Project acronym BIOFAGE
Project Interaction Dynamics of Bacterial Biofilms with Bacteriophages
Researcher (PI) Knut DRESCHER
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary Biofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance.
Summary
Biofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance.
Max ERC Funding
1 494 963 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym BrainDrain
Project Translational implications of the discovery of brain-draining lymphatics
Researcher (PI) Kari ALITALO
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Summary
In 2010, 800 billion Euros was spent on brain diseases in Europe and the cost is expected to increase due to the aging population. – Here I propose to exploit our new discovery for research to alleviate this disease burden. In work selected by Nature Medicine among the top 10 ”Notable Advances” and by Science as one of the 10 ”Breakthroughs of the year” 2015, we discovered a meningeal lymphatic vascular system that serves brain homeostasis. We want to reassess current concepts about cerebrovascular dynamics, fluid drainage and cellular trafficking in physiological conditions, in Alzheimer’s disease mouse models and in human postmortem tissues. First, we will study the development and properties of meningeal lymphatics and how they are sustained during aging. We then want to analyse the clearance of macromolecules and protein aggregates in Alzheimer’s disease in mice that lack the newly discovered meningeal lymphatic drainage system. We will study if growth factor-mediated expansion of lymphatic vessels alleviates the parenchymal accumulation of neurotoxic amyloid beta and pathogenesis of Alzheimer’s disease and brain damage after traumatic brain injury. We will further analyse the role of lymphangiogenic growth factors and lymphatic vessels in brain solute clearance, immune cell trafficking and in a mouse model of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable human and socioeconomic burden. Several of our previous concepts have already been translated to clinical development and we aim to develop proof-of-principle therapeutic concepts in this project. I feel that we are just now in a unique position to advance frontline European translational biomedical research in this suddenly emerging field, which has received great attention worldwide.
Max ERC Funding
2 420 429 €
Duration
Start date: 2017-08-01, End date: 2022-07-31
Project acronym DemandDemoc
Project Demand for Democracy
Researcher (PI) Davide Werner CANTONI
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), SH1, ERC-2016-STG
Summary Historically, people around the world have demanded democratic institutions. Such democratic movements propel political change and also determine economic outcomes. In this project, we ask, how do political preferences, beliefs, and second-order beliefs shape the strategic decision to participate in a movement demanding democracy? Existing scholarship is unsatisfactory because it is conducted ex post: preferences, beliefs, and behavior have converged to a new equilibrium. In contrast, we examine a democratic movement in real time, studying the ongoing democracy movement in Hong Kong.
Our study is composed of four parts. In Part 1, we collect panel survey data from Hong Kong university students, a particularly politically active subpopulation. We collect data on preferences, behavior, beliefs, and second-order beliefs using incentivized and indirect elicitation to encourage truthful reporting. We analyze the associations among these variables to shed light on the drivers of participation in the democracy movement.
In Part 2, we exploit experimental variation in the provision of information to study political coordination. Among participants in the panel survey, we provide information regarding the preferences and beliefs of other students. We examine whether exposure to information regarding peers causes students to update their beliefs and change their behavior.
In Part 3, we extend the analysis in Part 1 to a nationally representative sample of Hong Kong citizens. To do so, we have added a module regarding political preferences, beliefs, and behavior (including incentivized questions and questions providing cover for responses to politically sensitive topics) to the HKPSSD panel survey.
In Part 4, we study preferences for redistribution – plausibly a central driver for demands for political rights – among Hong Kong citizens and mainland Chinese. We examine how these preferences differ across populations, as well as their link to support for democracy.
Summary
Historically, people around the world have demanded democratic institutions. Such democratic movements propel political change and also determine economic outcomes. In this project, we ask, how do political preferences, beliefs, and second-order beliefs shape the strategic decision to participate in a movement demanding democracy? Existing scholarship is unsatisfactory because it is conducted ex post: preferences, beliefs, and behavior have converged to a new equilibrium. In contrast, we examine a democratic movement in real time, studying the ongoing democracy movement in Hong Kong.
Our study is composed of four parts. In Part 1, we collect panel survey data from Hong Kong university students, a particularly politically active subpopulation. We collect data on preferences, behavior, beliefs, and second-order beliefs using incentivized and indirect elicitation to encourage truthful reporting. We analyze the associations among these variables to shed light on the drivers of participation in the democracy movement.
