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Project acronym ANTHROPOID
Project Great ape organoids to reconstruct uniquely human development
Host Institution (HI) INSTITUT FUR MOLEKULARE UND KLINISCHE OPHTHALMOLOGIE BASEL
Summary Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?
Humans diverged from our closest living relatives, chimpanzees and other great apes, 6-10 million years ago. Since this divergence, our ancestors acquired genetic changes that enhanced cognition, altered metabolism, and endowed our species with an adaptive capacity to colonize the entire planet and reshape the biosphere. Through genome comparisons between modern humans, Neandertals, chimpanzees and other apes we have identified genetic changes that likely contribute to innovations in human metabolic and cognitive physiology. However, it has been difficult to assess the functional effects of these genetic changes due to the lack of cell culture systems that recapitulate great ape organ complexity. Human and chimpanzee pluripotent stem cells (PSCs) can self-organize into three-dimensional (3D) tissues that recapitulate the morphology, function, and genetic programs controlling organ development. Our vision is to use organoids to study the changes that set modern humans apart from our closest evolutionary relatives as well as all other organisms on the planet. In ANTHROPOID we will generate a great ape developmental cell atlas using cortex, liver, and small intestine organoids. We will use single-cell transcriptomics and chromatin accessibility to identify cell type-specific features of transcriptome divergence at cellular resolution. We will dissect enhancer evolution using single-cell genomic screens and ancestralize human cells to resurrect pre-human cellular phenotypes. ANTHROPOID utilizes quantitative and state-of-the-art methods to explore exciting high-risk questions at multiple branches of the modern human lineage. This project is a ground breaking starting point to replay evolution and tackle the ancient question of what makes us uniquely human?
Project acronym BARRAGE
Project Cell compartmentalization, individuation and diversity
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Summary Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Asymmetric cell division is a key mechanism for the generation of cell diversity in eukaryotes. During this process, a polarized mother cell divides into non-equivalent daughters. These may differentially inherit fate determinants, irreparable damages or age determinants. Our aim is to decipher the mechanisms governing the individualization of daughters from each other. In the past ten years, our studies identified several lateral diffusion barriers located in the plasma membrane and the endoplasmic reticulum of budding yeast. These barriers all restrict molecular exchanges between the mother cell and its bud, and thereby compartmentalize the cell already long before its division. They play key roles in the asymmetric segregation of various factors. On one side, they help maintain polarized factors into the bud. Thereby, they reinforce cell polarity and sequester daughter-specific fate determinants into the bud. On the other side they prevent aging factors of the mother from entering the bud. Hence, they play key roles in the rejuvenation of the bud, in the aging of the mother, and in the differentiation of mother and daughter from each other. Recently, we accumulated evidence that some of these barriers are subject to regulation, such as to help modulate the longevity of the mother cell in response to environmental signals. Our data also suggest that barriers help the mother cell keep traces of its life history, thereby contributing to its individuation and adaption to the environment. In this project, we will address the following questions: 1 How are these barriers assembled, functioning, and regulated? 2 What type of differentiation processes are they involved in? 3 Are they conserved in other eukaryotes, and what are their functions outside of budding yeast? These studies will shed light into the principles underlying and linking aging, rejuvenation and differentiation.
Project acronym BioMeTRe
Project Biophysical mechanisms of long-range transcriptional regulation
Host Institution (HI) FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Summary In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.
Project acronym BuildNet
Project Smart Building Networks
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Summary The Smart Building Networks (BuildNet) program will develop optimizing controllers capable of coordinating the flow of power to and from large networks of smart buildings in order to offer critical services to the power grid. The network will make use of the thermal storage of the structures and on-site micro generation capabilities of next-generation buildings, as well as the electrical capacity of attached electric vehicles in order to intelligently control the interaction between the network of buildings and the grid. The wide range of electric utility applications, such as wind capacity firming or congestion relief, that will be possible as a result of this coordinated control will in turn allow a significant increase in the percentage of European power generated from destabilizing renewable sources. Technologically, BuildNet will be built around optimization-based or model predictive control (MPC), a paradigm that is ideally suited to the task of incorporating the current network state and forward-looking information into an optimal decision-making process. The project team will develop novel distributed MPC controllers that utilize the flexibility in the consumption, storage and generation of a distributed network of buildings by exploiting the extensive experience of the PI in optimization-based control and MPC for energy efficient buildings. Because of its theoretically grounded optimization-based control approach, holistic view of building systems and connected networks, as well as a future-looking technological scope, BuildNet's outputs will deliver impact and be relevant to researchers and practitioners alike.
