ERC FUNDED PROJECTS

"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."

1 499 768 €

Start date: 2013-01-01, End date: 2017-12-31

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

The dielectric properties of biological tissues are of fundamental importance to the understanding of the interaction of electromagnetic fields with the human body. These properties are used to determine the safety of electronic devices, and in the design, development and refinement of electromagnetic medical imaging and therapeutic devices. Many historical studies have aimed to establish the dielectric properties of a broad range of tissues. A growing number of recent studies have sought to more accurately estimate these dielectric properties by standardising measurement procedures, and in some cases, measuring the dielectric properties in-vivo. However, these studies have often produced results in direct conflict with historical studies, casting doubt on the accuracy of the currently utilised dielectric properties. At best, this uncertainty could significantly delay the development of electromagnetic imaging or therapeutic medical devices. At worst, the health dangers of electromagnetic radiation could be under-estimated. The applicant will embark upon frontier research to develop improved methods and standards for the measurement of the dielectric properties of biological tissue. The research programme will accelerate the design and development of electromagnetic imaging and therapeutic devices, at a time when the technology is gaining significant momentum. The primary objective of the research is to develop a deep understanding of the fundamental factors which contribute to errors in dielectric property measurement. These factors will include in-vivo/ex-vivo measurements and dielectric measurement method used, amongst many others. Secondly, a new open-access repository of dielectric measurements will be created based on a greatly enhanced understanding of the mechanisms underlying dielectric property measurement. Finally, new electromagnetic-based imaging and therapeutic medical devices will be investigated, based on the solid foundation of dielectric data.

1 499 329 €

Start date: 2015-10-01, End date: 2020-09-30

By detailed evolutionary comparisons among multiple sequenced yeast genomes, we have identified several unusual regions where our preliminary evidence suggests that previously unknown molecular biology phenomena, involving rearrangement of genomic DNA, are occurring. I now propose to use a combination of dry-lab and wet-lab experimental approaches to characterize these regions and phenomena further. One region is a 24-kb section of chromosome XIV that appears to undergo recurrent 'flip/flop' inversion between two isomers at a fairly high rate in five species as diverse as Saccharomyces cerevisiae and Naumovia castellii, leading to a 1:1 ratio of the two isomers in each species. We hypothesize that this region is the site of a programmed DNA rearrangement analogous to mating-type switching. We have also identified two new genes related to the mating-type switching endonuclease HO, but different from it, that are potentially involved in rearrangement processes though not necessarily the inversion described above. We will determine the sites of action of these endonucleases. Separately, we have found evidence for a process of recurrent deletion of DNA from regions flanking the mating-type (MAT) locus in all yeast species that are descended from the whole-genome duplication (WGD) event, causing continual transpositions of genes from beside MAT to other locations in the genome. In related computational work, we propose to investigate an hypothesis that evolutionary loss of the MATa2 transcriptional activator may have been the cause of the WGD event.

1 516 960 €

Start date: 2011-06-01, End date: 2016-05-31

The genetic code was established at a very early stage during the evolution of life on Earth and is nearly universal. In eukaryotic nuclear genes, the only known examples of a sense codon that underwent an evolutionary change of meaning, from one amino acid to another, occur in yeast species. The codon CUG is translated as Leu in the universal genetic code, but it has long been known to be translated as Ser in some Candida species. In recent work, we discovered that this switch is one of three parallel reassignments of CUG that occurred in three closely related clades of yeasts. CUG was reassigned once from Leu to Ala, and twice from Leu to Ser, in three separate events. The meaning of sense codons in the nuclear genetic code has otherwise remained completely stable during all of eukaryotic evolution, so why was CUG so unstable in yeasts? CODEKILLER will test a radical new hypothesis that the genetic code changes were caused by a killer toxin that specifically attacked the tRNA that translated CUG as Leu. The hypothesis implies that the reassignments of CUG were not driven by selection in favor of their effects on the proteome, as commonly assumed, but by selection against the existence of a particular tRNA. As well as searching for this killer toxin, we will study the detailed mechanism of genetic code change by engineering a reversal of a CUG-Ser species back to CUG-Leu translation, and investigate translation in some species that naturally contain both tRNA-Leu and tRNA-Ser molecules capable of decoding CUG.