In Part 2, we exploit experimental variation in the provision of information to study political coordination. Among participants in the panel survey, we provide information regarding the preferences and beliefs of other students. We examine whether exposure to information regarding peers causes students to update their beliefs and change their behavior.
In Part 3, we extend the analysis in Part 1 to a nationally representative sample of Hong Kong citizens. To do so, we have added a module regarding political preferences, beliefs, and behavior (including incentivized questions and questions providing cover for responses to politically sensitive topics) to the HKPSSD panel survey.
In Part 4, we study preferences for redistribution – plausibly a central driver for demands for political rights – among Hong Kong citizens and mainland Chinese. We examine how these preferences differ across populations, as well as their link to support for democracy.
Max ERC Funding
1 494 647 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym DrugComb
Project Informatics approaches for the rational selection of personalized cancer drug combinations
Researcher (PI) Jing TANG
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Making cancer treatment more personalized and effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We critically need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. This project will develop mathematical and computational tools to identify drug combinations that can be used to provide personalized and more effective therapeutic strategies that may prevent acquired resistance. Utilizing molecular profiling and pharmacological screening data from patient-derived leukaemia and ovarian cancer samples, I will develop model-based clustering methods for identification of patient subgroups that are differentially responsive to first-line chemotherapy. For patients resistant to chemotherapy, I will develop network modelling approaches to predict the most potential drug combinations by understanding the underlying drug target interactions. The drug combination prediction will be made for each patient and will be validated using a preclinical drug testing platform on patient samples. I will explore the drug combination screen data to identify significant synergy at the therapeutically relevant doses. The drug combination hits will be mapped into signalling networks to infer their mechanisms. Drug combinations with selective efficacy in individual patient samples or in sample subgroups will be further translated into in treatment options by clinical collaborators. This will lead to novel and personalized strategies to treat cancer patients.
Summary
Making cancer treatment more personalized and effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We critically need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. This project will develop mathematical and computational tools to identify drug combinations that can be used to provide personalized and more effective therapeutic strategies that may prevent acquired resistance. Utilizing molecular profiling and pharmacological screening data from patient-derived leukaemia and ovarian cancer samples, I will develop model-based clustering methods for identification of patient subgroups that are differentially responsive to first-line chemotherapy. For patients resistant to chemotherapy, I will develop network modelling approaches to predict the most potential drug combinations by understanding the underlying drug target interactions. The drug combination prediction will be made for each patient and will be validated using a preclinical drug testing platform on patient samples. I will explore the drug combination screen data to identify significant synergy at the therapeutically relevant doses. The drug combination hits will be mapped into signalling networks to infer their mechanisms. Drug combinations with selective efficacy in individual patient samples or in sample subgroups will be further translated into in treatment options by clinical collaborators. This will lead to novel and personalized strategies to treat cancer patients.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym EEC
Project Economic Engineering of Cooperation in Modern Markets
Researcher (PI) Axel OCKENFELS
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Advanced Grant (AdG), SH1, ERC-2016-ADG
Summary Cooperation is essential for the functioning of the economy and society. Thus, with inappropriate mechanisms to harness self-interest by aligning it with the common good, the outcome of social and economic interaction can be bleak and even catastrophic.
Recent advances in computer technology lead to radical innovation in market design and trading strategies. This creates both, new challenges and exciting opportunities for “engineering cooperation”. This project uses the economic engineering approach (as advocated by Alvin Roth) to address some of the most pressing cooperation problems of modern markets and societies.
I propose three work packages, each using innovative experimental methods and (behavioral) game theory in order to address a specific challenge:
The first one studies the design of electronic reputation mechanisms that promote cooperation in the digital world. Previous research has shown that mechanisms to promote trust on the Internet are flawed. Yet, there is little empirical and normative guidance on how to repair these systems, and engineer better ones.
The second studies the design of mechanisms that avoid arms races for speed in real-time financial and electricity market trading. Traders use algorithmic sniping strategies, even when they are collectively wasteful and seriously threatening market liquidity and stability. Yet, little is known about the robust properties of alternative market designs to eliminate sniping.
The third one studies how to design modern markets that align with ethical considerations. People sometimes have a distaste for certain kinds of modern transactions, such as reciprocal kidney exchange and buying pollution rights. Yet, little is known about the underlying nature and robustness of this distaste.
