Project acronym 3D-REPAIR
Project Spatial organization of DNA repair within the nucleus
Researcher (PI) Evanthia Soutoglou
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Country United Kingdom
Call Details Consolidator Grant (CoG), LS2, ERC-2015-CoG
Summary Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Summary
Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer
Max ERC Funding
1 999 750 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym AMPLIFY
Project Amplifying Human Perception Through Interactive Digital Technologies
Researcher (PI) Albrecht Schmidt
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Country Germany
Call Details Consolidator Grant (CoG), PE6, ERC-2015-CoG
Summary Current technical sensor systems offer capabilities that are superior to human perception. Cameras can capture a spectrum that is wider than visible light, high-speed cameras can show movements that are invisible to the human eye, and directional microphones can pick up sounds at long distances. The vision of this project is to lay a foundation for the creation of digital technologies that provide novel sensory experiences and new perceptual capabilities for humans that are natural and intuitive to use. In a first step, the project will assess the feasibility of creating artificial human senses that provide new perceptual channels to the human mind, without increasing the experienced cognitive load. A particular focus is on creating intuitive and natural control mechanisms for amplified senses using eye gaze, muscle activity, and brain signals. Through the creation of a prototype that provides mildly unpleasant stimulations in response to perceived information, the feasibility of implementing an artificial reflex will be experimentally explored. The project will quantify the effectiveness of new senses and artificial perceptual aids compared to the baseline of unaugmented perception. The overall objective is to systematically research, explore, and model new means for increasing the human intake of information in order to lay the foundation for new and improved human senses enabled through digital technologies and to enable artificial reflexes. The ground-breaking contributions of this project are (1) to demonstrate the feasibility of reliably implementing amplified senses and new perceptual capabilities, (2) to prove the possibility of creating an artificial reflex, (3) to provide an example implementation of amplified cognition that is empirically validated, and (4) to develop models, concepts, components, and platforms that will enable and ease the creation of interactive systems that measurably increase human perceptual capabilities.
Summary
Current technical sensor systems offer capabilities that are superior to human perception. Cameras can capture a spectrum that is wider than visible light, high-speed cameras can show movements that are invisible to the human eye, and directional microphones can pick up sounds at long distances. The vision of this project is to lay a foundation for the creation of digital technologies that provide novel sensory experiences and new perceptual capabilities for humans that are natural and intuitive to use. In a first step, the project will assess the feasibility of creating artificial human senses that provide new perceptual channels to the human mind, without increasing the experienced cognitive load. A particular focus is on creating intuitive and natural control mechanisms for amplified senses using eye gaze, muscle activity, and brain signals. Through the creation of a prototype that provides mildly unpleasant stimulations in response to perceived information, the feasibility of implementing an artificial reflex will be experimentally explored. The project will quantify the effectiveness of new senses and artificial perceptual aids compared to the baseline of unaugmented perception. The overall objective is to systematically research, explore, and model new means for increasing the human intake of information in order to lay the foundation for new and improved human senses enabled through digital technologies and to enable artificial reflexes. The ground-breaking contributions of this project are (1) to demonstrate the feasibility of reliably implementing amplified senses and new perceptual capabilities, (2) to prove the possibility of creating an artificial reflex, (3) to provide an example implementation of amplified cognition that is empirically validated, and (4) to develop models, concepts, components, and platforms that will enable and ease the creation of interactive systems that measurably increase human perceptual capabilities.
Max ERC Funding
1 925 250 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ANGI
Project Adaptive significance of Non Genetic Inheritance
Researcher (PI) Benoit Francois Pujol
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Summary
Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.
Max ERC Funding
1 999 970 €
Duration
Start date: 2016-03-01, End date: 2022-02-28
Project acronym APPELS
Project A Probe of the Periodic Elements for Life in the Sea
Researcher (PI) Rosalind Emily Mayors Rickaby
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), PE10, ERC-2015-CoG
Summary "Chemical elements are the building blocks of life. The major elements, C, H. O, N, P, S are easily recognised as essential nutrients, but their use by life relies on metalloproteins. The identity of the metal centres of these metalloproteins and even the broader palette of trace elements fundamental to life are remarkably poorly known. Whole genomes remain opaque to decoding of this bioinorganic dimension, and optimal trace element concentrations for physiological function. Defining the elemental requirements for maximum growth rate of photosynthesising phytoplankton in the ocean, is critical to understanding Earth's climate. Although microscopic in stature, phytoplankton exert a gigantic influence on the biological pumping of carbon from the atmosphere to the deep ocean. Yet their metal requirements are poorly constrained, being inferred from cellular quotas and "nutrient-like" ocean metal distributions, susceptible to ambiguity between mistaken cellular uptake and use.
