Project acronym 3DBrainStrom
Project Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
Researcher (PI) Ronit Satchi Fainaro
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Summary
Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Max ERC Funding
2 353 125 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym 3Ps
Project 3Ps
Plastic-Antibodies, Plasmonics and Photovoltaic-Cells: on-site screening of cancer biomarkers made possible
Researcher (PI) Maria Goreti Ferreira Sales
Host Institution (HI) INSTITUTO SUPERIOR DE ENGENHARIA DO PORTO
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Summary
This project presents a new concept for the detection, diagnosis and monitoring of cancer biomarker patterns in point-of-care. The device under development will make use of the selectivity of the plastic antibodies as sensing materials and the interference they will play on the normal operation of a photovoltaic cell.
Plastic antibodies will be designed by surface imprinting procedures. Self-assembled monolayer and molecular imprinting techniques will be merged in this process because they allow the self-assembly of nanostructured materials on a “bottom-up” nanofabrication approach. A dye-sensitized solar cell will be used as photovoltaic cell. It includes a liquid interface in the cell circuit, which allows the introduction of the sample (also in liquid phase) without disturbing the normal cell operation. Furthermore, it works well with rather low cost materials and requires mild and easy processing conditions. The cell will be equipped with plasmonic structures to enhance light absorption and cell efficiency.
The device under development will be easily operated by any clinician or patient. It will require ambient light and a regular multimeter. Eye detection will be also tried out.
Max ERC Funding
998 584 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym AGENSI
Project A Genetic View into Past Sea Ice Variability in the Arctic
Researcher (PI) Stijn DE SCHEPPER
Host Institution (HI) NORCE NORWEGIAN RESEARCH CENTRE AS
Call Details Consolidator Grant (CoG), PE10, ERC-2018-COG
Summary Arctic sea ice decline is the exponent of the rapidly transforming Arctic climate. The ensuing local and global implications can be understood by studying past climate transitions, yet few methods are available to examine past Arctic sea ice cover, severely restricting our understanding of sea ice in the climate system. The decline in Arctic sea ice cover is a ‘canary in the coalmine’ for the state of our climate, and if greenhouse gas emissions remain unchecked, summer sea ice loss may pass a critical threshold that could drastically transform the Arctic. Because historical observations are limited, it is crucial to have reliable proxies for assessing natural sea ice variability, its stability and sensitivity to climate forcing on different time scales. Current proxies address aspects of sea ice variability, but are limited due to a selective fossil record, preservation effects, regional applicability, or being semi-quantitative. With such restraints on our knowledge about natural variations and drivers, major uncertainties about the future remain.
I propose to develop and apply a novel sea ice proxy that exploits genetic information stored in marine sediments, sedimentary ancient DNA (sedaDNA). This innovation uses the genetic signature of phytoplankton communities from surface waters and sea ice as it gets stored in sediments. This wealth of information has not been explored before for reconstructing sea ice conditions. Preliminary results from my cross-disciplinary team indicate that our unconventional approach can provide a detailed, qualitative account of past sea ice ecosystems and quantitative estimates of sea ice parameters. I will address fundamental questions about past Arctic sea ice variability on different timescales, information essential to provide a framework upon which to assess the ecological and socio-economic consequences of a changing Arctic. This new proxy is not limited to sea ice research and can transform the field of paleoceanography.
Summary
Arctic sea ice decline is the exponent of the rapidly transforming Arctic climate. The ensuing local and global implications can be understood by studying past climate transitions, yet few methods are available to examine past Arctic sea ice cover, severely restricting our understanding of sea ice in the climate system. The decline in Arctic sea ice cover is a ‘canary in the coalmine’ for the state of our climate, and if greenhouse gas emissions remain unchecked, summer sea ice loss may pass a critical threshold that could drastically transform the Arctic. Because historical observations are limited, it is crucial to have reliable proxies for assessing natural sea ice variability, its stability and sensitivity to climate forcing on different time scales. Current proxies address aspects of sea ice variability, but are limited due to a selective fossil record, preservation effects, regional applicability, or being semi-quantitative. With such restraints on our knowledge about natural variations and drivers, major uncertainties about the future remain.
I propose to develop and apply a novel sea ice proxy that exploits genetic information stored in marine sediments, sedimentary ancient DNA (sedaDNA). This innovation uses the genetic signature of phytoplankton communities from surface waters and sea ice as it gets stored in sediments. This wealth of information has not been explored before for reconstructing sea ice conditions. Preliminary results from my cross-disciplinary team indicate that our unconventional approach can provide a detailed, qualitative account of past sea ice ecosystems and quantitative estimates of sea ice parameters. I will address fundamental questions about past Arctic sea ice variability on different timescales, information essential to provide a framework upon which to assess the ecological and socio-economic consequences of a changing Arctic. This new proxy is not limited to sea ice research and can transform the field of paleoceanography.
