Project acronym ACCENT
Project How antibodies and complement orchestrate protective immune responses against bacteria
Researcher (PI) suzan ROOIJAKKERS
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), LS6, ERC-2020-COG
Summary Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Summary
Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
Project acronym AdLibYeast
Project Synthetic platforms for ad libitum remodelling of yeast central metabolism
Researcher (PI) Pascale Andree Simone Lapujade Daran
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Country Netherlands
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary Replacement of petrochemistry by bio-based processes is key to sustainable development and requires microbes equipped with novel-to-nature capabilities. The efficiency of such engineered microbes strongly depends on their native metabolic networks. However, aeons of evolution have optimized these networks for fitness in nature rather than for industrial performance. As a result, central metabolic networks are complex and encoded by mosaic microbial genomes in which genes, irrespective of their function, are scattered over the genome and chromosomes. This absence of a modular organization tremendously restricts genetic accessibility and presents a major hurdle for fundamental understanding and rational engineering of central metabolism. To conquer this limitation, I introduce the concept of ‘pathway swapping’, which will enable experimenters to remodel the core machinery of microbes at will.
Using the yeast Saccharomyces cerevisiae, an industrial biotechnology work horse and model eukaryotic cell, I propose to design and construct a microbial chassis in which all genes encoding enzymes in central carbon metabolism are relocated to a specialized synthetic chromosome, from which they can be easily swapped by any – homologous or heterologous – synthetic pathway. This challenging and innovative project paves the way for a modular approach to engineering of central metabolism.
Beyond providing a ground-breaking enabling technology, the ultimate goal of the pathway swapping technology is to address hitherto unanswered fundamental questions. Access to a sheer endless variety of configurations of central metabolism offers unique, new possibilities to study the fundamental design of metabolic pathways, the constraints that have shaped them and unifying principles for their structure and regulation. Moreover, this technology enables fast, combinatorial optimization studies on central metabolism to optimize its performance in biotechnological purposes.
Summary
Replacement of petrochemistry by bio-based processes is key to sustainable development and requires microbes equipped with novel-to-nature capabilities. The efficiency of such engineered microbes strongly depends on their native metabolic networks. However, aeons of evolution have optimized these networks for fitness in nature rather than for industrial performance. As a result, central metabolic networks are complex and encoded by mosaic microbial genomes in which genes, irrespective of their function, are scattered over the genome and chromosomes. This absence of a modular organization tremendously restricts genetic accessibility and presents a major hurdle for fundamental understanding and rational engineering of central metabolism. To conquer this limitation, I introduce the concept of ‘pathway swapping’, which will enable experimenters to remodel the core machinery of microbes at will.
Using the yeast Saccharomyces cerevisiae, an industrial biotechnology work horse and model eukaryotic cell, I propose to design and construct a microbial chassis in which all genes encoding enzymes in central carbon metabolism are relocated to a specialized synthetic chromosome, from which they can be easily swapped by any – homologous or heterologous – synthetic pathway. This challenging and innovative project paves the way for a modular approach to engineering of central metabolism.
Beyond providing a ground-breaking enabling technology, the ultimate goal of the pathway swapping technology is to address hitherto unanswered fundamental questions. Access to a sheer endless variety of configurations of central metabolism offers unique, new possibilities to study the fundamental design of metabolic pathways, the constraints that have shaped them and unifying principles for their structure and regulation. Moreover, this technology enables fast, combinatorial optimization studies on central metabolism to optimize its performance in biotechnological purposes.
