Project acronym BEBOP
Project Binaries Escorted By Orbiting Planets
Researcher (PI) Amaury TRIAUD
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Starting Grant (StG), PE9, ERC-2018-STG
Summary Planets orbiting both stars of a binary system -circumbinary planets- are challenging our understanding about how planets assemble, and how their orbits subsequently evolve. Long confined to science-fiction, circumbinary planets were confirmed by the Kepler spacecraft, in one of its most spectacular, and impactful result. Despite Kepler’s insights, a lot remains unknown about these planets. Kepler also suffered from intractable biases that the BEBOP project will solve.
BEBOP will revolutionise how we detect and study circumbinary planets. Conducting a Doppler survey, we will vastly improve the efficiency of circumbinary planet detection, and remove Kepler’s biases. BEBOP will construct a clearer picture of the circumbinary planet population, and free us from the inherent vagaries, and important costs of space-funding. Thanks to the Doppler method we will study dynamical effects unique to circumbinary planets, estimate their multiplicity, and compute their true occurrence rate.
Circumbinary planets are essential objects. Binaries disturbe planet formation. Any similarity, and any difference between the population of circumbinary planets and planets orbiting single stars, will bring novel information about how planets are produced. In addition, circumbinary planets have unique orbital properties that boost their probability to experience transits. BEBOP’s detections will open the door to atmospheric studies of colder worlds than presently available.
Based on already discovered systems, and on two successful proofs-of-concept, the BEBOP team will detect 15 circumbinary gas-giants, three times more than Kepler. BEBOP will provide an unambiguous measure of the efficiency of gas-giant formation in circumbinary environments. In addition the BEBOP project comes with an ambitious programme to combine three detection methods (Doppler, transits, and astrometry) in a holistic approach that will bolster investigations into circumbinary planets, and create a lasting legacy.
Summary
Planets orbiting both stars of a binary system -circumbinary planets- are challenging our understanding about how planets assemble, and how their orbits subsequently evolve. Long confined to science-fiction, circumbinary planets were confirmed by the Kepler spacecraft, in one of its most spectacular, and impactful result. Despite Kepler’s insights, a lot remains unknown about these planets. Kepler also suffered from intractable biases that the BEBOP project will solve.
BEBOP will revolutionise how we detect and study circumbinary planets. Conducting a Doppler survey, we will vastly improve the efficiency of circumbinary planet detection, and remove Kepler’s biases. BEBOP will construct a clearer picture of the circumbinary planet population, and free us from the inherent vagaries, and important costs of space-funding. Thanks to the Doppler method we will study dynamical effects unique to circumbinary planets, estimate their multiplicity, and compute their true occurrence rate.
Circumbinary planets are essential objects. Binaries disturbe planet formation. Any similarity, and any difference between the population of circumbinary planets and planets orbiting single stars, will bring novel information about how planets are produced. In addition, circumbinary planets have unique orbital properties that boost their probability to experience transits. BEBOP’s detections will open the door to atmospheric studies of colder worlds than presently available.
Based on already discovered systems, and on two successful proofs-of-concept, the BEBOP team will detect 15 circumbinary gas-giants, three times more than Kepler. BEBOP will provide an unambiguous measure of the efficiency of gas-giant formation in circumbinary environments. In addition the BEBOP project comes with an ambitious programme to combine three detection methods (Doppler, transits, and astrometry) in a holistic approach that will bolster investigations into circumbinary planets, and create a lasting legacy.
Max ERC Funding
1 186 313 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym BrainNanoFlow
Project Nanoscale dynamics in the extracellular space of the brain in vivo
Researcher (PI) Juan Alberto VARELA
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Summary
Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.
Max ERC Funding
1 552 948 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym CANCEREVO
Project Deciphering and predicting the evolution of cancer cell populations
Researcher (PI) Marco Helmut GERLINGER
Host Institution (HI) THE INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary The fundamental evolutionary nature of cancer is well recognized but an understanding of the dynamic evolutionary changes occurring throughout a tumour’s lifetime and their clinical implications is in its infancy. Current approaches to reveal cancer evolution by sequencing of multiple biopsies remain of limited use in the clinic due to sample access problems in multi-metastatic disease. Circulating tumour DNA (ctDNA) is thought to comprehensively sample subclones across metastatic sites. However, available technologies either have high sensitivity but are restricted to the analysis of small gene panels or they allow sequencing of large target regions such as exomes but with too limited sensitivity to detect rare subclones. We developed a novel error corrected sequencing technology that will be applied to perform deep exome sequencing on longitudinal ctDNA samples from highly heterogeneous metastatic gastro-oesophageal carcinomas. This will track the evolution of the entire cancer population over the lifetime of these tumours, from metastatic disease over drug therapy to end-stage disease and enable ground breaking insights into cancer population evolution rules and mechanisms. Specifically, we will: 1. Define the genomic landscape and drivers of metastatic and end stage disease. 2. Understand the rules of cancer evolutionary dynamics of entire cancer cell populations. 3. Predict cancer evolution and define the limits of predictability. 4. Rapidly identify drug resistance mechanisms to chemo- and immunotherapy based on signals of Darwinian selection such as parallel and convergent evolution. Our sequencing technology and analysis framework will also transform the way cancer evolution metrics can be accessed and interpreted in the clinic which will have major impacts, ranging from better biomarkers to predict cancer evolution to the identification of drug targets that drive disease progression and therapy resistance.
Summary
The fundamental evolutionary nature of cancer is well recognized but an understanding of the dynamic evolutionary changes occurring throughout a tumour’s lifetime and their clinical implications is in its infancy. Current approaches to reveal cancer evolution by sequencing of multiple biopsies remain of limited use in the clinic due to sample access problems in multi-metastatic disease. Circulating tumour DNA (ctDNA) is thought to comprehensively sample subclones across metastatic sites. However, available technologies either have high sensitivity but are restricted to the analysis of small gene panels or they allow sequencing of large target regions such as exomes but with too limited sensitivity to detect rare subclones. We developed a novel error corrected sequencing technology that will be applied to perform deep exome sequencing on longitudinal ctDNA samples from highly heterogeneous metastatic gastro-oesophageal carcinomas. This will track the evolution of the entire cancer population over the lifetime of these tumours, from metastatic disease over drug therapy to end-stage disease and enable ground breaking insights into cancer population evolution rules and mechanisms. Specifically, we will: 1. Define the genomic landscape and drivers of metastatic and end stage disease. 2. Understand the rules of cancer evolutionary dynamics of entire cancer cell populations. 3. Predict cancer evolution and define the limits of predictability. 4. Rapidly identify drug resistance mechanisms to chemo- and immunotherapy based on signals of Darwinian selection such as parallel and convergent evolution. Our sequencing technology and analysis framework will also transform the way cancer evolution metrics can be accessed and interpreted in the clinic which will have major impacts, ranging from better biomarkers to predict cancer evolution to the identification of drug targets that drive disease progression and therapy resistance.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym CartographY
Project Mapping Stellar Helium
Researcher (PI) Guy DAVIES
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Starting Grant (StG), PE9, ERC-2018-STG
Summary In the epoch of Gaia, fundamental stellar properties will be made widely available for large numbers of stars. These properties are expected to unleash a new wave of discovery in the field of astrophysics. But while many properties of stars are measurable, meaningful Helium abundances (Y) remain elusive and as a result fundamental properties are not accurate.