2 368 356 €

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

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. The macula, the central part of the retina, is responsible for optimal spatial vision. There is a growing body of evidence that a lack of a dietary pigment at the macula, known as macular pigment (MP), is associated with increased risk of AMD. MP contains the carotenoids lutein (L), zeaxanthin (Z) and meso-zeaxanthin (meso-Z). The typical western diet contains around 60 carotenoids, and 18 have been identified in human serum. However, only three are found at the macula, indicating the unique biological selectivity for their uptake at this location. The function of MP remains undetermined. It is likely that the accumulation of MP has evolved because of its optical and antioxidant properties; for example, MP limits retinal oxidative damage passively (through filtration of blue light) and actively (by quenching free radicals). Furthermore, its optical properties suggest a key role for MP in enhancing visual performance and supporting ‘super’ vision by reducing the effects of chromatic aberration and light scatter. Recent research has shown that MP can be augmented by dietary supplementation in most (but not all) subjects, suggesting that the macular concentrations of these carotenoids are suboptimal in many people. My laboratory has discovered that a dip in the central portion of this pigment, seen in around 12% of individuals, is an undesirable feature of its spatial profile and may be linked to an inability to generate meso-Z at the macula. However, we have identified that enrichment of MP can be achieved by inclusion of meso-Z in a dietary supplement. We propose to uniquely enrich MP and assess its impact on visual performance in normal subjects and visual function in patients with AMD. This groundbreaking study will advance our understanding of the protective and optical hypothesis of MP, and potentially improve normal vision and prevent or delay blindness due to AMD.

1 493 342 €

Start date: 2011-10-01, End date: 2016-09-30

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

"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

How do human infants develop complex cognition? We propose that artificial intelligence (AI) provides crucial insight into human curiosity-driven learning and the development of infant cognition. Deep learning—a technology that has revolutionised AI—involves the acquisition of informative internal representations through pre-training, as a critical precursory step to learning any specific task. We propose that, similarly, curiosity guides human infants to develop ‘hidden’ mature mental representations through pre-training well before the manifestation of behaviour. To test this proposal, for the first time we will use neuroimaging to measure the hidden changes in representations during infancy and compare these to predictions from deep learning in machines. Research Question 1 will ask how infants guide pre-training through directed curiosity, by testing quantitative models of curiosity adapted from developmental robotics. We will also test the hypothesis from pilot data that the fronto-parietal brain network guides curiosity from the start. Research Question 2 will further test the parallel with deep learning by characterising the developing infant’s mental representations within the visual system using the powerful neuroimaging technique of representational similarity analysis. Research Question 3 will investigate how individual differences in curiosity affect later cognitive performance, and test the prediction from deep learning that the effects of early experience during pre-training grow rather than shrink with subsequent experience. Finally, Research Question 4 will test the novel prediction from deep learning that, following perinatal brain injury, pre-training creates resilience provided that curiosity is intact. The investigations will answer the overarching question of how pre-training learning lays the foundations for cognition and pioneer the new field of Computational Developmental Cognitive Neuroscience.

2 500 000 €

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

How do we make reliable decisions given sensory information that is often weak or ambiguous? Current theories center on a brain mechanism whereby sensory evidence is integrated over time into a “decision variable” which triggers the appropriate action upon reaching a criterion. Neural signals fitting this role have been identified in monkey electrophysiology but efforts to study the neural dynamics underpinning human decision making have been hampered by technical challenges associated with non-invasive recording. This proposal builds on a recent paradigm breakthrough made by the applicant that enables parallel tracking of discrete neural signals that can be unambiguously linked to the three key information processing stages necessary for simple perceptual decisions: sensory encoding, decision formation and motor preparation. Chief among these is a freely-evolving decision variable signal which builds at an evidence-dependent rate up to an action-triggering threshold and precisely determines the timing and accuracy of perceptual reports at the single-trial level. This provides an unprecedented neurophysiological window onto the distinct parameters of the human decision process such that the underlying mechanisms of several major behavioral phenomena can finally be investigated. This proposal seeks to develop a systems-level understanding of perceptual decision making in the human brain by tackling three core questions: 1) what are the neural adaptations that allow us to deal with speed pressure and variations in the reliability of the physically presented evidence? 2) What neural mechanism determines our subjective confidence in a decision? and 3) How does aging impact on the distinct neural components underpinning perceptual decision making? Each of the experiments described in this proposal will definitively test key predictions from prominent theoretical models using a combination of temporally precise neurophysiological measurement and psychophysical modelling.

1 382 643 €

Start date: 2015-05-01, End date: 2020-04-30

Schizophrenia, affecting 0.5-1% of the population, is ranked by the World Health Organisation as more disabling than paraplegia or blindness in 18-34 year olds. Current treatments, developed over 50 years ago, are only partly effective in treating this disability, and new treatments are lacking. To address this treatment impasse, this project aims to develop and test a novel immune based model of deficits in social cognition – the set of mental operations that underlie social interactions (e.g. emotion recognition, theory of mind) and strongly predict social disability in schizophrenia. Based on recent discoveries in schizophrenia genetics, this project asks: (1) are genetic causes of deficits in social cognition mediated by effects on immune function during development and (2) does early social environment moderate these effects? To address these questions, the project has two parts. Part A focuses on neuropsychological and neuroimaging studies of social cognition in patients and healthy adults so as to (1) provide an innovative characterisation of the effects of inflammatory markers (e.g. pro-/anti- inflammatory cytokines) on social cognition, (2) establish whether these markers mediate the effects of recently identified genetic risk loci on schizophrenia, and (3) identify to what extent early social environment (e.g. parental relationships, childhood trauma) moderates this relationship. Part B focuses on behavioural and pharmacological studies in mice to (1) establish the causal effects of early immune challenge and early social environment on social cognition, and (2) test the translational benefits of anti-inflammatory treatment to normalize the resulting deficits. By validating an immune based model of schizophrenia, this project has the potential to move beyond current (dopamine based) treatments, and suggest groundbreaking alternatives for understanding and treating social disability in this and other neurodevelopmental disorders.