Max ERC Funding
2 149 718 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AlgoFinance
Project Algorithmic Finance: Inquiring into the Reshaping of Financial Markets
Researcher (PI) Christian BORCH
Host Institution (HI) COPENHAGEN BUSINESS SCHOOL
Country Denmark
Call Details Consolidator Grant (CoG), SH3, ERC-2016-COG
Summary Present-day financial markets are turning algorithmic, as market orders are increasingly being executed by fully automated computer algorithms, without any direct human intervention. Although algorithmic finance seems to fundamentally reshape the central dynamics in financial markets, and even though it prompts core sociological questions, it has not yet received any systematic attention. In a pioneering contribution to economic sociology and social studies of finance, ALGOFINANCE aims to understand how and with what consequences the turn to algorithms is changing financial markets. The overall concept and central contributions of ALGOFINANCE are the following: (1) on an intra-firm level, the project examines how the shift to algorithmic finance reshapes the ways in which trading firms operate, and does so by systematically and empirically investigating the reconfiguration of organizational structures and employee subjectivity; (2) on an inter-algorithmic level, it offers a ground-breaking methodology (agent-based modelling informed by qualitative data) to grasp how trading algorithms interact with one another in a fully digital space; and (3) on the level of market sociality, it proposes a novel theorization of how intra-firm and inter-algorithmic dynamics can be conceived of as introducing a particular form of sociality that is characteristic to algorithmic finance: a form of sociality-as-association heuristically analyzed as imitation. None of these three levels have received systematic attention in the state-of-the-art literature. Addressing them will significantly advance the understanding of present-day algorithmic finance in economic sociology. By contributing novel empirical, methodological, and theoretical understandings of the functioning and consequences of algorithms, ALGOFINANCE will pave the way for other research into digital sociology and the broader algorithmization of society.
Summary
Present-day financial markets are turning algorithmic, as market orders are increasingly being executed by fully automated computer algorithms, without any direct human intervention. Although algorithmic finance seems to fundamentally reshape the central dynamics in financial markets, and even though it prompts core sociological questions, it has not yet received any systematic attention. In a pioneering contribution to economic sociology and social studies of finance, ALGOFINANCE aims to understand how and with what consequences the turn to algorithms is changing financial markets. The overall concept and central contributions of ALGOFINANCE are the following: (1) on an intra-firm level, the project examines how the shift to algorithmic finance reshapes the ways in which trading firms operate, and does so by systematically and empirically investigating the reconfiguration of organizational structures and employee subjectivity; (2) on an inter-algorithmic level, it offers a ground-breaking methodology (agent-based modelling informed by qualitative data) to grasp how trading algorithms interact with one another in a fully digital space; and (3) on the level of market sociality, it proposes a novel theorization of how intra-firm and inter-algorithmic dynamics can be conceived of as introducing a particular form of sociality that is characteristic to algorithmic finance: a form of sociality-as-association heuristically analyzed as imitation. None of these three levels have received systematic attention in the state-of-the-art literature. Addressing them will significantly advance the understanding of present-day algorithmic finance in economic sociology. By contributing novel empirical, methodological, and theoretical understandings of the functioning and consequences of algorithms, ALGOFINANCE will pave the way for other research into digital sociology and the broader algorithmization of society.
Max ERC Funding
1 590 036 €
Duration
Start date: 2017-05-01, End date: 2021-04-30
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 ANT
Project Automata in Number Theory
Researcher (PI) Boris Adamczewski
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Consolidator Grant (CoG), PE1, ERC-2014-CoG
Summary Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics.
A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.
Summary
Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics.
A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.
Max ERC Funding
1 438 745 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym ANTILEAK
Project Development of antagonists of vascular leakage
Researcher (PI) Pipsa SAHARINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Country Finland
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Summary
Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.
Max ERC Funding
1 999 770 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym ArtHep
Project Hepatocytes-Like Microreactors for Liver Tissue Engineering
Researcher (PI) Brigitte STADLER
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Consolidator Grant (CoG), LS9, ERC-2018-COG
Summary The global epidemics of obesity and diabetes type 2 lead to higher abundancy of medical conditions like non-alcoholic fatty liver disease causing an increase in liver failure and demand for liver transplants. The shortage of donor organs and the insufficient success in tissue engineering to ex vivo grow complex organs like the liver is a global medical challenge.