The Smart Building Networks (BuildNet) program will develop optimizing controllers capable of coordinating the flow of power to and from large networks of smart buildings in order to offer critical services to the power grid. The network will make use of the thermal storage of the structures and on-site micro generation capabilities of next-generation buildings, as well as the electrical capacity of attached electric vehicles in order to intelligently control the interaction between the network of buildings and the grid. The wide range of electric utility applications, such as wind capacity firming or congestion relief, that will be possible as a result of this coordinated control will in turn allow a significant increase in the percentage of European power generated from destabilizing renewable sources. Technologically, BuildNet will be built around optimization-based or model predictive control (MPC), a paradigm that is ideally suited to the task of incorporating the current network state and forward-looking information into an optimal decision-making process. The project team will develop novel distributed MPC controllers that utilize the flexibility in the consumption, storage and generation of a distributed network of buildings by exploiting the extensive experience of the PI in optimization-based control and MPC for energy efficient buildings. Because of its theoretically grounded optimization-based control approach, holistic view of building systems and connected networks, as well as a future-looking technological scope, BuildNet's outputs will deliver impact and be relevant to researchers and practitioners alike.
Project acronym CCICO
Project Coupled and Competing Instabilities in Complex Oxides
Summary "The CCICO project will build a comprehensive understanding of how proximity to previously unexplored combinations of instabilities, as well as previously unidentified types of ordering, manifest in novel behaviors, and will develop design guidelines for practical realization of new materials with such behaviors. Taking transition-metal oxides as our model systems, we will develop and apply first-principles electronic structure theory methods to explore an extensive array of new combinations of orderings, with a focus on interactions between the electronic -- Jahn-Teller, orbital and charge -- and structural -- rotations, ferroelectric and other distortions -- degrees of freedom. Our goal is to spawn a new field of study based on a novel combination of orderings in the same way that the field of multiferroics was jump-started ten years ago by our work understanding the coexistence of ferroelectricity and magnetism. Conversely, we will apply the computational tools developed in our history of studying multiferroics, particularly descriptions of proximity to structural and magnetic phase transitions, to characterizing observed behaviors such as exotic superconductivity in existing materials. In the process we will search for and characterize elusive or poorly characterized forms of order in solids, with a focus on ferrotoroidicity and emergent local dipoles. A final application is to create designer materials for solid-state experiments relevant to high-energy physics and cosmology. Promising compounds that are amenable to bulk synthesis will be made in our new oxide single-crystal growth laboratory; materials that require thin-film routes will be pursued in collaboration with colleagues."
"The CCICO project will build a comprehensive understanding of how proximity to previously unexplored combinations of instabilities, as well as previously unidentified types of ordering, manifest in novel behaviors, and will develop design guidelines for practical realization of new materials with such behaviors. Taking transition-metal oxides as our model systems, we will develop and apply first-principles electronic structure theory methods to explore an extensive array of new combinations of orderings, with a focus on interactions between the electronic -- Jahn-Teller, orbital and charge -- and structural -- rotations, ferroelectric and other distortions -- degrees of freedom. Our goal is to spawn a new field of study based on a novel combination of orderings in the same way that the field of multiferroics was jump-started ten years ago by our work understanding the coexistence of ferroelectricity and magnetism. Conversely, we will apply the computational tools developed in our history of studying multiferroics, particularly descriptions of proximity to structural and magnetic phase transitions, to characterizing observed behaviors such as exotic superconductivity in existing materials. In the process we will search for and characterize elusive or poorly characterized forms of order in solids, with a focus on ferrotoroidicity and emergent local dipoles. A final application is to create designer materials for solid-state experiments relevant to high-energy physics and cosmology. Promising compounds that are amenable to bulk synthesis will be made in our new oxide single-crystal growth laboratory; materials that require thin-film routes will be pursued in collaboration with colleagues."