My project will generate important knowledge to improve the functioning of modern markets, and at the same time open new horizons in the sciences of cooperation and of “behavioral economic engineering”.
Summary
Cooperation is essential for the functioning of the economy and society. Thus, with inappropriate mechanisms to harness self-interest by aligning it with the common good, the outcome of social and economic interaction can be bleak and even catastrophic.
Recent advances in computer technology lead to radical innovation in market design and trading strategies. This creates both, new challenges and exciting opportunities for “engineering cooperation”. This project uses the economic engineering approach (as advocated by Alvin Roth) to address some of the most pressing cooperation problems of modern markets and societies.
I propose three work packages, each using innovative experimental methods and (behavioral) game theory in order to address a specific challenge:
The first one studies the design of electronic reputation mechanisms that promote cooperation in the digital world. Previous research has shown that mechanisms to promote trust on the Internet are flawed. Yet, there is little empirical and normative guidance on how to repair these systems, and engineer better ones.
The second studies the design of mechanisms that avoid arms races for speed in real-time financial and electricity market trading. Traders use algorithmic sniping strategies, even when they are collectively wasteful and seriously threatening market liquidity and stability. Yet, little is known about the robust properties of alternative market designs to eliminate sniping.
The third one studies how to design modern markets that align with ethical considerations. People sometimes have a distaste for certain kinds of modern transactions, such as reciprocal kidney exchange and buying pollution rights. Yet, little is known about the underlying nature and robustness of this distaste.
My project will generate important knowledge to improve the functioning of modern markets, and at the same time open new horizons in the sciences of cooperation and of “behavioral economic engineering”.
Max ERC Funding
1 155 104 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym FLUFLUX
Project Fluvial Meta-Ecosystem Functioning: Unravelling Regional Ecological Controls Behind Fluvial Carbon Fluxes
Researcher (PI) Gabriel SINGER
Host Institution (HI) FORSCHUNGSVERBUND BERLIN EV
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary Fluvial ecosystems are an important element in the global carbon cycle metabolizing large amounts of terrigenous organic matter (tOM). This contributes to CO2 evasion fluxes that are under continuous reevaluation at the global scale. In contrast, research on the underlying processes is concentrated at the local ecosystem scale. This scale-gap seriously hampers process understanding across scales, limits upscaling accuracy, and reduces our scope of reaction strategies.
Here, I suggest ground-breaking research on ecological processes at the intermediate ‘regional’ scale of the ‘fluvial network‘ to create a deeper mechanistic understanding of biogeochemically relevant carbon fluxes. My starting point is trifold: (1) detrital tOM has extremely high molecular-level diversity that requires consumers of equally high biodiversity for efficient respiration; (2) exactly this biodiversity of heterotrophic microbes, fungi and insects is constrained by metacommunity dynamics unfolding at a larger regional scale; and (3) the rules by which the conspicuously dendritic structure of the fluvial network shapes a metacommunity differ fundamentally from those governing regional diversity patterns of tOM resources.
I hypothesize regional carbon dissimilation in ‘fluvial metaecosystems’ to be the interactive product of spatially partitioned resource and consumer diversities. I posit that this coupling of metacommunity structure to metaecosystem function is influenced by fluvial network topology, anthropogenic network fragmentation, and terrestrial matrix variation. Research will combine experiments in innovative lab-scale metaecosystems, spatially explicit modelling using cellular automata, and field studies spanning gradients of regional anthropogenic impact in real fluvial networks. I expect this cross-disciplinary research at the crucial landscape scale to generate novel mechanistic process understanding behind fluvial carbon fluxes in a world changing at ever faster pace.
Summary
Fluvial ecosystems are an important element in the global carbon cycle metabolizing large amounts of terrigenous organic matter (tOM). This contributes to CO2 evasion fluxes that are under continuous reevaluation at the global scale. In contrast, research on the underlying processes is concentrated at the local ecosystem scale. This scale-gap seriously hampers process understanding across scales, limits upscaling accuracy, and reduces our scope of reaction strategies.