ArtHep targets the assembly of hepatic-like tissue, consisting of biological and synthetic entities, mimicking the core structure elements and key functions of the liver. ArtHep comprises an entirely new concept in liver regeneration with multi-angled core impact: i) cell mimics are expected to reduce the pressure to obtain donor cells, ii) the integrated biocatalytic subunits are destined to take over tasks of the damaged liver slowing down the progress of liver damage, and iii) the matching micro-environment in the bioprinted tissue is anticipated to facilitate the connection between the transplant and the liver.
Success criteria of ArtHep include engineering enzyme-mimics, which can perform core biocatalytic conversions similar to the liver, the assembly of biocatalytic active subunits and their encapsulation in cell-like carriers (microreactors), which have mechanical properties that match the liver tissue and that have a camouflaging coating to mimic the surface cues of liver tissue-relevant cells. Finally, matured bioprinted liver-lobules consisting of microreactors and live cells need to connect to liver tissue when transplanted into rats.
I am convinced that the ground-breaking research in ArtHep will contribute to the excellence of science in Europe while providing the game-changing foundation to counteract the ever increasing donor liver shortage. Further, consolidating my scientific efforts and moving them forward into unexplored dimensions in biomimicry for medical purposes, is a unique opportunity to advance my career.
Summary
The global epidemics of obesity and diabetes type 2 lead to higher abundancy of medical conditions like non-alcoholic fatty liver disease causing an increase in liver failure and demand for liver transplants. The shortage of donor organs and the insufficient success in tissue engineering to ex vivo grow complex organs like the liver is a global medical challenge.
ArtHep targets the assembly of hepatic-like tissue, consisting of biological and synthetic entities, mimicking the core structure elements and key functions of the liver. ArtHep comprises an entirely new concept in liver regeneration with multi-angled core impact: i) cell mimics are expected to reduce the pressure to obtain donor cells, ii) the integrated biocatalytic subunits are destined to take over tasks of the damaged liver slowing down the progress of liver damage, and iii) the matching micro-environment in the bioprinted tissue is anticipated to facilitate the connection between the transplant and the liver.
Success criteria of ArtHep include engineering enzyme-mimics, which can perform core biocatalytic conversions similar to the liver, the assembly of biocatalytic active subunits and their encapsulation in cell-like carriers (microreactors), which have mechanical properties that match the liver tissue and that have a camouflaging coating to mimic the surface cues of liver tissue-relevant cells. Finally, matured bioprinted liver-lobules consisting of microreactors and live cells need to connect to liver tissue when transplanted into rats.
I am convinced that the ground-breaking research in ArtHep will contribute to the excellence of science in Europe while providing the game-changing foundation to counteract the ever increasing donor liver shortage. Further, consolidating my scientific efforts and moving them forward into unexplored dimensions in biomimicry for medical purposes, is a unique opportunity to advance my career.
Max ERC Funding
1 992 289 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym BHIVE
Project Bio-derived HIgh Value polymers through novel Enzyme function
Researcher (PI) Emma Rusi Master
Host Institution (HI) AALTO KORKEAKOULUSAATIO SR
Country Finland
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary Recent advances in systems-level study of cells and organisms have revealed the enormous potential to live more sustainably through better use of biological processes. Plants sustainably synthesize the most abundant and diverse materials on Earth. By applying recent advances in life science technology, we can better harness renewable plant resources and bioconversion processes, to develop environmentally and politically sustainable human enterprise and lifestyles. At the same time, the global market for high-value biochemicals and bioplastics from forest and agricultural sources is rapidly increasing, which presents new opportunities for forest and agricultural sectors.
The overall aim of BHIVE is to illuminate uncharted regions of genome and metagenome sequences to discover entirely new protein families that can be used to sustainably synthesize novel, high-value biomaterials from renewable plant resources. The approach will include three parallel research thrusts: 1) strategic analysis of transcriptome and metagenome sequences to identify proteins with entirely unknown function relevant to biomass (lignocellulose) transformation, 2) mapping of uncharted regions within phylogenetic trees of poorly characterized enzyme families with recognized potential to modify the chemistry and biophysical properties of plant polysaccharides, and 3) the design and development of novel enzyme screens to directly address the increasing limitations of existing assays to uncover entirely new protein functions. BHIVE will be unique in its undivided focus on characterizing lignocellulose-active proteins encoded by the 30-40% of un-annotated sequence, or genomic “dark matter”, typical of nearly all genome sequences. In this way, BHIVE tackles a key constraint to fully realizing the societal and environmental benefits of the genomics era.