Helium enrichment laws, which underpin most stellar properties, link initial Y to initial metallicity, but these relations are very uncertain with gradients (dY/dZ) spanning the range 1 to 3. This uncertainty is the initial Y problem and this is a bottleneck that must be overcome to unleash the true potential of Gaia.
Without measurements of initial Y for all stars we need to find alternative observables that trace out the evolution of initial Y. We will search for better tracers using the power of asteroseismology as a calibrator.
Asteroseismic measures of Helium will be used to construct a map from observable properties (fundamental, chemical or even dynamical) back to initial Helium. This is a challenge that can only be solved through the use of the latest asteroseismic techniques coupled to a rigorous yet flexible statistical scheme. I am uniquely qualified in the cutting edge methods of asteroseismology and the application of advanced multi-level statistical models. The intersection of these two skill sets will allow me to solve the initial Helium problem.
The motivation for a timely solution to this problem could not be stronger. We have just entered an age of large asteroseismic datasets, vast spectroscopic surveys, and the billion star program of Gaia. The next wave of scientific breakthroughs in stellar physics, exoplanetary science, and Galactic archeology will be held back unless accurate fundamental stellar properties are available. We can only produce these accurate properties with a reliable map of stellar Helium.
Summary
In the epoch of Gaia, fundamental stellar properties will be made widely available for large numbers of stars. These properties are expected to unleash a new wave of discovery in the field of astrophysics. But while many properties of stars are measurable, meaningful Helium abundances (Y) remain elusive and as a result fundamental properties are not accurate.
Helium enrichment laws, which underpin most stellar properties, link initial Y to initial metallicity, but these relations are very uncertain with gradients (dY/dZ) spanning the range 1 to 3. This uncertainty is the initial Y problem and this is a bottleneck that must be overcome to unleash the true potential of Gaia.
Without measurements of initial Y for all stars we need to find alternative observables that trace out the evolution of initial Y. We will search for better tracers using the power of asteroseismology as a calibrator.
Asteroseismic measures of Helium will be used to construct a map from observable properties (fundamental, chemical or even dynamical) back to initial Helium. This is a challenge that can only be solved through the use of the latest asteroseismic techniques coupled to a rigorous yet flexible statistical scheme. I am uniquely qualified in the cutting edge methods of asteroseismology and the application of advanced multi-level statistical models. The intersection of these two skill sets will allow me to solve the initial Helium problem.
The motivation for a timely solution to this problem could not be stronger. We have just entered an age of large asteroseismic datasets, vast spectroscopic surveys, and the billion star program of Gaia. The next wave of scientific breakthroughs in stellar physics, exoplanetary science, and Galactic archeology will be held back unless accurate fundamental stellar properties are available. We can only produce these accurate properties with a reliable map of stellar Helium.
Max ERC Funding
1 496 203 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym CELL-in-CELL
Project Understanding host cellular systems that drive an endosymbiotic interaction
Researcher (PI) Thomas RICHARDS
Host Institution (HI) THE UNIVERSITY OF EXETER
Call Details Consolidator Grant (CoG), LS8, ERC-2018-COG
Summary Endosymbiosis is a key phenomenon that has played a critical role in shaping biological diversity, driving gene transfer and generating cellular complexity. During the process of endosymbiosis, one cell is integrated within another to become a critical component of the recipient, changing its characteristics and allowing it to chart a distinct evolutionary trajectory. Endosymbiosis was fundamentally important to the origin and evolution of eukaryotic cellular complexity, because an endosymbiotic event roots the diversification of all known eukaryotes and endosymbiosis has continually driven the diversification of huge sections of the eukaryotic tree of life. Little is known about how nascent endosymbioses are established or how they go on to form novel cellular compartments known as endosymbiotic organelles. Paramecium bursaria is a single celled protist that harbours multiple green algae within to form a phototrophic endosymbiosis. This relationship is nascent as the partners can be separated, grown separately, and the endosymbiosis reinitiated. This project will identify, for the first time, the gene functions that enable one cell to incubate another within to form a stable endosymbiotic interaction. To identify and explore which host genes control endosymbiosis in P. bursaria we have developed RNAi silencing technology. In the proposed project we will conduct genome sequencing, followed by a large-scale RNAi knockdown screening experiment, to identify host genes that when silenced perturb the endosymbiont population. Having identified candidate genes, we will investigate the localisation and function of the host encoded proteins. This project will significantly change our current understanding of the evolutionary phenomenon of endosymbiosis by identifying the cellular adaptations that drive these interactions, advancing our understanding of how these important moments in evolution occur and how core cellular systems can diversify in function.
Summary
Endosymbiosis is a key phenomenon that has played a critical role in shaping biological diversity, driving gene transfer and generating cellular complexity. During the process of endosymbiosis, one cell is integrated within another to become a critical component of the recipient, changing its characteristics and allowing it to chart a distinct evolutionary trajectory. Endosymbiosis was fundamentally important to the origin and evolution of eukaryotic cellular complexity, because an endosymbiotic event roots the diversification of all known eukaryotes and endosymbiosis has continually driven the diversification of huge sections of the eukaryotic tree of life. Little is known about how nascent endosymbioses are established or how they go on to form novel cellular compartments known as endosymbiotic organelles. Paramecium bursaria is a single celled protist that harbours multiple green algae within to form a phototrophic endosymbiosis. This relationship is nascent as the partners can be separated, grown separately, and the endosymbiosis reinitiated. This project will identify, for the first time, the gene functions that enable one cell to incubate another within to form a stable endosymbiotic interaction. To identify and explore which host genes control endosymbiosis in P. bursaria we have developed RNAi silencing technology. In the proposed project we will conduct genome sequencing, followed by a large-scale RNAi knockdown screening experiment, to identify host genes that when silenced perturb the endosymbiont population. Having identified candidate genes, we will investigate the localisation and function of the host encoded proteins. This project will significantly change our current understanding of the evolutionary phenomenon of endosymbiosis by identifying the cellular adaptations that drive these interactions, advancing our understanding of how these important moments in evolution occur and how core cellular systems can diversify in function.
Max ERC Funding
2 602 483 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym COEVOPRO
Project Drivers and consequences of coevolution in protective symbiosis
Researcher (PI) Kayla KING
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary All organisms in nature are targets for parasite attack. Over a century ago, it was first observed that symbiotic species living in hosts can provide a strong barrier against infection, beyond the host’s own defence responses. We now know that ‘protective’ microbial symbiont species are key components of plant, animal, and human microbiota, shaping host health in the face of parasite infection. I have shown that microbes can evolve within days to protect, providing the possibility that microbe-mediated defences can take-over from hosts in fighting with parasites over evolutionary time. This new discovery of an evolvable microbe-mediated defence challenges our fundamental understanding of the host-parasite relationship. Here, I will use a novel nematode-microbe interaction, an experimental evolution approach, and assays of phenotypic and genomic changes (the latter using state-of-the-art sequencing and CRISPR-Cas9 technologies) to generate new insights into the drivers and consequences of coevolving protective symbioses. Specifically, the objectives are to test: (i) the ability of microbe-mediated protection to evolve more rapidly than host-encoded resistance, (ii) the impacts of evolvable protective microbes on host-parasite coevolution, and the effect of community complexity, in the form of (iii) parasite and (iv) within-host microbial heterogeneity, in shaping host-protective microbe coevolution from scratch. Together, these objectives will generate a new, synthetic understanding of how protective symbioses evolve and influence host resistance and parasite infectivity, with far-reaching implications for tackling coevolution in communities.