APPELS will undertake a two-pronged approach to define the modern marine metallome/metalloproteome. I will explore the expanse of the periodic table for novel required elements by growing phytoplankton, representative of the broadest chemotypes, in manipulated media, to delineate optimal conditions for growth whereby any limitation at lowered concentrations implies use. The second prong uses cutting-edge techniques that unite methods from proteomics with geochemical mass-spectrometry to allow both metals and their associated proteins to be examined comprehensively. APPELS will transform our understanding of the essential elements in the ocean and how the biological pump of carbon is geared to ocean chemistry in an evolving world. More broadly, APPELS will provide a step change in documented protein-metal binding centres, with implications for discovery of novel biochemical pathways, and optimal nutrition."
Summary
"Chemical elements are the building blocks of life. The major elements, C, H. O, N, P, S are easily recognised as essential nutrients, but their use by life relies on metalloproteins. The identity of the metal centres of these metalloproteins and even the broader palette of trace elements fundamental to life are remarkably poorly known. Whole genomes remain opaque to decoding of this bioinorganic dimension, and optimal trace element concentrations for physiological function. Defining the elemental requirements for maximum growth rate of photosynthesising phytoplankton in the ocean, is critical to understanding Earth's climate. Although microscopic in stature, phytoplankton exert a gigantic influence on the biological pumping of carbon from the atmosphere to the deep ocean. Yet their metal requirements are poorly constrained, being inferred from cellular quotas and "nutrient-like" ocean metal distributions, susceptible to ambiguity between mistaken cellular uptake and use.
APPELS will undertake a two-pronged approach to define the modern marine metallome/metalloproteome. I will explore the expanse of the periodic table for novel required elements by growing phytoplankton, representative of the broadest chemotypes, in manipulated media, to delineate optimal conditions for growth whereby any limitation at lowered concentrations implies use. The second prong uses cutting-edge techniques that unite methods from proteomics with geochemical mass-spectrometry to allow both metals and their associated proteins to be examined comprehensively. APPELS will transform our understanding of the essential elements in the ocean and how the biological pump of carbon is geared to ocean chemistry in an evolving world. More broadly, APPELS will provide a step change in documented protein-metal binding centres, with implications for discovery of novel biochemical pathways, and optimal nutrition."
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym ARTIVISM
Project Art and Activism : Creativity and Performance as Subversive Forms of Political Expression in Super-Diverse Cities
Researcher (PI) Monika Salzbrunn
Host Institution (HI) UNIVERSITE DE LAUSANNE
Country Switzerland
Call Details Consolidator Grant (CoG), SH5, ERC-2015-CoG
Summary ARTIVISM aims at exploring new artistic forms of political expression under difficult, precarious and/or oppressive conditions. It asks how social actors create belonging and multiple forms of resistance when they use art in activism or activism in art. What kind of alliances do these two forms of social practices generate in super-diverse places, in times of crisis and in precarious situations? Thus, ARTIVISM seeks to understand how social actors engage artistically in order to bring about social, economic and political change. Going beyond former research in urban and migration studies, and beyond the anthropology of art, ARTIVISM focuses on a broad range of artistic tools, styles and means of expression, namely festive events and parades, cartoons and comics and street art. By articulating performance studies, street anthropology and the sociology of celebration with migration and diversity studies, the project challenges former concepts, which took stable social groups for granted and reified them with ethnic lenses. The applied methodology considerably renews the field by bringing together event-, actor- and condition-centred approaches and a multi-sensory framework. Besides its multidisciplinary design, the ground-breaking nature of ARTIVISM lies in the application of the core concepts of performativity and liminality, as well as in an examination of the way to advance and refine these concepts and to create new analytical tools to respond to recent social phenomena. We have developed and tested innovative methods that respond to a postmodern type of fluid and temporary social action: audio-visual ethnography, urban event ethnography, street ethnography, field-crossing, and sensory ethnography (apprenticeship). Therefore, ARTIVISM develops new methods and theories in order to introduce a multi-faceted trans-disciplinary approach to the study of an emerging field of social transformations that is of challenging significance to the social sciences.