Summary
Recent advances in systems-level study of cells and organisms have revealed the enormous potential to live more sustainably through better use of biological processes. Plants sustainably synthesize the most abundant and diverse materials on Earth. By applying recent advances in life science technology, we can better harness renewable plant resources and bioconversion processes, to develop environmentally and politically sustainable human enterprise and lifestyles. At the same time, the global market for high-value biochemicals and bioplastics from forest and agricultural sources is rapidly increasing, which presents new opportunities for forest and agricultural sectors.
The overall aim of BHIVE is to illuminate uncharted regions of genome and metagenome sequences to discover entirely new protein families that can be used to sustainably synthesize novel, high-value biomaterials from renewable plant resources. The approach will include three parallel research thrusts: 1) strategic analysis of transcriptome and metagenome sequences to identify proteins with entirely unknown function relevant to biomass (lignocellulose) transformation, 2) mapping of uncharted regions within phylogenetic trees of poorly characterized enzyme families with recognized potential to modify the chemistry and biophysical properties of plant polysaccharides, and 3) the design and development of novel enzyme screens to directly address the increasing limitations of existing assays to uncover entirely new protein functions. BHIVE will be unique in its undivided focus on characterizing lignocellulose-active proteins encoded by the 30-40% of un-annotated sequence, or genomic “dark matter”, typical of nearly all genome sequences. In this way, BHIVE tackles a key constraint to fully realizing the societal and environmental benefits of the genomics era.
Max ERC Funding
1 977 781 €
Duration
Start date: 2015-09-01, End date: 2020-12-31
Project acronym BioAqua
Project Water as cosubstrate for biocatalytic redox reactions
Researcher (PI) Frank Hollmann
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Country Netherlands
Call Details Consolidator Grant (CoG), LS9, ERC-2014-CoG
Summary The research proposed in BioAqua aims at breaking new ground in the area of catalysis by enabling water-driven biocatalytic redox reactions.
Oxidoreductases are a class of enzymes with a very high potential for preparative organic synthesis, which is why they are increasingly used also on industrial scale. The current state-of-the-art, however, utilises valuable high-energy cosubstrates (such as glucose and alcohols) to promote oxidoreductases. Thereby valuable (and edible) building blocks are wasted as sacrificial electron donors which will have significant ethical (food for chemistry), economic and environmental consequences once redox biocatalysis is applied at scale.
I envision utilizing water as sacrificial electron donor. Hence, a simple and abundant cosubstrate will be used instead of the valuable cosubstrates mentioned above. This will be a completely new approach in (bio)catalysis.
However, activating water for this purpose water is extremely difficult due to its kinetic and thermodynamic inertness. To solve this problem, I propose using visible light as external energy source and advanced chemical catalysts to facilitate water oxidation. The electrons liberated in this process will be made available (for the first time) to promote oxidoreductases-catalysed transformations.
BioAqua represents an entirely new paradigm in catalysis as I will bridge the gap between photocatalysis and biocatalysis enabling cleaner and more efficient reaction schemes.
Summary
The research proposed in BioAqua aims at breaking new ground in the area of catalysis by enabling water-driven biocatalytic redox reactions.
Oxidoreductases are a class of enzymes with a very high potential for preparative organic synthesis, which is why they are increasingly used also on industrial scale. The current state-of-the-art, however, utilises valuable high-energy cosubstrates (such as glucose and alcohols) to promote oxidoreductases. Thereby valuable (and edible) building blocks are wasted as sacrificial electron donors which will have significant ethical (food for chemistry), economic and environmental consequences once redox biocatalysis is applied at scale.
I envision utilizing water as sacrificial electron donor. Hence, a simple and abundant cosubstrate will be used instead of the valuable cosubstrates mentioned above. This will be a completely new approach in (bio)catalysis.