Max ERC Funding
2 615 858 €
Duration
Start date: 2019-08-01, End date: 2024-07-31
Project acronym ALCOHOLLIFECOURSE
Project Alcohol Consumption across the Life-course: Determinants and Consequences
Researcher (PI) Anne Rebecca Britton
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary The epidemiology of alcohol use and related health consequences plays a vital role by monitoring populations’ alcohol consumption patterns and problems associated with drinking. Such studies seek to explain mechanisms linking consumption to harm and ultimately to reduce the health burden. Research needs to consider changes in drinking behaviour over the life-course. The current evidence base lacks the consideration of the complexity of lifetime consumption patterns, the predictors of change and subsequent health risks.
Aims of the study
1. To describe age-related trajectories of drinking in different settings and to determine the extent to which individual and social contextual factors, including socioeconomic position, social networks and life events influence drinking pattern trajectories.
2. To estimate the impact of drinking trajectories on physical functioning and disease and to disentangle the exposure-outcome associations in terms of a) timing, i.e. health effect of drinking patterns in early, mid and late life; and b) duration, i.e. whether the impact of drinking accumulates over time.
3. To test the bidirectional associations between health and changes in consumption over the life-course in order to estimate the relative importance of these effects and to determine the dominant temporal direction.
4. To explore mechanisms and pathways through which drinking trajectories affect health and functioning in later life and to examine the role played by potential effect modifiers of the association between drinking and poor health.
Several large, longitudinal cohort studies from European countries with repeated measures of alcohol consumption will be combined and analysed to address the aims. A new team will be formed consisting of the PI, a Research Associate and two PhD students. Dissemination will be through journals, conferences, and culminating in a one-day workshop for academics, practitioners and policy makers in the alcohol field.
Summary
The epidemiology of alcohol use and related health consequences plays a vital role by monitoring populations’ alcohol consumption patterns and problems associated with drinking. Such studies seek to explain mechanisms linking consumption to harm and ultimately to reduce the health burden. Research needs to consider changes in drinking behaviour over the life-course. The current evidence base lacks the consideration of the complexity of lifetime consumption patterns, the predictors of change and subsequent health risks.
Aims of the study
1. To describe age-related trajectories of drinking in different settings and to determine the extent to which individual and social contextual factors, including socioeconomic position, social networks and life events influence drinking pattern trajectories.
2. To estimate the impact of drinking trajectories on physical functioning and disease and to disentangle the exposure-outcome associations in terms of a) timing, i.e. health effect of drinking patterns in early, mid and late life; and b) duration, i.e. whether the impact of drinking accumulates over time.
3. To test the bidirectional associations between health and changes in consumption over the life-course in order to estimate the relative importance of these effects and to determine the dominant temporal direction.
4. To explore mechanisms and pathways through which drinking trajectories affect health and functioning in later life and to examine the role played by potential effect modifiers of the association between drinking and poor health.
Several large, longitudinal cohort studies from European countries with repeated measures of alcohol consumption will be combined and analysed to address the aims. A new team will be formed consisting of the PI, a Research Associate and two PhD students. Dissemination will be through journals, conferences, and culminating in a one-day workshop for academics, practitioners and policy makers in the alcohol field.
Max ERC Funding
1 032 815 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym ALLELECHOKER
Project DNA binding proteins for treatment of gain of function mutations
Researcher (PI) Enrico Maria Surace
Host Institution (HI) FONDAZIONE TELETHON
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Summary
Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations
Max ERC Funding
1 354 840 €
Duration
Start date: 2013-02-01, End date: 2018-01-31
Project acronym AMYTOX
Project Amyloid fibril cytotoxicity: new insights from novel approaches
Researcher (PI) Sheena Radford
Host Institution (HI) UNIVERSITY OF LEEDS
Call Details Advanced Grant (AdG), LS1, ERC-2012-ADG_20120314
Summary Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Summary
Despite the discovery of amyloidosis more than a century ago, the molecular and cellular mechanisms of these devastating human disorders remain obscure. In addition to their involvement in disease, amyloid fibrils perform physiological functions, whilst others have potentials as biomaterials. To realise their use in nanotechnology and to enable the development of amyloid therapies, there is an urgent need to understand the molecular pathways of amyloid assembly and to determine how amyloid fibrils interact with cells and cellular components. The challenges lie in the transient nature and low population of aggregating species and the panoply of amyloid fibril structures. This molecular complexity renders identification of the culprits of amyloid disease impossible to achieve using traditional methods.