Summary
All organisms in nature are targets for parasite attack. Over a century ago, it was first observed that symbiotic species living in hosts can provide a strong barrier against infection, beyond the host’s own defence responses. We now know that ‘protective’ microbial symbiont species are key components of plant, animal, and human microbiota, shaping host health in the face of parasite infection. I have shown that microbes can evolve within days to protect, providing the possibility that microbe-mediated defences can take-over from hosts in fighting with parasites over evolutionary time. This new discovery of an evolvable microbe-mediated defence challenges our fundamental understanding of the host-parasite relationship. Here, I will use a novel nematode-microbe interaction, an experimental evolution approach, and assays of phenotypic and genomic changes (the latter using state-of-the-art sequencing and CRISPR-Cas9 technologies) to generate new insights into the drivers and consequences of coevolving protective symbioses. Specifically, the objectives are to test: (i) the ability of microbe-mediated protection to evolve more rapidly than host-encoded resistance, (ii) the impacts of evolvable protective microbes on host-parasite coevolution, and the effect of community complexity, in the form of (iii) parasite and (iv) within-host microbial heterogeneity, in shaping host-protective microbe coevolution from scratch. Together, these objectives will generate a new, synthetic understanding of how protective symbioses evolve and influence host resistance and parasite infectivity, with far-reaching implications for tackling coevolution in communities.
Max ERC Funding
1 499 275 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym CRYOREP
Project Chromosome Replication Visualised by Cryo-EM
Researcher (PI) Alessandro COSTA
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary In eukaryotic cells, DNA replication is tightly regulated to ensure that the genome is duplicated only once per cell cycle. Errors in the control mechanisms that regulate chromosome ploidy cause genomic instability, which is linked to the development of cellular abnormalities, genetic disease and the onset of cancer. Recent reconstitution experiments performed with purified proteins revealed that initiation of eukaryotic genome duplication requires three distinct steps. First, DNA replication start sites are identified and targeted for the loading of an inactive MCM helicase motor, which encircles the double helix. Second, MCM activators are recruited, causing duplex-DNA untwisting. Third, upon interaction with a firing factor, the MCM ring opens to eject one DNA strand, leading to unwinding of the replication fork and duplication by dedicated replicative polymerases. These three events are not understood at a molecular level. Structural investigations so far aimed at imaging artificially isolated replication steps and used simplified templates, such as linear duplex DNA to study helicase loading or pre-formed forks to understand unwinding. However, the natural substrate of the eukaryotic replication machinery is not DNA but rather chromatin, formed of nucleosome arrays that compact the genome. Chromatin plays important regulatory roles in all steps of DNA replication, by dictating origin start-site selection and stimulating replication fork progression. Only by studying chromatin replication, we argue, will we understand the molecular basis of genome propagation. To this end, we have developed new protocols to perform visual biochemistry experiments under the cryo-electron microscope, to image chromatin duplication at high resolution, frozen as it is being catalysed. Using these strategies we want to generate a molecular movie of the entire replication reaction. Our achievements will change the way we think about genome stability in eukaryotic cells.
Summary
In eukaryotic cells, DNA replication is tightly regulated to ensure that the genome is duplicated only once per cell cycle. Errors in the control mechanisms that regulate chromosome ploidy cause genomic instability, which is linked to the development of cellular abnormalities, genetic disease and the onset of cancer. Recent reconstitution experiments performed with purified proteins revealed that initiation of eukaryotic genome duplication requires three distinct steps. First, DNA replication start sites are identified and targeted for the loading of an inactive MCM helicase motor, which encircles the double helix. Second, MCM activators are recruited, causing duplex-DNA untwisting. Third, upon interaction with a firing factor, the MCM ring opens to eject one DNA strand, leading to unwinding of the replication fork and duplication by dedicated replicative polymerases. These three events are not understood at a molecular level. Structural investigations so far aimed at imaging artificially isolated replication steps and used simplified templates, such as linear duplex DNA to study helicase loading or pre-formed forks to understand unwinding. However, the natural substrate of the eukaryotic replication machinery is not DNA but rather chromatin, formed of nucleosome arrays that compact the genome. Chromatin plays important regulatory roles in all steps of DNA replication, by dictating origin start-site selection and stimulating replication fork progression. Only by studying chromatin replication, we argue, will we understand the molecular basis of genome propagation. To this end, we have developed new protocols to perform visual biochemistry experiments under the cryo-electron microscope, to image chromatin duplication at high resolution, frozen as it is being catalysed. Using these strategies we want to generate a molecular movie of the entire replication reaction. Our achievements will change the way we think about genome stability in eukaryotic cells.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym DISEASE
Project Disease Risk And Immune Strategies In Social Insects
Researcher (PI) Nathalie STROEYMEYT
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary Group-living has been predicted to have opposing effects on disease risk and immune strategies. First, since repeated contacts between individuals facilitate pathogen transmission, sociality may favour high investment in personal immunity. Alternatively, because social animals can limit disease spread through collective sanitary actions (e.g., mutual grooming) or organisational features (e.g., division of the group’s social network into distinct subsets), sociality may instead favour low investment in personal immunity. The overall goal of this project is to experimentally test these conflicting predictions in ants using advanced data collection and analytical tools. I will first quantify the effect of social organisation on disease transmission using a combination of automated behavioural tracking, social network analysis, and empirical tracking of transmission markers (fluorescent beads). Experimental network manipulations and controlled disease seeding by a robotic ant will allow key predictions from network epidemiology to be tested, with broad implications for disease management strategies. I will then study the effect of colony size on social network structure and disease transmission, and how this in turn affects investment in personal immunity. This will shed light on far-reaching hypotheses about the effect of group size on social organisation ('size-complexity’ hypothesis) and immune investment (‘density-dependent prophylaxis’). Finally, I will explore whether prolonged pathogen pressure induces colonies to reinforce the transmission-inhibiting aspects of their social organisation (e.g., colony fragmentation) or to invest more in personal immunity. This project will represent the first empirical investigation of the role of social organisation in disease risk management, and allow its importance to be compared with other immune strategies. This will constitute a significant advance in our understanding of the complex feedback between sociality and health.
Summary
Group-living has been predicted to have opposing effects on disease risk and immune strategies. First, since repeated contacts between individuals facilitate pathogen transmission, sociality may favour high investment in personal immunity. Alternatively, because social animals can limit disease spread through collective sanitary actions (e.g., mutual grooming) or organisational features (e.g., division of the group’s social network into distinct subsets), sociality may instead favour low investment in personal immunity. The overall goal of this project is to experimentally test these conflicting predictions in ants using advanced data collection and analytical tools. I will first quantify the effect of social organisation on disease transmission using a combination of automated behavioural tracking, social network analysis, and empirical tracking of transmission markers (fluorescent beads). Experimental network manipulations and controlled disease seeding by a robotic ant will allow key predictions from network epidemiology to be tested, with broad implications for disease management strategies. I will then study the effect of colony size on social network structure and disease transmission, and how this in turn affects investment in personal immunity. This will shed light on far-reaching hypotheses about the effect of group size on social organisation ('size-complexity’ hypothesis) and immune investment (‘density-dependent prophylaxis’). Finally, I will explore whether prolonged pathogen pressure induces colonies to reinforce the transmission-inhibiting aspects of their social organisation (e.g., colony fragmentation) or to invest more in personal immunity. This project will represent the first empirical investigation of the role of social organisation in disease risk management, and allow its importance to be compared with other immune strategies. This will constitute a significant advance in our understanding of the complex feedback between sociality and health.