Project acronym CELLFUSION
Project Molecular dissection of the mechanisms of cell-cell fusion in the fission yeast
Host Institution (HI) UNIVERSITE DE LAUSANNE
Summary Cell fusion is critical for fertilization and development, for instance underlying muscle or bone formation. Cell fusion may also play important roles in regeneration and cancer. A conceptual understanding is emerging that cell fusion requires cell-cell communication, polarization of the cells towards each other, and assembly of a fusion machinery, in which an actin-based structure promotes membrane juxtaposition and fusogenic factors drive membrane fusion. However, in no single system have the molecular nature of all these parts been described, and thus the molecular basis of cell fusion remains poorly understood. This proposal aims to depict the complete fusion process in a single organism, using the simple yeast model Schizosaccharomyces pombe, which has a long track record of discoveries in fundamental cellular processes. These haploid cells, which fuse to generate a diploid zygote, use highly conserved mechanisms of cell-cell communication (through pheromones and GPCR signaling), cell polarization (centred around the small GTPase Cdc42) and fusion. Indeed, we recently showed that these cells assemble an actin-based fusion structure, dubbed the actin fusion focus. Our five aims probe the molecular nature of, and the links between, signaling, polarization and the fusion machinery from initiation to termination of the process. These are: 1: To define the roles and feedback regulation of Cdc42 during cell fusion 2: To understand the molecular mechanisms of actin fusion focus formation 3: To identify the fusogen(s) promoting membrane fusion 4: To probe the GPCR signal for fusion initiation 5: To define the mechanism of fusion termination By combining genetic, optogenetic, biochemical, live-imaging, synthetic and modeling approaches, this project will bring a molecular and conceptual understanding of cell fusion. This work will have far-ranging relevance for cell polarization, cytoskeletal organization, cell signalling and communication, and cell fate regulation.
Cell fusion is critical for fertilization and development, for instance underlying muscle or bone formation. Cell fusion may also play important roles in regeneration and cancer. A conceptual understanding is emerging that cell fusion requires cell-cell communication, polarization of the cells towards each other, and assembly of a fusion machinery, in which an actin-based structure promotes membrane juxtaposition and fusogenic factors drive membrane fusion. However, in no single system have the molecular nature of all these parts been described, and thus the molecular basis of cell fusion remains poorly understood. This proposal aims to depict the complete fusion process in a single organism, using the simple yeast model Schizosaccharomyces pombe, which has a long track record of discoveries in fundamental cellular processes. These haploid cells, which fuse to generate a diploid zygote, use highly conserved mechanisms of cell-cell communication (through pheromones and GPCR signaling), cell polarization (centred around the small GTPase Cdc42) and fusion. Indeed, we recently showed that these cells assemble an actin-based fusion structure, dubbed the actin fusion focus. Our five aims probe the molecular nature of, and the links between, signaling, polarization and the fusion machinery from initiation to termination of the process. These are: 1: To define the roles and feedback regulation of Cdc42 during cell fusion 2: To understand the molecular mechanisms of actin fusion focus formation 3: To identify the fusogen(s) promoting membrane fusion 4: To probe the GPCR signal for fusion initiation 5: To define the mechanism of fusion termination By combining genetic, optogenetic, biochemical, live-imaging, synthetic and modeling approaches, this project will bring a molecular and conceptual understanding of cell fusion. This work will have far-ranging relevance for cell polarization, cytoskeletal organization, cell signalling and communication, and cell fate regulation.
Project acronym CellularBiographies
Project Global views of cell type specification and differentiation
Host Institution (HI) UNIVERSITAT BASEL
Summary Each cell in our body has a specific biography that is defined by its pedigree relationship with other cells (lineage) and by its history of gene expression (trajectory). A fundamental question in cellular and developmental biology has been how the lineage and trajectory of a cell lead to its specification and differentiation. Remarkable progress in genome editing and single-cell sequencing has generated the opportunity to understand this process at global scales and single-cell resolution. We have recently developed methods to reconstruct the cellular ancestry and transcriptional trajectories of cells during embryogenesis. The resulting lineage and trajectory trees can be analyzed to gain comprehensive views of how cellular diversity arises and how differentiation leads to physiologically specialized cell types. To generate such global views of cellular development, we will: 1. Define the cellular diversity and gene expression trajectories during zebrafish embryogenesis and organogenesis. Trajectory trees will be generated from scRNA-seq data and analyzed to reconstruct the gene expression pathways underlying fate specification. 2. Reveal the relationships between lineage and transcriptional trajectories during fate specification. Lineage trees will be generated by marking cells via genome editing and combined with trajectory trees to reveal the cellular paths towards fate specification. 3. Discover the gene expression cascades that remodel cells into physiologically functional types. Cell biological modules will be identified by comparing gene enrichment in differentiation trajectories and reveal the specialized and shared mechanisms of differentiation. These studies will help provide the first comprehensive and global view of the trajectories and lineages underlying vertebrate development. Our focus is on the zebrafish model system, but the data and concepts developed in this project will be applicable to other developmental and cellular systems.
