Project acronym 3D-JOINT
Project 3D Bioprinting of JOINT Replacements
Researcher (PI) Johannes Jos Malda
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Summary
The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Max ERC Funding
1 998 871 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym AdLibYeast
Project Synthetic platforms for ad libitum remodelling of yeast central metabolism
Researcher (PI) Pascale Andrée Simone Lapujade Daran
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
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 APOLOGY
Project Political Apologies across Cultures
Researcher (PI) Juliëtte Schaafsma
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT BRABANT
Call Details Consolidator Grant (CoG), SH2, ERC-2015-CoG
Summary In the past decades, there has been a considerable rise in the number of apologies offered by states for injustices and human rights violations. Among transitional justice scholars, there is significant debate about how useful such apologies are. Whereas some have applauded these gestures as an important step in peacemaking processes, others have argued that they may not fit in all cultures and may even be a risky tool for peacemaking. Unfortunately, theorizing and research in the field of transitional justice is still in its infancy and has not systematically addressed questions of cross-cultural variability yet. So, at present, we do not know whether political apologies are a universally viable way to restore justice and harmony. My project addresses this challenge. Using an innovative, interdisciplinary, and multi-method approach with in-depth interviews, (experimental) surveys, and content analyses of apologies, I analyze whether there are universals in how political apologies are valued, expressed, and interpreted or whether this varies as a function of cross-cultural differences in key values (collectivism and individualism) and norms (face and honor). Based on these findings, I build a theoretical framework that will fundamentally advance our understanding of the potential value and role of apologies in transitional justice processes. This project breaks new ground because it is the first to take the difficult step to collect cross-cultural data to examine whether key assumptions regarding political apologies hold across cultures. It is also the first in this area to use a multi-method approach, which makes it possible to take into account the complex reality of political apologies. Combining insights from transitional justice, cross-cultural psychology and anthropology, this project places theorizing on transitional justice on a much firmer footing and paves the way to more cross-culturally valid models to restore justice and promote reconciliation.
Summary
In the past decades, there has been a considerable rise in the number of apologies offered by states for injustices and human rights violations. Among transitional justice scholars, there is significant debate about how useful such apologies are. Whereas some have applauded these gestures as an important step in peacemaking processes, others have argued that they may not fit in all cultures and may even be a risky tool for peacemaking. Unfortunately, theorizing and research in the field of transitional justice is still in its infancy and has not systematically addressed questions of cross-cultural variability yet. So, at present, we do not know whether political apologies are a universally viable way to restore justice and harmony. My project addresses this challenge. Using an innovative, interdisciplinary, and multi-method approach with in-depth interviews, (experimental) surveys, and content analyses of apologies, I analyze whether there are universals in how political apologies are valued, expressed, and interpreted or whether this varies as a function of cross-cultural differences in key values (collectivism and individualism) and norms (face and honor). Based on these findings, I build a theoretical framework that will fundamentally advance our understanding of the potential value and role of apologies in transitional justice processes. This project breaks new ground because it is the first to take the difficult step to collect cross-cultural data to examine whether key assumptions regarding political apologies hold across cultures. It is also the first in this area to use a multi-method approach, which makes it possible to take into account the complex reality of political apologies. Combining insights from transitional justice, cross-cultural psychology and anthropology, this project places theorizing on transitional justice on a much firmer footing and paves the way to more cross-culturally valid models to restore justice and promote reconciliation.
Max ERC Funding
1 917 713 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym AUTOCOMPLEMENT
Project The role of complement in the induction of autoimmunity against post-translationally modified proteins
Researcher (PI) Leendert TROUW
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Consolidator Grant (CoG), LS7, ERC-2016-COG
Summary In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Summary
In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed.
Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions:
1) What is the physiological function of complement binding to PTM proteins?
2) Is the breach of tolerance towards PTM proteins influenced by complement?
3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity?
With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.