Max ERC Funding
1 499 995 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym DISKtoHALO
Project From the accretion disk to the cluster halo: the multi-scale physics of black hole feedback
Researcher (PI) Christopher REYNOLDS
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Advanced Grant (AdG), PE9, ERC-2018-ADG
Summary It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
Summary
It is firmly established that supermassive black holes (SMBHs) have a profound influence on the evolution of galaxies and galaxy groups/clusters. Yet, almost 20 years after this realization, fundamental questions remain. What determines the efficiency with which an active galactic nucleus (AGN) couples to its surroundings? Why does AGN feedback appear to be ineffective in low-mass galaxies? In maintenance-mode feedback, how does the AGN regulate to closely balance cooling? How does the nature of AGN feedback change as we consider higher redshifts and push back to the epoch of the first galaxies? AGN feedback is a truly multi-scale phenomenon. Observations show that AGN have an energetic impact on galactic-, group-, and cluster-halo scales. Yet the efficiency with which an accreting SMBH releases energy, and the partitioning of that energy into radiation, winds, and relativistic jets, is dictated by complex processes in the accretion disk on AU scales, 10^10 times smaller than the halo. Furthermore, especially in massive systems where feedback proceeds via the heating of a hot circumgalactic or intracluster medium (CGM/ICM), the relevant microphysics of the hot baryons is unclear, requiring an understanding of plasma instabilities on 10^-9pc scales. We propose a set of projects that explore the multiscale physics of AGN feedback. Magnetohydrodynamic models of accretion disks will be constructed to study the AGN radiation/winds/jets and calibrate observable proxies of SMBH mass and accretion rate. We will use the machinery of plasma physics to characterize the CGM/ICM microphysics relevant to the thermalization of AGN-injected energy. Finally, we will produce new galaxy-, group- and cluster-scale models incorporating the new microphysical prescriptions and AGN models. Our new theoretical understanding of AGN feedback as a function of halo mass, environment, and cosmic time is essential for interpreting the torrent of data from current and future observatories
Max ERC Funding
2 489 918 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym Division
Project Division of Labour and the Evolution of Complexity
Researcher (PI) Stuart WEST
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Advanced Grant (AdG), LS8, ERC-2018-ADG
Summary Division of labour is fundamental to the evolution of life on earth, allowing genes to work together to form genomes, cells to build organisms, pathogens to escape immune attack, and eusocial insect societies to achieve ecological dominance. Consequently, if we want to understand how life on earth evolved, we need to understand why division of labour does or, just as importantly, does not evolve. There are two major outstanding problems for our understanding of division of labour: First, how can we explain why division of labour has evolved with some traits, in some species, but not others? Given the potential benefits of dividing labour, why does it not arise more frequently in cooperative species? Second, in cases where division of labour has evolved, how can we explain the form that it takes? Why do factors such as the degree of specialisation, or mechanism used to produce different phenotypes, vary across species? I will combine my social evolution expertise with novel synthetic and genomic approaches to address these problems. I will explain the distribution and form of division of labour in the natural world, with an interdisciplinary research programme, divided into four work packages: (1) I will provide the first experimental test of the fundamental assumption that division of labour provides an efficiency benefit, by synthetically manipulating bacteria. (2) I will test how selection has acted for and against the evolution of division of labour in natural populations of bacteria, using novel genomic analysis techniques. (3) I will determine why division of labour evolved in some species, but not others, with an across species study on insects, and experimental evolution of bacteria. (4) I will establish a new field of research on why different species use different mechanisms to divide labour: genetic differences, environmental cues, or random assignment of roles. I will develop theory to explain this variation, and test this theory experimentally.
Summary
Division of labour is fundamental to the evolution of life on earth, allowing genes to work together to form genomes, cells to build organisms, pathogens to escape immune attack, and eusocial insect societies to achieve ecological dominance. Consequently, if we want to understand how life on earth evolved, we need to understand why division of labour does or, just as importantly, does not evolve. There are two major outstanding problems for our understanding of division of labour: First, how can we explain why division of labour has evolved with some traits, in some species, but not others? Given the potential benefits of dividing labour, why does it not arise more frequently in cooperative species? Second, in cases where division of labour has evolved, how can we explain the form that it takes? Why do factors such as the degree of specialisation, or mechanism used to produce different phenotypes, vary across species? I will combine my social evolution expertise with novel synthetic and genomic approaches to address these problems. I will explain the distribution and form of division of labour in the natural world, with an interdisciplinary research programme, divided into four work packages: (1) I will provide the first experimental test of the fundamental assumption that division of labour provides an efficiency benefit, by synthetically manipulating bacteria. (2) I will test how selection has acted for and against the evolution of division of labour in natural populations of bacteria, using novel genomic analysis techniques. (3) I will determine why division of labour evolved in some species, but not others, with an across species study on insects, and experimental evolution of bacteria. (4) I will establish a new field of research on why different species use different mechanisms to divide labour: genetic differences, environmental cues, or random assignment of roles. I will develop theory to explain this variation, and test this theory experimentally.
Max ERC Funding
2 491 766 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym DNA-DOCK
Project Precision Docking of Very Large DNA Cargos in Mammalian Genomes
Researcher (PI) Imre Berger
Host Institution (HI) UNIVERSITY OF BRISTOL
Call Details Advanced Grant (AdG), LS9, ERC-2018-ADG
Summary Gene editing has developed at breath-taking speed. In particular CRISPR/Cas9 provides a tool-set thousands of researchers worldwide now utilize with unprecedented ease to edit genes, catalysing a broad range of biomedical and industrial applications. Gene synthesis technologies producing thousands of base pairs of synthetic DNA have become affordable. Current gene editing technology is highly effective for local, small genomic DNA edits and insertions. To unlock the full potential of this revolution, however, our capacities to disrupt or rewrite small local elements of code must be complemented by equal capacities to efficiently insert very large synthetic DNA cargos with a wide range of functions into genomic sites. Large designer cargos would carry multicomponent DNA circuitry including programmable and fine-tuneable functionalities, representing the vital interface between gene editing which is the state-of-the-art at present, and genome engineering, which is the future. This challenge remained largely unaddressed to date.
We aspire to resolve this bottleneck by creating ground-breaking, generally applicable, easy-to-use technology to enable docking of large DNA cargos with base pair precision and unparalleled efficiency into mammalian genomes. To achieve our ambitious goals, we will apply a whole array of sophisticated tools. We will unlock a small non-human virus to rational design, creating safe, flexible and easy-to-produce, large capacity DNA delivery nanodevices with unmatched transduction capability. We will exploit a range of techniques including Darwinian in vitro selection/evolution to accomplish unprecedented precision DNA integration efficiency into genomic sites. We will use parallelized DNA assembly methods to generate multifunctional circuits, to accelerate T cell engineering, resolving unmet needs. Once we accomplish our tasks, our technology has the potential to be exceptionally rewarding to the scientific, industrial and medical communities.