Each cell in our body has a specific biography that is defined by its pedigree relationship with other cells (lineage) and by its history of gene expression (trajectory). A fundamental question in cellular and developmental biology has been how the lineage and trajectory of a cell lead to its specification and differentiation. Remarkable progress in genome editing and single-cell sequencing has generated the opportunity to understand this process at global scales and single-cell resolution. We have recently developed methods to reconstruct the cellular ancestry and transcriptional trajectories of cells during embryogenesis. The resulting lineage and trajectory trees can be analyzed to gain comprehensive views of how cellular diversity arises and how differentiation leads to physiologically specialized cell types. To generate such global views of cellular development, we will: 1. Define the cellular diversity and gene expression trajectories during zebrafish embryogenesis and organogenesis. Trajectory trees will be generated from scRNA-seq data and analyzed to reconstruct the gene expression pathways underlying fate specification. 2. Reveal the relationships between lineage and transcriptional trajectories during fate specification. Lineage trees will be generated by marking cells via genome editing and combined with trajectory trees to reveal the cellular paths towards fate specification. 3. Discover the gene expression cascades that remodel cells into physiologically functional types. Cell biological modules will be identified by comparing gene enrichment in differentiation trajectories and reveal the specialized and shared mechanisms of differentiation. These studies will help provide the first comprehensive and global view of the trajectories and lineages underlying vertebrate development. Our focus is on the zebrafish model system, but the data and concepts developed in this project will be applicable to other developmental and cellular systems.
Project acronym CEMAS
Project Controlling and Exploring Molecular Systems at the Atomic Scale with Atomic Force Microscopy
Host Institution (HI) IBM RESEARCH GMBH
Summary The objective of this project is to advance and use Atomic Force Microscopy (AFM) to explore the physical and chemical properties of single molecules and molecular systems with unprecedented spatial resolution. We will use AFM to develop atomically resolved molecular imaging with structural and chemical identification and investigate charge distribution and transfer in molecular systems. The AFM will allow the extension of seminal Scanning Tunneling Microscopy (STM) work on atoms/molecules on ultra-thin insulating films to thick insulating films, to control and explore single molecule chemistry processes in utmost detail. The whole work will be significantly based on the development and exploitation of novel atomic and molecular manipulation processes to control matter at the atomic scale, both for fabricating novel complex molecular nanostructures with atomic scale precision and understanding these systems, as well as for probe-tip functionalization to tailor tip-substrate interaction. Instrumental enhancements will focus on fabricating novel AFM sensors for simultaneous lateral and vertical force measurement and on developing a new original approach to increase the time resolution in AFM measurements. Due to the fundamental nature of this work we expect the long term impact of this work to be in surface science, chemistry, molecular electronics and life sciences. In the short term we expect to develop the AFM into a practical tool for chemical structure determination of unknown molecules and we will employ atomic manipulation and high resolution AFM imaging to image, modify and functionalize graphene edge structures with atomic scale precision with the prospect of exploring and developing novel molecular devices.
The objective of this project is to advance and use Atomic Force Microscopy (AFM) to explore the physical and chemical properties of single molecules and molecular systems with unprecedented spatial resolution. We will use AFM to develop atomically resolved molecular imaging with structural and chemical identification and investigate charge distribution and transfer in molecular systems. The AFM will allow the extension of seminal Scanning Tunneling Microscopy (STM) work on atoms/molecules on ultra-thin insulating films to thick insulating films, to control and explore single molecule chemistry processes in utmost detail. The whole work will be significantly based on the development and exploitation of novel atomic and molecular manipulation processes to control matter at the atomic scale, both for fabricating novel complex molecular nanostructures with atomic scale precision and understanding these systems, as well as for probe-tip functionalization to tailor tip-substrate interaction. Instrumental enhancements will focus on fabricating novel AFM sensors for simultaneous lateral and vertical force measurement and on developing a new original approach to increase the time resolution in AFM measurements. Due to the fundamental nature of this work we expect the long term impact of this work to be in surface science, chemistry, molecular electronics and life sciences. In the short term we expect to develop the AFM into a practical tool for chemical structure determination of unknown molecules and we will employ atomic manipulation and high resolution AFM imaging to image, modify and functionalize graphene edge structures with atomic scale precision with the prospect of exploring and developing novel molecular devices.