Here I propose a series of exciting experiments that aim to cast new light on the molecular and cellular mechanisms of amyloidosis by exploiting approaches capable of imaging individual protein molecules or single protein fibrils in vitro and in living cells. The proposal builds on new data from our laboratory that have shown that amyloid fibrils (disease-associated, functional and created from de novo designed sequences) kill cells by a mechanism that depends on fibril length and on cellular uptake. Specifically, I will (i) use single molecule fluorescence and non-covalent mass spectrometry and to determine why short fibril samples disrupt biological membranes more than their longer counterparts and electron tomography to determine, for the first time, the structural properties of cytotoxic fibril ends; (ii) develop single molecule force spectroscopy to probe the interactions between amyloid precursors, fibrils and cellular membranes; and (iii) develop cell biological assays to discover the biological mechanism(s) of amyloid-induced cell death and high resolution imaging and electron tomography to visualise amyloid fibrils in the act of killing living cells.
Max ERC Funding
2 498 465 €
Duration
Start date: 2013-05-01, End date: 2019-04-30
Project acronym Antivessel-T-Cells
Project Development of Vascular-Disrupting Lymphocyte Therapy for Tumours
Researcher (PI) Georgios Coukos
Host Institution (HI) CENTRE HOSPITALIER UNIVERSITAIRE VAUDOIS
Call Details Advanced Grant (AdG), LS7, ERC-2012-ADG_20120314
Summary T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory.
I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.
Summary
T cell engineering with chimeric antigen receptors has opened the door to effective immunotherapy. CARs are fusion genes encoding receptors whose extracellular domain comprises a single chain variable fragment (scFv) antibody that binds to a tumour surface epitope, while the intracellular domain comprises the signalling module of CD3ζ along with powerful costimulatory domains (e.g. CD28 and/or 4-1BB). CARs are a major breakthrough, since they allow bypassing HLA restrictions or loss, and they can incorporate potent costimulatory signals tailored to optimize T cell function. However, solid tumours present challenges, since they are often genetically unstable, and the tumour microenvironment impedes T cell function. The tumour vasculature is a much more stable and accessible target, and its disruption has catastrophic consequences for tumours. Nevertheless, the lack of affinity reagents has impeded progress in this area. The objectives of this proposal are to develop the first potent and safe tumour vascular-disrupting tumour immunotherapy using scFv’s and CARs uniquely available in my laboratory.
I propose to use these innovative CARs to understand for the first time the molecular mechanisms underlying the interactions between anti-vascular CAR-T cells and tumour endothelium, and exploit them to maximize tumour vascular destruction. I also intend to employ innovative engineering approaches to minimize the chance of reactivity against normal vasculature. Lastly, I propose to manipulate the tumour damage mechanisms ensuing anti-vascular therapy, to maximize tumour rejection through immunomodulation. We are poised to elucidate critical interactions between tumour endothelium and anti-vascular T cells, and bring to bear cancer therapy of unparalleled power. The impact of this work could be transforming, given the applicability of tumour-vascular disruption across most common tumour types.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-08-01, End date: 2018-07-31
Project acronym ARCHEIS
Project Understanding the onset and impact of Aquatic Resource Consumption in Human Evolution using novel Isotopic tracerS
Researcher (PI) Klervia Marie Madalen JAOUEN
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), PE10, ERC-2018-STG
Summary The onset of the systematic consumption of marine resources is thought to mark a turning point for the hominin lineage. To date, this onset cannot be traced, since classic isotope markers are not preserved beyond 50 - 100 ky. Aquatic food products are essential in human nutrition as the main source of polyunsaturated fatty acids in hunter-gatherer diets. The exploitation of marine resources is also thought to have reduced human mobility and enhanced social and technological complexification. Systematic aquatic food consumption could well have been a distinctive feature of Homo sapiens species among his fellow hominins, and has been linked to the astonishing leap in human intelligence and conscience. Yet, this hypothesis is challenged by the existence of mollusk and marine mammal bone remains at Neanderthal archeological sites. Recent work demonstrated the sensitivity of Zn isotope composition in bioapatite, the mineral part of bones and teeth, to dietary Zn. By combining classic (C and C/N isotope analyses) and innovative techniques (compound specific C/N and bulk Zn isotope analyses), I will develop a suite of sensitive tracers for shellfish, fish and marine mammal consumption. Shellfish consumption will be investigated by comparing various South American and European prehistoric populations from the Atlantic coast associated to shell-midden and fish-mounds. Marine mammal consumption will be traced using an Inuit population of Arctic Canada and the Wairau Bar population of New Zealand. C/N/Zn isotope compositions of various aquatic products will also be assessed, as well as isotope fractionation during intestinal absorption. I will then use the fully calibrated isotope tools to detect and characterize the onset of marine food exploitation in human history, which will answer the question of its specificity to our species. Neanderthal, early modern humans and possibly other hominin remains from coastal and inland sites will be compared in that purpose.