Summary
ARTIVISM aims at exploring new artistic forms of political expression under difficult, precarious and/or oppressive conditions. It asks how social actors create belonging and multiple forms of resistance when they use art in activism or activism in art. What kind of alliances do these two forms of social practices generate in super-diverse places, in times of crisis and in precarious situations? Thus, ARTIVISM seeks to understand how social actors engage artistically in order to bring about social, economic and political change. Going beyond former research in urban and migration studies, and beyond the anthropology of art, ARTIVISM focuses on a broad range of artistic tools, styles and means of expression, namely festive events and parades, cartoons and comics and street art. By articulating performance studies, street anthropology and the sociology of celebration with migration and diversity studies, the project challenges former concepts, which took stable social groups for granted and reified them with ethnic lenses. The applied methodology considerably renews the field by bringing together event-, actor- and condition-centred approaches and a multi-sensory framework. Besides its multidisciplinary design, the ground-breaking nature of ARTIVISM lies in the application of the core concepts of performativity and liminality, as well as in an examination of the way to advance and refine these concepts and to create new analytical tools to respond to recent social phenomena. We have developed and tested innovative methods that respond to a postmodern type of fluid and temporary social action: audio-visual ethnography, urban event ethnography, street ethnography, field-crossing, and sensory ethnography (apprenticeship). Therefore, ARTIVISM develops new methods and theories in order to introduce a multi-faceted trans-disciplinary approach to the study of an emerging field of social transformations that is of challenging significance to the social sciences.
Max ERC Funding
1 999 287 €
Duration
Start date: 2016-09-01, End date: 2022-02-28
Project acronym ATUNE
Project Attenuation Tomography Using Novel observations of Earth's free oscillations
Researcher (PI) Arwen Fedora Deuss
Host Institution (HI) UNIVERSITEIT UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), PE10, ERC-2015-CoG
Summary Tectonic phenomena at the Earth's surface, like volcanic eruptions and earthquakes,are driven by convection deep in the mantle. Seismic tomography has been very successful in elucidating the Earth's internal velocity structure. However, seismic velocity is insufficient to obtain robust estimates of temperature and composition, and make direct links with mantle convection. Thus, fundamental questions remain unanswered: Do subducting slabs bring water into the lower mantle? Are the large low-shear velocity provinces under the Pacific and Africa mainly thermal or compositional? Is there any partial melt or water near the mantle transition zone or core mantle boundary?
Seismic attenuation, or loss of energy, is key to mapping melt, water and temperature variations, and answering these questions. Unfortunately, attenuation has only been imaged using short- and intermediate-period seismic data, showing little similarity even for the upper mantle and no reliable lower mantle models exist. The aim of ATUNE is to develop novel full-spectrum techniques and apply them to Earth's long period free oscillations to observe global-scale regional variations in seismic attenuation from the lithosphere to the core mantle boundary. Scattering and focussing - problematic for shorter period techniques - are easily included using cross-coupling (or resonance) between free oscillations not requiring approximations. The recent occurrence of large earthquakes, increase in computer power and my world-leading expertise in free oscillations now make it possible to increase the frequency dependence of attenuation to a much wider frequency band, allowing us to distinguish between scattering (redistribution of energy) versus intrinsic attenuation. ATUNE will deliver the first ever full-waveform global tomographic model of 3D attenuation variations in the lower mantle, providing essential constraints on melt, water and temperature for understanding the complex dynamics of our planet.
Summary
Tectonic phenomena at the Earth's surface, like volcanic eruptions and earthquakes,are driven by convection deep in the mantle. Seismic tomography has been very successful in elucidating the Earth's internal velocity structure. However, seismic velocity is insufficient to obtain robust estimates of temperature and composition, and make direct links with mantle convection. Thus, fundamental questions remain unanswered: Do subducting slabs bring water into the lower mantle? Are the large low-shear velocity provinces under the Pacific and Africa mainly thermal or compositional? Is there any partial melt or water near the mantle transition zone or core mantle boundary?
Seismic attenuation, or loss of energy, is key to mapping melt, water and temperature variations, and answering these questions. Unfortunately, attenuation has only been imaged using short- and intermediate-period seismic data, showing little similarity even for the upper mantle and no reliable lower mantle models exist. The aim of ATUNE is to develop novel full-spectrum techniques and apply them to Earth's long period free oscillations to observe global-scale regional variations in seismic attenuation from the lithosphere to the core mantle boundary. Scattering and focussing - problematic for shorter period techniques - are easily included using cross-coupling (or resonance) between free oscillations not requiring approximations. The recent occurrence of large earthquakes, increase in computer power and my world-leading expertise in free oscillations now make it possible to increase the frequency dependence of attenuation to a much wider frequency band, allowing us to distinguish between scattering (redistribution of energy) versus intrinsic attenuation. ATUNE will deliver the first ever full-waveform global tomographic model of 3D attenuation variations in the lower mantle, providing essential constraints on melt, water and temperature for understanding the complex dynamics of our planet.
