics and statistical laws of adaptation. Experimental evolution with bacteria presents us with the opportunity to directly measure key parameters and to test theoretical predictions about the genetic basis of adaptive evolution in increasingly complex ecosystems. As Dobzansky pointed out The greater the diversity of inhabitants in a territory, the more adaptive opportunities exist in it. The main goal of this research project is to measure rates and effects of adaptive mutations, as well as patterns of epistasis amongst beneficial mutations in environments with different strengths of abiotic versus biotic interactions.

1 167 600 €

Start date: 2010-12-01, End date: 2015-11-30

Obesity has reached epidemic proportions globally. At least 2.8 million people die each year as a result of being overweight or obese, the biggest burden being obesity-related diseases. It is now clear that inflammation is an underlying cause or contributor to many of these diseases, including type 2 diabetes, atherosclerosis, and cancer. Recognition that the immune system can regulate metabolic pathways has prompted a new way of thinking about diabetes and weight management. Despite much recent progress, most immunometabolic pathways, and how to target them, are currently unknown. One such pathway is the cross-talk between invariant natural killer (iNKT) cells and neighboring adipocytes. iNKT cells are the innate lipid-sensing arm of the immune system. Since our discovery that mammalian adipose tissue is enriched for iNKT cells, we have identified a critical role for iNKT cells in regulating adipose inflammation and body weight. The goal of this project is to use a multi-disciplinary approach to identify key signals and molecules used by iNKT cells to induce metabolic control and weight loss in obesity. Using immunological assays and multi-photon intravital microscopy, cells and pathways that control the unique regulatory functions of adipose iNKT cells will be identified and characterised. Novel lipid antigens in adipose tissue will be identified using a biochemical approach, perhaps explaining iNKT cell conservation in adipose depots, and providing safe tools for iNKT cell manipulation in vivo. Finally, using proteomics and whole body metabolic analysis in vivo, novel ‘weight-loss inducing’ factors produced by adipose iNKT cells will be identified. This ambitious and high impact project has the potential to yield major insights into immunometabolic interactions at steady state and in obesity. The ability to activate or induce adipose iNKT cells holds remarkable potential as an entirely new therapeutic direction for treating obesity and type 2 diabetes.

1 804 052 €

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

A major challenge in evolutionary biology is to quantify the processes and mechanisms by which populations adapt to new environments. In particular, the role of epistasis, which is the genetic-background dependent effect of mutations, and the constraints it imposes on adaptation, has been contentious for decades. This question can be approached using the concept of a fitness landscape: a map of genotypes or phenotypes to fitness, which dictates the dynamics and the possible paths towards increased reproductive success. This analogy has inspired a large body of theoretical work, in which various models of fitness landscapes have been proposed and analysed. Only recently, novel experimental approaches and advances in sequencing technologies have provided us with large empirical fitness landscapes at impressive resolution, which call for the evaluation of the related theory. The aim of this proposal is to build on the theory of fitness landscapes to quantify epistasis across levels of biological organization and across environments, and to study its impact on the population genetics of adaptation and hybridization. Each work package involves classical theoretical modelling, statistical inference and method development, and data analysis and interpretation; a combination of approaches for which my research group has strong expertise. In addition, we will perform experimental evolution in Escherichia coli and influenza to test hypotheses related to the change of fitness effects across environments, and to adaptation by means of highly epistatic mutations. We will specifically apply our methods to evaluate the potential for predicting routes to drug resistance in pathogens. The long-term goal lies in the development of a modeling and inference framework that utilizes fitness landscape theory to infer the ecological history of a genome, which may ultimately allow for a prediction of its future adaptive potential.

1 366 250 €

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

Acute Respiratory Distress Syndrome and Acute Lung Injury [ALI/ARDS] are devastating diseases, causing over 20,000 deaths annually in the US. Mechanical ventilation may worsen ALI/ARDS, a process termed Ventilator Induced Lung Injury [VILI]. Hypercapnic acidosis (HA) is a central component of lung ventilatory strategies to minimize VILI, and is a potent biologic agent, exerting a myriad of effects on diverse biologic pathways. Deliberately induced HA is protective in multiple lung injury models. However, HA may inhibit the host response to bacterial sepsis. Furthermore, HA may retard the repair process and slow recovery following ALI/ARDS. Hence, the diverse biologic actions of HA may result in net beneficial – or deleterious – effects depending on the specific context. An alternative approach is to manipulate a single key effector pathway, central to the protective effects of HA, which would also be effective in patients in whom hypercapnia is contra-indicated. Hypercapnia attenuates NF-kB activation, and may exert its effects – both beneficial and deleterious – via this mechanism. NF-kB is a pivotal regulator of the pro-inflammatory response, but is also a key epithelial cytoprotectant. Selective modulation of the NF-kB pathway, at the pulmonary epithelial surface, may accentuate the beneficial effects of HA on injury but minimize the potential for delayed tissue repair. We will investigate the contribution of NF-kB to the effects of HA, and characterize the direct effects modulation of NF-kB, in both in vitro and preclinical models of lung injury and repair. We will utilize pulmonary gene therapy, which facilitates delivery of high quantities of the therapeutic agent directly to the injury site, to maximize the potential for therapeutic benefit. These studies will provide novel insights into: key pathways contributing to lung injury and to repair; the role of HA and NF-kB in these processes; and the potential of pulmonary gene therapy in ALI/ARDS.

1 052 556 €

Start date: 2009-01-01, End date: 2013-12-31