Summary
The onset of the systematic consumption of marine resources is thought to mark a turning point for the hominin lineage. To date, this onset cannot be traced, since classic isotope markers are not preserved beyond 50 - 100 ky. Aquatic food products are essential in human nutrition as the main source of polyunsaturated fatty acids in hunter-gatherer diets. The exploitation of marine resources is also thought to have reduced human mobility and enhanced social and technological complexification. Systematic aquatic food consumption could well have been a distinctive feature of Homo sapiens species among his fellow hominins, and has been linked to the astonishing leap in human intelligence and conscience. Yet, this hypothesis is challenged by the existence of mollusk and marine mammal bone remains at Neanderthal archeological sites. Recent work demonstrated the sensitivity of Zn isotope composition in bioapatite, the mineral part of bones and teeth, to dietary Zn. By combining classic (C and C/N isotope analyses) and innovative techniques (compound specific C/N and bulk Zn isotope analyses), I will develop a suite of sensitive tracers for shellfish, fish and marine mammal consumption. Shellfish consumption will be investigated by comparing various South American and European prehistoric populations from the Atlantic coast associated to shell-midden and fish-mounds. Marine mammal consumption will be traced using an Inuit population of Arctic Canada and the Wairau Bar population of New Zealand. C/N/Zn isotope compositions of various aquatic products will also be assessed, as well as isotope fractionation during intestinal absorption. I will then use the fully calibrated isotope tools to detect and characterize the onset of marine food exploitation in human history, which will answer the question of its specificity to our species. Neanderthal, early modern humans and possibly other hominin remains from coastal and inland sites will be compared in that purpose.
Max ERC Funding
1 361 991 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym ARGO
Project The Quest of the Argonautes - from Myth to Reality
Researcher (PI) JOHN VAN DER OOST
Host Institution (HI) WAGENINGEN UNIVERSITY
Call Details Advanced Grant (AdG), LS1, ERC-2018-ADG
Summary Argonaute nucleases are key players of the eukaryotic RNA interference (RNAi) system. Using small RNA guides, these Argonaute (Ago) proteins specifically target complementary RNA molecules, resulting in regulation of a wide range of crucial processes, including chromosome organization, gene expression and anti-virus defence. Since 2010, my research team has studied closely-related prokaryotic Argonaute (pAgo) variants. This has revealed spectacular mechanistic variations: several thermophilic pAgos catalyse DNA-guided cleavage of double stranded DNA, but only at elevated temperatures. Interestingly, a recently discovered mesophilic Argonaute (CbAgo) can generate double strand DNA breaks at moderate temperatures, providing an excellent basis for this ARGO project. In addition, genome analysis has revealed many distantly-related Argonaute variants, often with unique domain architectures. Hence, the currently known Argonaute homologs are just the tip of the iceberg, and the stage is set for making a big leap in the exploration of the Argonaute family. Initially we will dissect the molecular basis of functional and mechanistic features of uncharacterized natural Argonaute variants, both in eukaryotes (the presence of an Ago-like subunit in the Mediator complex, strongly suggests a regulatory role of an elusive non-coding RNA ligand) and in prokaryotes (selected Ago variants possess distinct domains indicating novel functionalities). After their thorough biochemical characterization, I aim at engineering the functionality of the aforementioned CbAgo through an integrated rational & random approach, i.e. by tinkering of domains, and by an unprecedented in vitro laboratory evolution approach. Eventually, natural & synthetic Argonautes will be selected for their exploitation, and used for developing original genome editing applications (from silencing to base editing). Embarking on this ambitious ARGO expedition will lead us to many exciting discoveries.