Max ERC Funding
1 999 803 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym Becoming Men
Project Becoming Men: Performing responsible masculinities in contemporary urban Africa
Researcher (PI) Eileen Marie Moyer
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Consolidator Grant (CoG), SH2, ERC-2014-CoG
Summary This anthropological study examines the reconfiguration of masculinities in urban Africa over the last 30 years. Focusing on how practices and discourses of empowerment and equality shape male subjectivities, this study builds upon a significant body of nuanced research on masculinities in Africa. Since the mid-1980s academic and public discourses have depicted African masculinity as both precarious and predatory. Economic insecurity, urbanization, shifting gender norms, and growing gender parity have accompanied claims that African masculinity is ‘in crisis’. More recently, new stories of urban men embracing responsible fatherhood, condemning intimate partner violence, and demanding homosexual rights have emerged as exemplars of progressive possibility. To disentangle these seemingly competing claims about African masculinities and shed light on the scientific, political, and economic projects that shape them, this research theorises that the discourses and practices that pathologise and politicise masculinity are simultaneously performing and producing gendered selves on multiple scales in the name of gender equality. Recently, ‘male involvement’ has become a rallying cry throughout the vast global development assemblage, around which governments, NGOs, research networks, activists, and local communities fight gender inequality to promote health, economic development, and human rights. In this research, a range of male-involvement initiatives provides a lens through which to study how masculinities are diversely imagined, (re)configured, and performed through men’s engagements with this assemblage, in both its local and global manifestations. Multi-sited ethnographic research will focus on six cities where the PI has active research ties: Nairobi and Kisumu, Kenya; Johannesburg and Durban, South Africa; and Dar es Salaam and Mwanza, Tanzania.
Summary
This anthropological study examines the reconfiguration of masculinities in urban Africa over the last 30 years. Focusing on how practices and discourses of empowerment and equality shape male subjectivities, this study builds upon a significant body of nuanced research on masculinities in Africa. Since the mid-1980s academic and public discourses have depicted African masculinity as both precarious and predatory. Economic insecurity, urbanization, shifting gender norms, and growing gender parity have accompanied claims that African masculinity is ‘in crisis’. More recently, new stories of urban men embracing responsible fatherhood, condemning intimate partner violence, and demanding homosexual rights have emerged as exemplars of progressive possibility. To disentangle these seemingly competing claims about African masculinities and shed light on the scientific, political, and economic projects that shape them, this research theorises that the discourses and practices that pathologise and politicise masculinity are simultaneously performing and producing gendered selves on multiple scales in the name of gender equality. Recently, ‘male involvement’ has become a rallying cry throughout the vast global development assemblage, around which governments, NGOs, research networks, activists, and local communities fight gender inequality to promote health, economic development, and human rights. In this research, a range of male-involvement initiatives provides a lens through which to study how masculinities are diversely imagined, (re)configured, and performed through men’s engagements with this assemblage, in both its local and global manifestations. Multi-sited ethnographic research will focus on six cities where the PI has active research ties: Nairobi and Kisumu, Kenya; Johannesburg and Durban, South Africa; and Dar es Salaam and Mwanza, Tanzania.
Max ERC Funding
1 999 830 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym BEHAVE
Project New discrete choice theory for understanding moral decision making behaviour
Researcher (PI) Caspar Gerard CHORUS
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Consolidator Grant (CoG), SH2, ERC-2016-COG
Summary Discrete choice theory provides a mathematically rigorous framework to analyse and predict choice behaviour. While many of the theory’s key developments originate from the domain of transportation (mobility, travel behaviour), it is now widely used throughout the social sciences.
The theory has a blind spot for moral choice behaviour. It was designed to analyse situations where people make choices that are optimal given their consumer preferences, rather than situations where people attempt to make choices that are right, given their moral preferences. This neglect of the morality of choice is striking, in light of the fact that many of the most important choices people make, have a moral dimension.
This research program extends discrete choice theory to the domain of moral decision making.
It will produce a suite of new mathematical representations of choice behaviour (i.e., choice models), which are designed to capture the decision rules and decision weights that determine how individuals behave in moral choice situations. In these models, particular emphasis is given to heterogeneity in moral decision rules and to the role of social influences. Models will be estimated and validated using data obtained through a series of interviews, surveys and choice experiments. Empirical analyses will take place in the context of moral choice situations concerning i) co-operative road using and ii) unsafe driving practices. Estimation results will be used as input for agent based models, to identify how social interaction processes lead to the emergence, persistence or dissolution of moral (traffic) equilibria at larger spatio-temporal scales.
Together, these proposed research efforts promise to generate a major breakthrough in discrete choice theory. In addition, the program will result in important methodological contributions to the empirical study of moral decision making behaviour in general; and to new insights into the moral aspects of (travel) behaviour.
Summary
Discrete choice theory provides a mathematically rigorous framework to analyse and predict choice behaviour. While many of the theory’s key developments originate from the domain of transportation (mobility, travel behaviour), it is now widely used throughout the social sciences.
The theory has a blind spot for moral choice behaviour. It was designed to analyse situations where people make choices that are optimal given their consumer preferences, rather than situations where people attempt to make choices that are right, given their moral preferences. This neglect of the morality of choice is striking, in light of the fact that many of the most important choices people make, have a moral dimension.