Here, I suggest ground-breaking research on ecological processes at the intermediate ‘regional’ scale of the ‘fluvial network‘ to create a deeper mechanistic understanding of biogeochemically relevant carbon fluxes. My starting point is trifold: (1) detrital tOM has extremely high molecular-level diversity that requires consumers of equally high biodiversity for efficient respiration; (2) exactly this biodiversity of heterotrophic microbes, fungi and insects is constrained by metacommunity dynamics unfolding at a larger regional scale; and (3) the rules by which the conspicuously dendritic structure of the fluvial network shapes a metacommunity differ fundamentally from those governing regional diversity patterns of tOM resources.
I hypothesize regional carbon dissimilation in ‘fluvial metaecosystems’ to be the interactive product of spatially partitioned resource and consumer diversities. I posit that this coupling of metacommunity structure to metaecosystem function is influenced by fluvial network topology, anthropogenic network fragmentation, and terrestrial matrix variation. Research will combine experiments in innovative lab-scale metaecosystems, spatially explicit modelling using cellular automata, and field studies spanning gradients of regional anthropogenic impact in real fluvial networks. I expect this cross-disciplinary research at the crucial landscape scale to generate novel mechanistic process understanding behind fluvial carbon fluxes in a world changing at ever faster pace.
Max ERC Funding
1 487 171 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym FORENSICS
Project Illicit Markets, Unobserved Competitors, and Illegal Behavior
Researcher (PI) Michelle SOVINSKY
Host Institution (HI) UNIVERSITAET MANNHEIM
Call Details Consolidator Grant (CoG), SH1, ERC-2016-COG
Summary Many markets are characterized by illicit or illegal behavior by agents. To the extent that the empirical economic framework does not incorporate these unobserved actions or control for them in estimation, the resulting models are likely to be mis-specified. Naturally, if the models do not contain all elements relevant for decision making, then predictions based on the estimates will be misleading, which could result in incorrect policy recommendations. This project directly addresses three situations in which unobserved behavior plays a crucial role. The first concerns markets where consumers engage in illicit behavior. These markets are prevalent in society as they constitute the market for illicit drugs, which is estimated at more than $300 billion per year (UN, 2012). The second concerns markets where firms make strategic decisions in the presence of an unidentified competitor - a counterfeiter, where the global value of counterfeit products rivals that of illegal drugs (OECD, 2007). The third concerns situations where firms use legal tools for illegal purposes, for which the impact is challenging to quantify and one goal of this project. In each area, the project (i) develops state-of-the-art empirical models that incorporate illicit behaviors, (ii) proposes novel estimation methods that can be used to detect illegal behavior, and (iii) provides evidence that the proposed methodology is feasible and the data are sufficient to estimate the models. Incorporating and estimating unobserved behavior in a variety of settings is an ambitious undertaking. However, it is vital as a key objective of the proposal is to provide policy makers with tangible tools that accurately reflect the unobserved nature of these markets. Given the global significance of illicit markets, the novel concepts proposed, and the focus on policy, this project has the potential to make a sizable impact, both in and beyond academia, representing an ambitious but worthwhile pursuit.
Summary
Many markets are characterized by illicit or illegal behavior by agents. To the extent that the empirical economic framework does not incorporate these unobserved actions or control for them in estimation, the resulting models are likely to be mis-specified. Naturally, if the models do not contain all elements relevant for decision making, then predictions based on the estimates will be misleading, which could result in incorrect policy recommendations. This project directly addresses three situations in which unobserved behavior plays a crucial role. The first concerns markets where consumers engage in illicit behavior. These markets are prevalent in society as they constitute the market for illicit drugs, which is estimated at more than $300 billion per year (UN, 2012). The second concerns markets where firms make strategic decisions in the presence of an unidentified competitor - a counterfeiter, where the global value of counterfeit products rivals that of illegal drugs (OECD, 2007). The third concerns situations where firms use legal tools for illegal purposes, for which the impact is challenging to quantify and one goal of this project. In each area, the project (i) develops state-of-the-art empirical models that incorporate illicit behaviors, (ii) proposes novel estimation methods that can be used to detect illegal behavior, and (iii) provides evidence that the proposed methodology is feasible and the data are sufficient to estimate the models. Incorporating and estimating unobserved behavior in a variety of settings is an ambitious undertaking. However, it is vital as a key objective of the proposal is to provide policy makers with tangible tools that accurately reflect the unobserved nature of these markets. Given the global significance of illicit markets, the novel concepts proposed, and the focus on policy, this project has the potential to make a sizable impact, both in and beyond academia, representing an ambitious but worthwhile pursuit.