Summary
Gene editing has developed at breath-taking speed. In particular CRISPR/Cas9 provides a tool-set thousands of researchers worldwide now utilize with unprecedented ease to edit genes, catalysing a broad range of biomedical and industrial applications. Gene synthesis technologies producing thousands of base pairs of synthetic DNA have become affordable. Current gene editing technology is highly effective for local, small genomic DNA edits and insertions. To unlock the full potential of this revolution, however, our capacities to disrupt or rewrite small local elements of code must be complemented by equal capacities to efficiently insert very large synthetic DNA cargos with a wide range of functions into genomic sites. Large designer cargos would carry multicomponent DNA circuitry including programmable and fine-tuneable functionalities, representing the vital interface between gene editing which is the state-of-the-art at present, and genome engineering, which is the future. This challenge remained largely unaddressed to date.
We aspire to resolve this bottleneck by creating ground-breaking, generally applicable, easy-to-use technology to enable docking of large DNA cargos with base pair precision and unparalleled efficiency into mammalian genomes. To achieve our ambitious goals, we will apply a whole array of sophisticated tools. We will unlock a small non-human virus to rational design, creating safe, flexible and easy-to-produce, large capacity DNA delivery nanodevices with unmatched transduction capability. We will exploit a range of techniques including Darwinian in vitro selection/evolution to accomplish unprecedented precision DNA integration efficiency into genomic sites. We will use parallelized DNA assembly methods to generate multifunctional circuits, to accelerate T cell engineering, resolving unmet needs. Once we accomplish our tasks, our technology has the potential to be exceptionally rewarding to the scientific, industrial and medical communities.
Max ERC Funding
2 498 578 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym ENDOMICS
Project Raman Endoscopic Proteo-lipidomics of Bladder Cancer
Researcher (PI) Mads SYLVEST BERGHOLT
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary The goal of ENDOMICS is to drive forward a new paradigm of Raman endoscopic technology that enables proteomic and lipidomic analysis for diagnosis of bladder cancers in vivo. Raman endoscopy is a label-free optical technique that can provide a point-wise vibrational molecular fingerprint of tissue “optical biopsy” for cancer diagnosis in vivo. State-of-the-art Raman endoscopy, however, does not offer specific compositional analysis or insights into molecular biology of tissue. This is because the vibrational Raman bands are overlapping and cannot be deciphered into the myriad of biomolecules in complex tissue.
We will introduce a ground-breaking new methodology to enable Raman proteomic and lipidomic analysis in vivo. To this end, heterospectral co-registered Raman and mass spectrometry imaging will be used to develop a multivariate regression model “Rosetta Stone” for translating vibrational structural information (Raman spectroscopy) into compositional information. To meet the unmet clinical needs in urology we will tailor the first fibre-optic Raman endoscopic technology that can measure depth-dependent molecular profiles to simultaneously enable detection, grading and staging of bladder cancers. We will finally conduct a clinical trial by applying the technique to measure a comprehensive molecular database of bladder pathologies in vivo. The latter will allow for the identification of proteomic and lipidomic biomarkers to develop novel algorithms for real-time diagnosis of bladder cancers.
The synergy between scientific and technological advances in ENDOMICS will break ground for shedding new light on the molecular biology of bladder cancer in vivo including new insights into clinical diversity and identification of biomarkers for diagnostics, prognostics and novel therapeutic targets.
Summary
The goal of ENDOMICS is to drive forward a new paradigm of Raman endoscopic technology that enables proteomic and lipidomic analysis for diagnosis of bladder cancers in vivo. Raman endoscopy is a label-free optical technique that can provide a point-wise vibrational molecular fingerprint of tissue “optical biopsy” for cancer diagnosis in vivo. State-of-the-art Raman endoscopy, however, does not offer specific compositional analysis or insights into molecular biology of tissue. This is because the vibrational Raman bands are overlapping and cannot be deciphered into the myriad of biomolecules in complex tissue.
We will introduce a ground-breaking new methodology to enable Raman proteomic and lipidomic analysis in vivo. To this end, heterospectral co-registered Raman and mass spectrometry imaging will be used to develop a multivariate regression model “Rosetta Stone” for translating vibrational structural information (Raman spectroscopy) into compositional information. To meet the unmet clinical needs in urology we will tailor the first fibre-optic Raman endoscopic technology that can measure depth-dependent molecular profiles to simultaneously enable detection, grading and staging of bladder cancers. We will finally conduct a clinical trial by applying the technique to measure a comprehensive molecular database of bladder pathologies in vivo. The latter will allow for the identification of proteomic and lipidomic biomarkers to develop novel algorithms for real-time diagnosis of bladder cancers.
The synergy between scientific and technological advances in ENDOMICS will break ground for shedding new light on the molecular biology of bladder cancer in vivo including new insights into clinical diversity and identification of biomarkers for diagnostics, prognostics and novel therapeutic targets.
Max ERC Funding
1 490 950 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym EPISWITCH
Project Mechanistic basis of nucleation and spreading underlying a Polycomb-mediated epigenetic switch
Researcher (PI) Caroline DEAN
Host Institution (HI) JOHN INNES CENTRE
Call Details Advanced Grant (AdG), LS1, ERC-2018-ADG
Summary Polycomb-mediated epigenetic regulation of gene expression is central to development and environmental plasticity in most eukaryotes. Polycomb Repressive Complex 2 (PRC2) is targeted to genomic sites, known as nucleation regions or Polycomb Response elements, and switches those targets to an epigenetically silenced state. But what constitutes the switching mechanism is unknown. Core epigenetic switching mechanisms have proven difficult to elucidate due to the complex molecular feedbacks involved. We will exploit a well-characterized gene system, Arabidopsis FLC, to address a central question – what are the core events that constitute a Polycomb switch?
Our hypothesis is that the epigenetic switch involves stochastic conformationally-induced oligomerization, generating an ordered protein assembly of PRC2 accessory proteins and PRC2, that is then robustly distributed onto both daughter strands during DNA replication through self-templating feedback mechanisms. We will determine the local chromatin features that promote the epigenetic switch independently at each allele (i.e., in cis). We will also dissect the involvement of DNA replication in the transition from metastable to long-term epigenetic silencing, associated with the Polycomb complex spreading across the body of the locus.
This interdisciplinary proposal combines molecular genetics/biology, computational biology, with structural biology, achieved through close working relationships with Prof. Martin Howard (John Innes Centre), Dr Mariann Bienz (MRC Laboratory of Molecular Biology, Cambridge) and Dr Julian Sale, (MRC Laboratory of Molecular Biology, Cambridge). This blue-sky programme aims to provide important new concepts in Polycomb-mediated epigenetic switching mechanisms, important for the whole epigenetics field.
Summary
Polycomb-mediated epigenetic regulation of gene expression is central to development and environmental plasticity in most eukaryotes. Polycomb Repressive Complex 2 (PRC2) is targeted to genomic sites, known as nucleation regions or Polycomb Response elements, and switches those targets to an epigenetically silenced state. But what constitutes the switching mechanism is unknown. Core epigenetic switching mechanisms have proven difficult to elucidate due to the complex molecular feedbacks involved. We will exploit a well-characterized gene system, Arabidopsis FLC, to address a central question – what are the core events that constitute a Polycomb switch?
Our hypothesis is that the epigenetic switch involves stochastic conformationally-induced oligomerization, generating an ordered protein assembly of PRC2 accessory proteins and PRC2, that is then robustly distributed onto both daughter strands during DNA replication through self-templating feedback mechanisms. We will determine the local chromatin features that promote the epigenetic switch independently at each allele (i.e., in cis). We will also dissect the involvement of DNA replication in the transition from metastable to long-term epigenetic silencing, associated with the Polycomb complex spreading across the body of the locus.