This research program extends discrete choice theory to the domain of moral decision making.
It will produce a suite of new mathematical representations of choice behaviour (i.e., choice models), which are designed to capture the decision rules and decision weights that determine how individuals behave in moral choice situations. In these models, particular emphasis is given to heterogeneity in moral decision rules and to the role of social influences. Models will be estimated and validated using data obtained through a series of interviews, surveys and choice experiments. Empirical analyses will take place in the context of moral choice situations concerning i) co-operative road using and ii) unsafe driving practices. Estimation results will be used as input for agent based models, to identify how social interaction processes lead to the emergence, persistence or dissolution of moral (traffic) equilibria at larger spatio-temporal scales.
Together, these proposed research efforts promise to generate a major breakthrough in discrete choice theory. In addition, the program will result in important methodological contributions to the empirical study of moral decision making behaviour in general; and to new insights into the moral aspects of (travel) behaviour.
Max ERC Funding
1 998 750 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym BENDER
Project BiogENesis and Degradation of Endoplasmic Reticulum proteins
Researcher (PI) Friedrich Förster
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Summary
The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Max ERC Funding
2 496 611 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym BioAqua
Project Water as cosubstrate for biocatalytic redox reactions
Researcher (PI) Frank Hollmann
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
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
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
Project acronym CAPABLE
Project Enhancing Capabilities? Rethinking Work-life Policies and their Impact from a New Perspective
Researcher (PI) Mara YERKES
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), SH3, ERC-2017-COG
Summary We have witnessed significant work-life policy advancements designed to help men and women more equally combine employment with other spheres of life in recent decades, yet gender inequality persists. Improving gender equality in work-life balance is therefore high on policy agendas throughout Europe. Decades of research in this area have produced key insights but work-family theories fail to sufficiently explain the tenacity of this inequality. Earlier applications of a capabilities approach to work-life balance offer promising inroads, yet the importance of community remains absent. The CAPABLE project will generate fundamentally new knowledge on how work-life balance policies impact an individual’s capability to achieve this balance in Europe by incorporating the understudied dimension of community.
Capabilities reflect what individuals are effectively able to achieve. CAPABLE asks: To what extent do work-life balance policies enhance men and women’s capabilities to achieve work-life balance? To answer this question, we will develop and apply complex models derived from Sen’s capability approach to analyse: 1. the availability, accessibility and design of work-family policies; 2. what these policies mean for men and women’s capabilities to achieve work-life balance based on their embeddedness in individual, community and social contexts; 3. whether work-life policies enhance individual wellbeing; and 4. what policy tools are needed for developing sustainable work-life balance policies that enhance gender equal work-life capabilities. CAPABLE will progress scientific and policy frontiers using innovative, mixed-methods approaches at multiple policy levels. The conceptual clarity and empirical advancements provided will significantly expand our understanding of work-life policies in relation to individual capabilities. Furthermore, it will produce key insights into how sustainable work-life policies addressing gender inequality in work-life can be developed.
Summary
We have witnessed significant work-life policy advancements designed to help men and women more equally combine employment with other spheres of life in recent decades, yet gender inequality persists. Improving gender equality in work-life balance is therefore high on policy agendas throughout Europe. Decades of research in this area have produced key insights but work-family theories fail to sufficiently explain the tenacity of this inequality. Earlier applications of a capabilities approach to work-life balance offer promising inroads, yet the importance of community remains absent. The CAPABLE project will generate fundamentally new knowledge on how work-life balance policies impact an individual’s capability to achieve this balance in Europe by incorporating the understudied dimension of community.
Capabilities reflect what individuals are effectively able to achieve. CAPABLE asks: To what extent do work-life balance policies enhance men and women’s capabilities to achieve work-life balance? To answer this question, we will develop and apply complex models derived from Sen’s capability approach to analyse: 1. the availability, accessibility and design of work-family policies; 2. what these policies mean for men and women’s capabilities to achieve work-life balance based on their embeddedness in individual, community and social contexts; 3. whether work-life policies enhance individual wellbeing; and 4. what policy tools are needed for developing sustainable work-life balance policies that enhance gender equal work-life capabilities. CAPABLE will progress scientific and policy frontiers using innovative, mixed-methods approaches at multiple policy levels. The conceptual clarity and empirical advancements provided will significantly expand our understanding of work-life policies in relation to individual capabilities. Furthermore, it will produce key insights into how sustainable work-life policies addressing gender inequality in work-life can be developed.
Max ERC Funding
1 999 748 €
Duration
Start date: 2018-12-01, End date: 2023-11-30