Max ERC Funding
1 212 934 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym FunKeyGut
Project Illuminating Functional Networks and Keystone Species in the Gut
Researcher (PI) David Michael BERRY
Host Institution (HI) UNIVERSITAT WIEN
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary We live in an intimate symbiosis with our gut microbiota, which provides us services such as vitamin production, breakdown of dietary compounds, and immune training. Sequencing-based approaches that have been applied to catalogue the gut microbiota have revealed intriguing discoveries associating the microbiome with diet and disease. The next outstanding challenge is to unravel the many activities and interactions that define gut microbiota function.
The gut microbiota is a diverse community of cooperating and competing microbes. These interactions form a network that links organisms with each other and their environment. Interactions in such a “functional network” are based partially, though not exclusively, on food webs. Certain “keystone species”, such as Rumonicoccus bromii, are thought to play a major role in these networks. Though some evidence exists for the presence of keystone species, their identity and activity remains largely unknown. As keystone species are vital to networks they are ideal targets for manipulating the gut microbiota to improve metabolic health and protect against enteropathogen infection.
Given the complexity of the gut microbiota, networks can only be elucidated directly in the native community. This project aims to identify functional networks and keystone species in the human gut using novel approaches that are uniquely and ideally suited for studying microbial activity in complex communities. Using state-of-the-art methods such as stable isotope labeling, Raman microspectroscopy, and secondary ion mass spectrometry (NanoSIMS) we will illuminate functional networks in situ. This will allow us to identify what factors shape gut microbiota activity, reveal important food webs, and ultimately use network knowledge to target the microbiota with prebiotic/probiotic treatments rationally designed to promote health.
Summary
We live in an intimate symbiosis with our gut microbiota, which provides us services such as vitamin production, breakdown of dietary compounds, and immune training. Sequencing-based approaches that have been applied to catalogue the gut microbiota have revealed intriguing discoveries associating the microbiome with diet and disease. The next outstanding challenge is to unravel the many activities and interactions that define gut microbiota function.
The gut microbiota is a diverse community of cooperating and competing microbes. These interactions form a network that links organisms with each other and their environment. Interactions in such a “functional network” are based partially, though not exclusively, on food webs. Certain “keystone species”, such as Rumonicoccus bromii, are thought to play a major role in these networks. Though some evidence exists for the presence of keystone species, their identity and activity remains largely unknown. As keystone species are vital to networks they are ideal targets for manipulating the gut microbiota to improve metabolic health and protect against enteropathogen infection.
Given the complexity of the gut microbiota, networks can only be elucidated directly in the native community. This project aims to identify functional networks and keystone species in the human gut using novel approaches that are uniquely and ideally suited for studying microbial activity in complex communities. Using state-of-the-art methods such as stable isotope labeling, Raman microspectroscopy, and secondary ion mass spectrometry (NanoSIMS) we will illuminate functional networks in situ. This will allow us to identify what factors shape gut microbiota activity, reveal important food webs, and ultimately use network knowledge to target the microbiota with prebiotic/probiotic treatments rationally designed to promote health.
Max ERC Funding
1 498 279 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym GENECLOCKS
Project Reconstructing a dated tree of life using phylogenetic incongruence
Researcher (PI) Gergely Janos SZOLLOSI
Host Institution (HI) EOTVOS LORAND TUDOMANYEGYETEM
Call Details Starting Grant (StG), LS8, ERC-2016-STG
Summary With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Summary
With the advent of genome-scale sequencing, molecular phylogeny, which reconstructs gene trees from homologous sequences, has reached an impasse. Instead of answering open questions, new genomes have reignited old debates. The problem is clear, gene trees are not species trees, each is the unique result of series of evolutionary events. If, however, we model these differences in the context of a common species tree, we can access a wealth of information on genome evolution and the diversification of species that is not available to traditional methods. For example, as horizontal gene transfer (HGT) can only occur between coexisting species, HGTs provide information on the order of speciations. When HGT is rare, lineage sorting can generate incongruence between gene trees and the dating problem can be formulated in terms of biologically meaningful parameters (such as population size), that are informative on the rate of evolution and hence invaluable to molecular dating.
My first goal is to develop methods that systematically extract information on the pattern and timing of genomic evolution by explaining differences between gene trees. This will allow us to, for the first time, reconstruct a dated tree of life from genome-scale data. We will use parallel programming to maximise the number of genomes analysed.