Summary
Argonaute nucleases are key players of the eukaryotic RNA interference (RNAi) system. Using small RNA guides, these Argonaute (Ago) proteins specifically target complementary RNA molecules, resulting in regulation of a wide range of crucial processes, including chromosome organization, gene expression and anti-virus defence. Since 2010, my research team has studied closely-related prokaryotic Argonaute (pAgo) variants. This has revealed spectacular mechanistic variations: several thermophilic pAgos catalyse DNA-guided cleavage of double stranded DNA, but only at elevated temperatures. Interestingly, a recently discovered mesophilic Argonaute (CbAgo) can generate double strand DNA breaks at moderate temperatures, providing an excellent basis for this ARGO project. In addition, genome analysis has revealed many distantly-related Argonaute variants, often with unique domain architectures. Hence, the currently known Argonaute homologs are just the tip of the iceberg, and the stage is set for making a big leap in the exploration of the Argonaute family. Initially we will dissect the molecular basis of functional and mechanistic features of uncharacterized natural Argonaute variants, both in eukaryotes (the presence of an Ago-like subunit in the Mediator complex, strongly suggests a regulatory role of an elusive non-coding RNA ligand) and in prokaryotes (selected Ago variants possess distinct domains indicating novel functionalities). After their thorough biochemical characterization, I aim at engineering the functionality of the aforementioned CbAgo through an integrated rational & random approach, i.e. by tinkering of domains, and by an unprecedented in vitro laboratory evolution approach. Eventually, natural & synthetic Argonautes will be selected for their exploitation, and used for developing original genome editing applications (from silencing to base editing). Embarking on this ambitious ARGO expedition will lead us to many exciting discoveries.
Max ERC Funding
2 177 158 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym ARTimmune
Project Programmable ARTificial immune systems to fight cancer
Researcher (PI) Carl FIGDOR
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Immunotherapy has entered centre stage as a novel treatment modality for cancer. Notwithstanding this major step forward, toxicity and immunosuppression remain major obstacles, and illustrate the pressing need for more powerful and specific immunotherapies against cancer. To overcome these roadblocks, in ARTimmune, I propose to follow a radically different approach by developing local rather than systemic immunotherapies. Taking advantage of the architecture of a lymph node (LN), I aim to design fully synthetic immune niches to locally instruct immune cell function. I hypothesize that programmable synthetic immune niches, when injected next to a tumour, will act as local powerhouses to generate bursts of cytotoxic T cells for tumour destruction, without toxic side effects. Single cell transcriptomics on LN, obtained from patients that are vaccinated against cancer, will provide unique insight in communication within immune cell clusters and provide a blueprint for the intelligent design of synthetic immune niches. Chemical tools will be used to build branched polymeric structures decorated with immunomodulating molecules to mimic LN architecture. These will be injected, mixed with sponge-like scaffolds to provide porosity needed for immune cell infiltration. Programming of immune cell function will be accomplished by in vivo targeting- and proteolytic activation- of immunomodulators for fine-tuning, and to extend the life span of these local powerhouses. The innovative character of ARTimmune comes from: 1) novel fundamental immunological insight in complex communication within LN cell clusters, 2) a revolutionary new approach in immunotherapy, by the development of 3) injectable- and 4) programmable- synthetic immune niches by state-of-the-art chemical technology. When successful, it will revolutionize cancer immunotherapy, moving from maximal tolerable dose systemic treatment with significant toxicity to local low dose treatment in the direct vicinity of a tumour
Summary
Immunotherapy has entered centre stage as a novel treatment modality for cancer. Notwithstanding this major step forward, toxicity and immunosuppression remain major obstacles, and illustrate the pressing need for more powerful and specific immunotherapies against cancer. To overcome these roadblocks, in ARTimmune, I propose to follow a radically different approach by developing local rather than systemic immunotherapies. Taking advantage of the architecture of a lymph node (LN), I aim to design fully synthetic immune niches to locally instruct immune cell function. I hypothesize that programmable synthetic immune niches, when injected next to a tumour, will act as local powerhouses to generate bursts of cytotoxic T cells for tumour destruction, without toxic side effects. Single cell transcriptomics on LN, obtained from patients that are vaccinated against cancer, will provide unique insight in communication within immune cell clusters and provide a blueprint for the intelligent design of synthetic immune niches. Chemical tools will be used to build branched polymeric structures decorated with immunomodulating molecules to mimic LN architecture. These will be injected, mixed with sponge-like scaffolds to provide porosity needed for immune cell infiltration. Programming of immune cell function will be accomplished by in vivo targeting- and proteolytic activation- of immunomodulators for fine-tuning, and to extend the life span of these local powerhouses. The innovative character of ARTimmune comes from: 1) novel fundamental immunological insight in complex communication within LN cell clusters, 2) a revolutionary new approach in immunotherapy, by the development of 3) injectable- and 4) programmable- synthetic immune niches by state-of-the-art chemical technology. When successful, it will revolutionize cancer immunotherapy, moving from maximal tolerable dose systemic treatment with significant toxicity to local low dose treatment in the direct vicinity of a tumour
Max ERC Funding
2 500 000 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