1 477 622 €

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

The study of the molecular basis to the immune response has for decades concerned receptors and the signalling pathways they activate which lead to immune cell activation. Recently metabolic changes have also been shown to couple to immune effector responses. A shift in appreciation of the role of metabolites beyond energy metabolism and biosynthetic processes has emerged. We have been examining the role of three metabolites in macrophages. We have evidence that two of these, malonyl-CoA and 2-hydroxyglutarate (2-HG) are pro-inflammatory, whilst the third, itaconate, has profound anti-inflammatory effects. In many ways, they mirror cytokines, with malonyl-CoA and 2-HG being akin to pro-inflammatory cytokines, whilst itaconate resembles anti-inflammatory cytokines. The specificity and breadth of the role of these metabolites in macrophages will be mapped in this proposal. For malonyl-CoA we have evidence that it regulates GAPDH, IRG1/CAD (which synthesises itaconate) and the key cytokine IL-1beta. For 2-HG, we will examine the production and actions of its 2 enantiomers, D-2-HG and L-2-HG, focusing on their effect on HIF1alpha and epigenetic regulation. For itaconate we have evidence for a role in Type I interferon modulation, antigen presentation, inflammasome regulation and GAPDH and LDHA (which can produce 2-HG) activities. We also have evidence that OXGR1 is the receptor for itaconate. All of these aspects will be explored in detail. Critically we will also determine the relationship between these metabolites since we have evidence for cross-talk. Their dynamic regulation is likely to be a key aspect of how metabolic reprogramming controls macrophage function. Our studies point to a major shift in our understanding of how intracellular metabolic changes lead to inflammation. The overall aim is therefore to elucidate how metabolic reprogramming controls inflammatory macrophage activation, which may lead to new therapeutic targets for inflammatory diseases.

2 484 858 €

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

Open angle glaucoma (OAG) is the second leading cause of world blindness. Treatments involving topically applied pressure-reducing medications or surgery targeting ocular drainage channels are effective, although significant complications exist. We propose to address the hypothesis that it is possible to develop a radical approach to management of intraocular pressure employing an AAV-mediated system for increasing the permeability of Schlemm’s canal endothelial cells (SCEC), based on published supportive data from this laboratory showing that RNAi-mediated down regulation of mRNA encoding components of tight junctions of neuronal vascular endothelia induces increased cell permeability, a process which has been used to validate a procedure for acute treatment of neuronal edema. While tight junctions of neuronal vascular endothelial cells have been extensively studied and comprise of a series of up to 30 protein components, less is known of the organization of adherence mechanisms of SCEC, although electron- and immunofluorescence microscopy show the presence of tight junctions. We propose a comprehensive analysis of tight junction protein expression in SCEC in vitro. In vivo studies will involve introduction of AAV vectors into the anterior chamber of the eye in rodent models of elevated IOP. The vectors will be designed to express shRNAs targeting a variety of tight junction transcripts expressed in SCEC using an inducible system. The effect of RNAi-mediated increase in the permeability of SCEC will be assessed using aqueous humour outflow measurement methods and we will also explore the utility of high resolution and diffusion-weighted MRI for this purpose, which may prove to be a simpler, non-invasive and clinically relevant method. This research will provide further fundamental insights into the mechanisms of ocular pressure maintenance and could provide benefit to those patients not responsive to conventional means of therapy.

2 499 838 €

Start date: 2013-04-01, End date: 2018-09-30

Predicting the electron and spin transport properties of organic crystals is a formidable theoretical challenge as these are determined both by the electronic structure of the individual molecules and by the morphology of the crystal. Quest's research program seeks at developing a fully quantitative theory for electron and spin transport in organic crystals, which does not rely on external parameters and can be applied to materials underpinning a multitude of applications, ranging from organic electronics, to spintronics, to energy. In particular we aim at combining state of the art density functional theory with advanced quantum transport methods and Monte Carlo simulations. We will then construct a hierarchical computational protocol enabling us to evaluate electron and spin transport across different length scales at finite temperature, including effects originating from external fields (electric and magnetic). Our developed tools will form a software package to be distributed freely to academia.

1 492 728 €

Start date: 2012-12-01, End date: 2018-11-30