My second goal is to apply these methods to open problems, e.g.: i) to resolve the timing of microbial evolution and its relationship to Earth history, where the extreme paucity of fossils limits the use of molecular dating methods, by using HGT events as “molecular fossils”; ii) to reconstruct rooted phylogenies from complete genomes and harness phylogenetic incongruence to answer long standing questions, such as the of diversification of animals or the position of eukaryotes among archaea; and iii) for eukaryotic groups such as Fungi, where evidence of significant amounts of HGT is emerging our methods will also allow the quantification of the extent of HGT.
Max ERC Funding
1 453 542 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym iAML-lncTARGET
Project Targeting the transcriptional landscape in infant AML
Researcher (PI) Jan-Henning Cornelius KLUSMANN
Host Institution (HI) MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Infant acute myeloid leukemia (AML) has a dismal prognosis, with a high prevalence of unfavorable features and increased susceptibility to therapy-related toxicities, highlighting the need for innovative treatment approaches. Despite the discovery of an enormous number and diversity of transcriptional products arising from the previously presumed wastelands of the non-protein-coding genome, our knowledge of non-coding RNAs is far from being incorporated into standards of AML diagnosis and treatment. I hypothesize that the highly developmental stage- and cell-specific expression of long non-coding RNAs shapes a chromatin and transcriptional landscape in fetal hematopoietic stem cells that renders them permissive towards transformation. I predict this landscape to synergize with particular oncogenes that are otherwise not oncogenic in adult cells, by providing a fertile transcriptional background for establishing and maintaining oncogenic programs. Therefore, the non-coding transcriptome, inherited from the fetal cell of origin, may reflect a previously unrecognized Achilles heel of infant AML, which I will identify with my expertise to understand and edit the AML genome and transcriptome.
I will apply recent breakthroughs from various research areas to i) create a comprehensive transcriptomic atlas of infant AML and fetal stem cells, ii) define aberrant or fetal stage-specific non-coding RNAs that drive leukemia progression, and iii) resolve their features to probe the oncogenic interactome. After iv) establishing a biobank of patient-derived xenografts, I will v) evaluate preclinical RNA-centered therapeutic interventions to overcome current obstacles in the treatment of infant AML. Targeting the vulnerable fetal stage-specific background of infant AML inherited from the cell of origin may set a paradigm shift for cancer treatment, by focusing on the permissive basis required by the oncogene for inducing and sustaining cancer, rather than on the oncogene itself.
Summary
Infant acute myeloid leukemia (AML) has a dismal prognosis, with a high prevalence of unfavorable features and increased susceptibility to therapy-related toxicities, highlighting the need for innovative treatment approaches. Despite the discovery of an enormous number and diversity of transcriptional products arising from the previously presumed wastelands of the non-protein-coding genome, our knowledge of non-coding RNAs is far from being incorporated into standards of AML diagnosis and treatment. I hypothesize that the highly developmental stage- and cell-specific expression of long non-coding RNAs shapes a chromatin and transcriptional landscape in fetal hematopoietic stem cells that renders them permissive towards transformation. I predict this landscape to synergize with particular oncogenes that are otherwise not oncogenic in adult cells, by providing a fertile transcriptional background for establishing and maintaining oncogenic programs. Therefore, the non-coding transcriptome, inherited from the fetal cell of origin, may reflect a previously unrecognized Achilles heel of infant AML, which I will identify with my expertise to understand and edit the AML genome and transcriptome.
I will apply recent breakthroughs from various research areas to i) create a comprehensive transcriptomic atlas of infant AML and fetal stem cells, ii) define aberrant or fetal stage-specific non-coding RNAs that drive leukemia progression, and iii) resolve their features to probe the oncogenic interactome. After iv) establishing a biobank of patient-derived xenografts, I will v) evaluate preclinical RNA-centered therapeutic interventions to overcome current obstacles in the treatment of infant AML. Targeting the vulnerable fetal stage-specific background of infant AML inherited from the cell of origin may set a paradigm shift for cancer treatment, by focusing on the permissive basis required by the oncogene for inducing and sustaining cancer, rather than on the oncogene itself.
Max ERC Funding
1 499 750 €
Duration
Start date: 2017-06-01, End date: 2022-05-31