Max ERC Funding
2 000 000 €
Duration
Start date: 2016-06-01, End date: 2022-05-31
Project acronym AWESoMeStars
Project Accretion, Winds, and Evolution of Spins and Magnetism of Stars
Researcher (PI) Sean Patrick Matt
Host Institution (HI) THE UNIVERSITY OF EXETER
Country United Kingdom
Call Details Consolidator Grant (CoG), PE9, ERC-2015-CoG
Summary This project focuses on Sun-like stars, which possess convective envelopes and universally exhibit magnetic activity (in the mass range 0.1 to 1.3 MSun). The rotation of these stars influences their internal structure, energy and chemical transport, and magnetic field generation, as well as their external magnetic activity and environmental interactions. Due to the huge range of timescales, spatial scales, and physics involved, understanding how each of these processes relate to each other and to the long-term evolution remains an enormous challenge in astrophysics. To face this challenge, the AWESoMeStars project will develop a comprehensive, physical picture of the evolution of stellar rotation, magnetic activity, mass loss, and accretion.
In doing so, we will
(1) Discover how stars lose the vast majority of their angular momentum, which happens in the accretion phase
(2) Explain the observed rotation-activity relationship and saturation in terms of the evolution of magnetic properties & coronal physics
(3) Characterize coronal heating and mass loss across the full range of mass & age
(4) Explain the Skumanich (1972) relationship and distributions of spin rates observed in young clusters & old field stars
(5) Develop physics-based gyrochronology as a tool for using rotation rates to constrain stellar ages.
We will accomplish these goals using a fundamentally new and multi-faceted approach, which combines the power of multi-dimensional MHD simulations with long-timescale rotational-evolution models. Specifically, we will develop a next generation of MHD simulations of both star-disk interactions and stellar winds, to model stars over the full range of mass & age, and to characterize how magnetically active stars impact their environments. Simultaneously, we will create a new class of rotational-evolution models that include external torques derived from our simulations, compute the evolution of spin rates of entire star clusters, & compare with observations.
Summary
This project focuses on Sun-like stars, which possess convective envelopes and universally exhibit magnetic activity (in the mass range 0.1 to 1.3 MSun). The rotation of these stars influences their internal structure, energy and chemical transport, and magnetic field generation, as well as their external magnetic activity and environmental interactions. Due to the huge range of timescales, spatial scales, and physics involved, understanding how each of these processes relate to each other and to the long-term evolution remains an enormous challenge in astrophysics. To face this challenge, the AWESoMeStars project will develop a comprehensive, physical picture of the evolution of stellar rotation, magnetic activity, mass loss, and accretion.
In doing so, we will
(1) Discover how stars lose the vast majority of their angular momentum, which happens in the accretion phase
(2) Explain the observed rotation-activity relationship and saturation in terms of the evolution of magnetic properties & coronal physics
(3) Characterize coronal heating and mass loss across the full range of mass & age
(4) Explain the Skumanich (1972) relationship and distributions of spin rates observed in young clusters & old field stars
(5) Develop physics-based gyrochronology as a tool for using rotation rates to constrain stellar ages.
We will accomplish these goals using a fundamentally new and multi-faceted approach, which combines the power of multi-dimensional MHD simulations with long-timescale rotational-evolution models. Specifically, we will develop a next generation of MHD simulations of both star-disk interactions and stellar winds, to model stars over the full range of mass & age, and to characterize how magnetically active stars impact their environments. Simultaneously, we will create a new class of rotational-evolution models that include external torques derived from our simulations, compute the evolution of spin rates of entire star clusters, & compare with observations.
Max ERC Funding
2 206 205 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym BactInd
Project Bacterial cooperation at the individual cell level
Researcher (PI) Rolf Kuemmerli
Host Institution (HI) UNIVERSITAT ZURICH
Country Switzerland
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Summary
All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Max ERC Funding
1 994 981 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BCM-UPS
Project Dissecting the role of the ubiquitin proteasome system in the pathogenesis and therapy of B-cell malignancies
Researcher (PI) Florian Christoph Bassermann
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Country Germany
Call Details Consolidator Grant (CoG), LS4, ERC-2015-CoG
Summary B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive.
Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers.
We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance.
We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.
Summary
B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive.
Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers.
We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance.
We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.
Max ERC Funding
1 973 255 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BEAL
Project Bioenergetics in microalgae : regulation modes of mitochondrial respiration, photosynthesis, and fermentative pathways, and their interactions in secondary algae
Researcher (PI) Pierre Antoine Georges Cardol
Host Institution (HI) UNIVERSITE DE LIEGE
Country Belgium
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Summary
During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth.
ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date.
Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.
Max ERC Funding
1 837 625 €
Duration
Start date: 2016-06-01, End date: 2021-11-30