This interdisciplinary proposal combines molecular genetics/biology, computational biology, with structural biology, achieved through close working relationships with Prof. Martin Howard (John Innes Centre), Dr Mariann Bienz (MRC Laboratory of Molecular Biology, Cambridge) and Dr Julian Sale, (MRC Laboratory of Molecular Biology, Cambridge). This blue-sky programme aims to provide important new concepts in Polycomb-mediated epigenetic switching mechanisms, important for the whole epigenetics field.
Max ERC Funding
2 101 325 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym EVOCELFATE
Project Evolution of cell fate specification modes in spiral cleavage
Researcher (PI) Jose Maria MARTIN DURAN
Host Institution (HI) QUEEN MARY UNIVERSITY OF LONDON
Call Details Starting Grant (StG), LS3, ERC-2018-STG
Summary Spiral cleavage is a highly stereotypical early embryonic program, and the ancestral, defining feature to Spiralia, a major phylogenetic clade including almost half of the animal phyla. Remarkably, spiral-cleaving embryos specify homologous cell fates (e.g. the progenitor cell of posterodorsal structures) conditionally –via cell interactions– or autonomously –via segregation of maternal inputs. This variation occurs naturally, even between closely related species, and has been related to the precocious formation of adult characters (adultation) in larvae of autonomous spiral-cleaving species. How spiralian lineages repeatedly shifted between these two cell fate specification modes is largely unexplored, because the mechanisms controlling spiral cleavage are still poorly characterized.
This project tests the hypothesis that maternal chromatin and transcriptional regulators differentially incorporated in oocytes with autonomous spiral cleavage explain the evolution of this mode of cell fate specification. Through a comparative and phylogenetic-guided approach, we will combine bioinformatics, live imaging, and molecular and experimental techniques to: (i) Comprehensively identify differentially supplied maternal factors among spiral cleaving oocytes with distinct cell fate specification modes using comparative RNA-seq and proteomics; (ii) Uncover the developmental mechanisms driving conditional spiral cleavage, which is the ancestral embryonic mode; and (iii) Investigate how maternal chromatin and transcriptional regulators define early cell fates, and whether these factors account for the repeated evolution of autonomous specification modes.
Our results will fill a large gap of knowledge in our understanding of spiral cleavage and its evolution. In a broader context, this project will deliver fundamental insights into two core questions in evolutionary developmental biology: how early embryonic programs evolve, and how they contribute to phenotypic change.
Summary
Spiral cleavage is a highly stereotypical early embryonic program, and the ancestral, defining feature to Spiralia, a major phylogenetic clade including almost half of the animal phyla. Remarkably, spiral-cleaving embryos specify homologous cell fates (e.g. the progenitor cell of posterodorsal structures) conditionally –via cell interactions– or autonomously –via segregation of maternal inputs. This variation occurs naturally, even between closely related species, and has been related to the precocious formation of adult characters (adultation) in larvae of autonomous spiral-cleaving species. How spiralian lineages repeatedly shifted between these two cell fate specification modes is largely unexplored, because the mechanisms controlling spiral cleavage are still poorly characterized.
This project tests the hypothesis that maternal chromatin and transcriptional regulators differentially incorporated in oocytes with autonomous spiral cleavage explain the evolution of this mode of cell fate specification. Through a comparative and phylogenetic-guided approach, we will combine bioinformatics, live imaging, and molecular and experimental techniques to: (i) Comprehensively identify differentially supplied maternal factors among spiral cleaving oocytes with distinct cell fate specification modes using comparative RNA-seq and proteomics; (ii) Uncover the developmental mechanisms driving conditional spiral cleavage, which is the ancestral embryonic mode; and (iii) Investigate how maternal chromatin and transcriptional regulators define early cell fates, and whether these factors account for the repeated evolution of autonomous specification modes.
Our results will fill a large gap of knowledge in our understanding of spiral cleavage and its evolution. In a broader context, this project will deliver fundamental insights into two core questions in evolutionary developmental biology: how early embryonic programs evolve, and how they contribute to phenotypic change.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym EvolutioNeuroCircuit
Project Cellular and genetic bases of neural circuits evolution
Researcher (PI) Lucia PRIETO GODINO
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Starting Grant (StG), LS5, ERC-2018-STG
Summary Sensory systems encode the world around us to produce context-dependent appropriate behaviours. However, we know little about the way new sensory evoked behaviours arise as neural circuits are re-shaped during evolution. Tackling this question requires a deep understanding of the circuits underlying specific behaviours and integration of this knowledge with tools from other fields, including evolutionary and developmental biology. Recent technological advancements on neural circuit interrogation and genome editing have put progress on this fundamental biological question within reach.
The olfactory system of the larval stage of the fly Drosophila melanogaster and related species is an ideal model for investigating these questions because (i) D. melanogaster has pioneered both the fields of population genetics and neurogenetics and (ii) its olfactory system is one of the best-characterised neural circuits. We will address the question of how olfactory circuits evolve by studying four species with divergent odour-guided behaviours through the following multidisciplinary aims:
1. Which olfactory pathways are targeted in the evolution of ecological specialisation? – Combining high-throughput behavioural assays, optogenetics and calcium imaging in the larva of all four species we will determine whether/which olfactory pathways have switched valences or sensitivity.
2. How have central neural circuits diverged? – We will address this question at unprecedented resolution through whole-brain calcium imaging and serial electron microscopy reconstruction.
3. What are the molecular and genetic bases of neural circuits rewiring during evolution? – Using transcriptomic profiling we will identify differentially expressed genes in conserved and divergent circuits across species, and functionally probe selected candidates to establish causality.
4. How do evolutionary forces shape olfactory circuits? – We will investigate this question using field studies and population genetics
Summary
Sensory systems encode the world around us to produce context-dependent appropriate behaviours. However, we know little about the way new sensory evoked behaviours arise as neural circuits are re-shaped during evolution. Tackling this question requires a deep understanding of the circuits underlying specific behaviours and integration of this knowledge with tools from other fields, including evolutionary and developmental biology. Recent technological advancements on neural circuit interrogation and genome editing have put progress on this fundamental biological question within reach.
The olfactory system of the larval stage of the fly Drosophila melanogaster and related species is an ideal model for investigating these questions because (i) D. melanogaster has pioneered both the fields of population genetics and neurogenetics and (ii) its olfactory system is one of the best-characterised neural circuits. We will address the question of how olfactory circuits evolve by studying four species with divergent odour-guided behaviours through the following multidisciplinary aims:
1. Which olfactory pathways are targeted in the evolution of ecological specialisation? – Combining high-throughput behavioural assays, optogenetics and calcium imaging in the larva of all four species we will determine whether/which olfactory pathways have switched valences or sensitivity.
2. How have central neural circuits diverged? – We will address this question at unprecedented resolution through whole-brain calcium imaging and serial electron microscopy reconstruction.
3. What are the molecular and genetic bases of neural circuits rewiring during evolution? – Using transcriptomic profiling we will identify differentially expressed genes in conserved and divergent circuits across species, and functionally probe selected candidates to establish causality.