However, activating water for this purpose water is extremely difficult due to its kinetic and thermodynamic inertness. To solve this problem, I propose using visible light as external energy source and advanced chemical catalysts to facilitate water oxidation. The electrons liberated in this process will be made available (for the first time) to promote oxidoreductases-catalysed transformations.
BioAqua represents an entirely new paradigm in catalysis as I will bridge the gap between photocatalysis and biocatalysis enabling cleaner and more efficient reaction schemes.
Max ERC Funding
1 998 020 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym Cancer-Recurrence
Project Tumor cell death supports recurrence of cancer
Researcher (PI) Jacobus Emiel van Rheenen
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Country Netherlands
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Introduction: Current anti-cancer treatments are often inefficient, while many patients initially benefit from anti-cancer drugs eventually experience relapse of resistant tumors throughout the body. Current clinical strategies mainly aim at inducing tumor cell death, but this induction may have unintentional and unwanted side effects on surviving tumor cells.
Preliminary data: We show that after chemotherapy-induced initial regression, PyMT mammary tumors reappear. During regression, we observe an increased number of cells that have undergone epithelial-mesenchymal transition (EMT) and become migratory. We show that migration can be induced upon uptake of extracellular vesicles (e.g. apoptotic bodies). Our findings suggest that EMT is induced upon chemotherapy, through e.g. EV uptake, potentially leading to migration and growth of surviving cells.
Hypothesis and main aim: Based on preliminary data, we hypothesize that tumor cell death induces migration and growth of the surviving tumor cells. We aim to identify the key cell types and mechanisms that mediate this effect, and establish whether interference with these cells and mechanisms can reduce recurrence of tumors after chemotherapy.
Approach: We have developed unique intravital imaging tools and genetically engineered fluorescent mice to visualize and characterize if and how dying tumor cells can affect surrounding surviving tumor and stromal cells. We will test whether dying tumor cells can influence the growth, migration, dissemination and metastasis of surviving tumor cells directly or indirectly through stromal cells. We will identify potential targets to block the influence of the dying tumor cells, and test whether this blockade inhibits the unintended side-effects of tumor cell death.
Conclusion: With the studies proposed in this grant, we will gain fundamental insights on how induction of tumor cell death, the universal aim of therapy, could play a role in growth and spread of surviving tumor cells.
Summary
Introduction: Current anti-cancer treatments are often inefficient, while many patients initially benefit from anti-cancer drugs eventually experience relapse of resistant tumors throughout the body. Current clinical strategies mainly aim at inducing tumor cell death, but this induction may have unintentional and unwanted side effects on surviving tumor cells.
Preliminary data: We show that after chemotherapy-induced initial regression, PyMT mammary tumors reappear. During regression, we observe an increased number of cells that have undergone epithelial-mesenchymal transition (EMT) and become migratory. We show that migration can be induced upon uptake of extracellular vesicles (e.g. apoptotic bodies). Our findings suggest that EMT is induced upon chemotherapy, through e.g. EV uptake, potentially leading to migration and growth of surviving cells.
Hypothesis and main aim: Based on preliminary data, we hypothesize that tumor cell death induces migration and growth of the surviving tumor cells. We aim to identify the key cell types and mechanisms that mediate this effect, and establish whether interference with these cells and mechanisms can reduce recurrence of tumors after chemotherapy.
Approach: We have developed unique intravital imaging tools and genetically engineered fluorescent mice to visualize and characterize if and how dying tumor cells can affect surrounding surviving tumor and stromal cells. We will test whether dying tumor cells can influence the growth, migration, dissemination and metastasis of surviving tumor cells directly or indirectly through stromal cells. We will identify potential targets to block the influence of the dying tumor cells, and test whether this blockade inhibits the unintended side-effects of tumor cell death.
Conclusion: With the studies proposed in this grant, we will gain fundamental insights on how induction of tumor cell death, the universal aim of therapy, could play a role in growth and spread of surviving tumor cells.
Max ERC Funding
2 000 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