4. How do evolutionary forces shape olfactory circuits? – We will investigate this question using field studies and population genetics
Max ERC Funding
1 312 500 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym FIRM
Project Form and Function of the Mitochondrial Retrograde Response
Researcher (PI) Michelangelo CAMPANELLA
Host Institution (HI) THE ROYAL VETERINARY COLLEGE
Call Details Consolidator Grant (CoG), LS4, ERC-2018-COG
Summary The molecular communication between mitochondria and nucleus is an integrated bi-directional crosstalk - anterograde (nucleus to mitochondria) and retrograde (mitochondria to nucleus) signalling pathways. The mitochondrial retrograde response (MRR) is driven by defective mitochondrial function, which increases cytosolic reactive oxygen species (ROS) and Ca2+. Metabolic reprogramming is a key feature in highly proliferative cells to meet the energy needs for rapid growth by generating substrates for cellular biogenesis. In these mitochondria retro-communicate with the nucleus to induce wide-ranging cytoprotective effects exploited to develop resistance against treatment and sustain uncontrolled growth. Recently, the mitochondrial management of cholesterol-derived intermediates for the synthesis of steroids has been demonstrated as a determinant in the oncogenic reprogramming of cellular environment.
We hypothesise that cholesterol-enriched domains facilitate the communication between remodelled mitochondria and nucleus to expedite MRR. This mechanism may be exploited during abnormal cell growth in which cholesterol metabolism and associated molecules are increased.
This application capitalizes on expertise in cell signalling and metabolism to interrogate core pathways and unveil molecular sensors and effectors that define form and function of the MRR by:
I. Elucidating the mechanism of metabolic regulation of MRR, describing the role exerted by cholesterol trafficking;
II. Unveiling microdomains for mito-nuclear communication established by remodelled, autophagy escaped, mitochondria;
III. Validating protocols to modulate and target MRR for diagnostic and therapeutic benefit;
The experimental plan will (i) define a molecular signalling axis that currently stands uncharacterized, (ii) provide mechanistic knowledge for preventive, and (iii) therapeutic applications to counteract deficiencies associated with stressed, dysregulated mitochondria.
Summary
The molecular communication between mitochondria and nucleus is an integrated bi-directional crosstalk - anterograde (nucleus to mitochondria) and retrograde (mitochondria to nucleus) signalling pathways. The mitochondrial retrograde response (MRR) is driven by defective mitochondrial function, which increases cytosolic reactive oxygen species (ROS) and Ca2+. Metabolic reprogramming is a key feature in highly proliferative cells to meet the energy needs for rapid growth by generating substrates for cellular biogenesis. In these mitochondria retro-communicate with the nucleus to induce wide-ranging cytoprotective effects exploited to develop resistance against treatment and sustain uncontrolled growth. Recently, the mitochondrial management of cholesterol-derived intermediates for the synthesis of steroids has been demonstrated as a determinant in the oncogenic reprogramming of cellular environment.
We hypothesise that cholesterol-enriched domains facilitate the communication between remodelled mitochondria and nucleus to expedite MRR. This mechanism may be exploited during abnormal cell growth in which cholesterol metabolism and associated molecules are increased.
This application capitalizes on expertise in cell signalling and metabolism to interrogate core pathways and unveil molecular sensors and effectors that define form and function of the MRR by:
I. Elucidating the mechanism of metabolic regulation of MRR, describing the role exerted by cholesterol trafficking;
II. Unveiling microdomains for mito-nuclear communication established by remodelled, autophagy escaped, mitochondria;
III. Validating protocols to modulate and target MRR for diagnostic and therapeutic benefit;
The experimental plan will (i) define a molecular signalling axis that currently stands uncharacterized, (ii) provide mechanistic knowledge for preventive, and (iii) therapeutic applications to counteract deficiencies associated with stressed, dysregulated mitochondria.
Max ERC Funding
1 450 060 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym GMGalaxies
Project Understanding the diversity of galaxy morphology in the era of large spectroscopic surveys
Researcher (PI) Andrew PONTZEN
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Consolidator Grant (CoG), PE9, ERC-2018-COG
Summary Galaxies are the building blocks of structure in the Universe; this proposal seeks to understand how their shapes, colours and dynamics are determined. For example, what happened in the history of some galaxies to transform them into passive ellipticals while others, seemingly of the same mass and in the same environment, are star-forming spirals? Even such a basic question about the link between morphology and star formation has not yet been answered, revealing our theories of galaxy formation are inadequate. This is a major concern in an era where understanding the shapes of galaxies and how they relate to the underlying dark matter is essential for progress in precision cosmology.
This project will build the missing link between the history of a galaxy and its observational properties (i.e. between cause and effect) by using numerical simulations. Current research in this area rightly gives significant attention to the crucial problem of how feedback – energy input from supernovae, active galactic nuclei, and more – affect observable properties. But as well as investigating this avenue, GM Galaxies will uniquely make use of my new technique (“genetic modification”) to systematically investigate the role of the galaxy’s merging and accretion history at high resolution.
To distinguish the fingerprints of history from the effects of feedback, we will compare to rich new data from integral field unit surveys; these reveal, for example, galactic metallicity and velocity maps. My pilot study for this project shows that such measures of a galaxy disambiguate between alternative formation routes to galaxies which would appear similar by photometric measures alone. Similarly, we will make predictions for the observable properties of the gas reservoir surrounding galaxies and for integral field observations at high redshift. In this way we will make a predictive account of how galactic structure is determined by the interaction of the accretion history with feedback.
Summary
Galaxies are the building blocks of structure in the Universe; this proposal seeks to understand how their shapes, colours and dynamics are determined. For example, what happened in the history of some galaxies to transform them into passive ellipticals while others, seemingly of the same mass and in the same environment, are star-forming spirals? Even such a basic question about the link between morphology and star formation has not yet been answered, revealing our theories of galaxy formation are inadequate. This is a major concern in an era where understanding the shapes of galaxies and how they relate to the underlying dark matter is essential for progress in precision cosmology.
This project will build the missing link between the history of a galaxy and its observational properties (i.e. between cause and effect) by using numerical simulations. Current research in this area rightly gives significant attention to the crucial problem of how feedback – energy input from supernovae, active galactic nuclei, and more – affect observable properties. But as well as investigating this avenue, GM Galaxies will uniquely make use of my new technique (“genetic modification”) to systematically investigate the role of the galaxy’s merging and accretion history at high resolution.
To distinguish the fingerprints of history from the effects of feedback, we will compare to rich new data from integral field unit surveys; these reveal, for example, galactic metallicity and velocity maps. My pilot study for this project shows that such measures of a galaxy disambiguate between alternative formation routes to galaxies which would appear similar by photometric measures alone. Similarly, we will make predictions for the observable properties of the gas reservoir surrounding galaxies and for integral field observations at high redshift. In this way we will make a predictive account of how galactic structure is determined by the interaction of the accretion history with feedback.
Max ERC Funding
1 741 230 €
Duration
Start date: 2019-10-01, End date: 2024-09-30
Project acronym ICYBOB
Project Initial Conditions of YMCs, Birth of OB associations and long term evolution of stellar clusters
Researcher (PI) Clare Louise DOBBS
Host Institution (HI) THE UNIVERSITY OF EXETER
Call Details Consolidator Grant (CoG), PE9, ERC-2018-COG
Summary The goal of this proposal is to establish a new era of stellar cluster evolution research by performing numerical simulations on different scales, and of different stages of a cluster’s life, from the formation of YMCs, the formation and evolution of OB associations, to the evolution of clusters and associations in galaxies. The PI is one of the pioneers of galactic simulations of GMC and star formation was one of the first numericists to perform galactic scale simulations of molecular cloud formation and evolution, and has produced some of the most realistic and sophisticated isolated simulations of galaxies in this field to date. The next challenge is to follow cluster evolution, something which has not yet been attempted numerically. And, with the GaiaAIA instrument set to transform stellar astronomy in our Galaxy, our work will provide a fundamental theoretical counterpart. Key questions we will address include i) how does gas disperse from new clusters and what happens to that gas, ii) how do YMCs form, iii) how do new clustersGiant Molecular Clouds (GMCs) evolve into OB associations, and ivii) how long can clusters survive for as they orbit a galaxy and what causes their destruction.
Summary
The goal of this proposal is to establish a new era of stellar cluster evolution research by performing numerical simulations on different scales, and of different stages of a cluster’s life, from the formation of YMCs, the formation and evolution of OB associations, to the evolution of clusters and associations in galaxies. The PI is one of the pioneers of galactic simulations of GMC and star formation was one of the first numericists to perform galactic scale simulations of molecular cloud formation and evolution, and has produced some of the most realistic and sophisticated isolated simulations of galaxies in this field to date. The next challenge is to follow cluster evolution, something which has not yet been attempted numerically. And, with the GaiaAIA instrument set to transform stellar astronomy in our Galaxy, our work will provide a fundamental theoretical counterpart. Key questions we will address include i) how does gas disperse from new clusters and what happens to that gas, ii) how do YMCs form, iii) how do new clustersGiant Molecular Clouds (GMCs) evolve into OB associations, and ivii) how long can clusters survive for as they orbit a galaxy and what causes their destruction.
Max ERC Funding
1 980 385 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym LeaRNN
Project Principles of Learning in a Recurrent Neural Network
Researcher (PI) Marta Zlatic
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary Forming memories, generating predictions based on memories, and updating memories when predictions no longer match actual experience are fundamental brain functions. Dopaminergic neurons provide a so-called “teaching signal” that drives the formation and updates of associative memories across the animal kingdom. Many theoretical models propose how neural circuits could compute the teaching signals, but the actual implementation of this computation in real nervous systems is unknown.
This project will discover the basic principles by which neural circuits compute the teaching signals that drive memory formation and updates using a tractable insect model system, the Drosophila larva. We will generate, for the first time in any animal, the following essential datasets for a distributed, multilayered, recurrent learning circuit, the mushroom body-related circuitry in the larval brain. First, building on our preliminary work that provides the synaptic-resolution connectome of the circuit, including all feedforward and feedback pathways upstream of all dopaminergic neurons, we will generate a map of functional monosynaptic connections. Second, we will obtain cellular-resolution whole-nervous system activity maps in intact living animals, as they form, extinguish, or consolidate memories to discover the features represented in each layer of the circuit (e.g. predictions, actual reinforcement, and prediction errors), the learning algorithms, and the candidate circuit motifs that implement them. Finally, we will develop a model of the circuit constrained by these datasets and test the predictions about the necessity and sufficiency of uniquely identified circuit elements for implementing learning algorithms by selectively manipulating their activity.
Understanding the basic functional principles of an entire multilayered recurrent learning circuit in an animal has the potential to revolutionize, not only neuroscience and medicine, but also machine-learning and robotics.
Summary
Forming memories, generating predictions based on memories, and updating memories when predictions no longer match actual experience are fundamental brain functions. Dopaminergic neurons provide a so-called “teaching signal” that drives the formation and updates of associative memories across the animal kingdom. Many theoretical models propose how neural circuits could compute the teaching signals, but the actual implementation of this computation in real nervous systems is unknown.
This project will discover the basic principles by which neural circuits compute the teaching signals that drive memory formation and updates using a tractable insect model system, the Drosophila larva. We will generate, for the first time in any animal, the following essential datasets for a distributed, multilayered, recurrent learning circuit, the mushroom body-related circuitry in the larval brain. First, building on our preliminary work that provides the synaptic-resolution connectome of the circuit, including all feedforward and feedback pathways upstream of all dopaminergic neurons, we will generate a map of functional monosynaptic connections. Second, we will obtain cellular-resolution whole-nervous system activity maps in intact living animals, as they form, extinguish, or consolidate memories to discover the features represented in each layer of the circuit (e.g. predictions, actual reinforcement, and prediction errors), the learning algorithms, and the candidate circuit motifs that implement them. Finally, we will develop a model of the circuit constrained by these datasets and test the predictions about the necessity and sufficiency of uniquely identified circuit elements for implementing learning algorithms by selectively manipulating their activity.
Understanding the basic functional principles of an entire multilayered recurrent learning circuit in an animal has the potential to revolutionize, not only neuroscience and medicine, but also machine-learning and robotics.
Max ERC Funding
2 350 000 €
Duration
Start date: 2019-09-01, End date: 2024-08-31
Project acronym METANICHE
Project Regulation of bone metastases by age-associated angiocrine signals
Researcher (PI) Anjali KUSUMBE
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Blood vessels form a versatile transport network and provide inductive signals called angiocrine factors to regulate tissue-specific functions. Blood vessels in bone are heterogeneous with distinct capillary subtypes that exhibit remarkable alterations with age. Bone is the most prevalent site of metastasis, and ageing is linked to the reactivation of dormant tumor cells (dorTCs) and metastatic relapse. Bone remodeling processes are also associated with metastatic relapse. Here, I will define the role of distinct vascular niches in regulating the fate of DTCs in bone. Finally, I will unravel the age-related angiocrine factors and identify key angiocrine signals that drive the reactivation of dorTCs. I will employ a powerful combination of advanced 3D, intravital, and whole body imaging, cell specific-inducible mouse genetics, transcriptional profiling and bioinformatics in an unprecedented manner to achieve my goals. New cutting-edge techniques such as advanced 3D and 4D bone imaging are important aspects of my proposal. I will also define the role of highly promising novel candidate age-related angiocrine signals with sophisticated inducible endothelial-specific humanised mouse models. My work will break new ground by unraveling a repertoire of age-related angiocrine factors and will contribute to a wider scientific community in bone, blood, and age-related diseases. This interdisciplinary work at the frontiers of bone, cancer and vascular biology will provide the first conceptual link between vascular ageing and bone metastasis and will contribute towards the development of therapeutic strategies for targeting DTCs in bone.
Summary
Blood vessels form a versatile transport network and provide inductive signals called angiocrine factors to regulate tissue-specific functions. Blood vessels in bone are heterogeneous with distinct capillary subtypes that exhibit remarkable alterations with age. Bone is the most prevalent site of metastasis, and ageing is linked to the reactivation of dormant tumor cells (dorTCs) and metastatic relapse. Bone remodeling processes are also associated with metastatic relapse. Here, I will define the role of distinct vascular niches in regulating the fate of DTCs in bone. Finally, I will unravel the age-related angiocrine factors and identify key angiocrine signals that drive the reactivation of dorTCs. I will employ a powerful combination of advanced 3D, intravital, and whole body imaging, cell specific-inducible mouse genetics, transcriptional profiling and bioinformatics in an unprecedented manner to achieve my goals. New cutting-edge techniques such as advanced 3D and 4D bone imaging are important aspects of my proposal. I will also define the role of highly promising novel candidate age-related angiocrine signals with sophisticated inducible endothelial-specific humanised mouse models. My work will break new ground by unraveling a repertoire of age-related angiocrine factors and will contribute to a wider scientific community in bone, blood, and age-related diseases. This interdisciplinary work at the frontiers of bone, cancer and vascular biology will provide the first conceptual link between vascular ageing and bone metastasis and will contribute towards the development of therapeutic strategies for targeting DTCs in bone.
Max ERC Funding
1 496 613 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