Project acronym CENDUP
Project Decoding the mechanisms of centrosome duplication
Summary Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Centrosome duplication entails the formation of a single procentriole next to each centriole once per cell cycle. The mechanisms governing procentriole formation are poorly understood and constitute a fundamental open question in cell biology. We will launch an innovative multidisciplinary research program to gain significant insight into these mechanisms using C. elegans and human cells. This research program is also expected to have a significant impact by contributing important novel assays to the field. Six specific aims will be pursued: 1) SAS-6 as a ZYG-1 substrate: mechanisms of procentriole formation in C. elegans. We will test in vivo the consequence of SAS-6 phosphorylation by ZYG-1. 2) Biochemical and structural analysis of SAS-6-containing macromolecular complexes (SAMACs). We will isolate and characterize SAMACs from C. elegans embryos and human cells, and analyze their structure using single-particle electron microscopy. 3) Novel cell-free assay for procentriole formation in human cells. We will develop such an assay and use it to test whether SAMACs can direct procentriole formation and whether candidate proteins are needed at centrioles or in the cytoplasm. 4) Mapping interactions between centriolar proteins in live human cells. We will use chemical methods developed by our collaborators to probe interactions between HsSAS-6 and centriolar proteins in a time- and space-resolved manner. 5) Functional genomic and chemical genetic screens in human cells. We will conduct high-throughput fluorescence-based screens in human cells to identify novel genes required for procentriole formation and small molecule inhibitors of this process. 6) Mechanisms underlying differential centriolar maintenance in the germline. In C. elegans, we will characterize how the sas-1 locus is required for centriole maintenance during spermatogenesis, as well as analyze centriole elimination during oogenesis and identify components needed for this process
Project acronym COSMICLENS
Project Cosmology with Strong Gravitational Lensing
Summary Measuring cosmological distances has revolutionized our understanding of the Universe, and is still doing so! Early work in the 1920s led to the discovery of the expansion of the Universe. More precise distance measurements in the 90s with type-Ia supernovae revealed that this expansion is accelerating, with crucial consequences in cosmology and physics. Is the acceleration due to some repulsive form of dark energy? To Einstein's cosmological constant? Do we need to consider new physics? Answering these fundamental questions requires a precise measurement of the Hubble parameter, H0, which is my goal using the time delay (TD) method in strongly lensed quasars. The TD method exploits well-known physics on galaxy-scales. It is one of the very few techniques that can yield H0 to <2% using a single methodology. It involves no calibration, and is truly independent of any other cosmological probe. Capitalizing on the successful pathfinders COSMOGRAIL (PI: Courbin) and H0LiCOW (PI: Suyu, CoI: Courbin) time has come to fully exploit TDs with an observational, modeling and technical boost, organized in 2 phases. Phase I will secure H0 to 2% using the current chain of analysis, with feasible enhancements beyond the current state-of the-art. This will confirm or refute the tension seen between H0 values with different cosmological probes. Phase II targets 1% precision, improving the FoM of Stage-IV cosmological surveys by 40%. The 4 proposed Work Packages can transform the field within the next 5 years by 1- implementing the first high-cadence photometric monitoring of lensed quasars to measure 50 new TDs, 2- providing new flexible non-parameteric lens models based on sparse regularization of the reconstructed source and lens mass/light distributions, 3- providing a modular end-to-end simulation framework to mock lensed systems from hydro-simulations and to evaluate in detail the impact model degeneracies on H0, 4- discovering new suitable lensed quasars in current surveys.
Measuring cosmological distances has revolutionized our understanding of the Universe, and is still doing so! Early work in the 1920s led to the discovery of the expansion of the Universe. More precise distance measurements in the 90s with type-Ia supernovae revealed that this expansion is accelerating, with crucial consequences in cosmology and physics. Is the acceleration due to some repulsive form of dark energy? To Einstein's cosmological constant? Do we need to consider new physics? Answering these fundamental questions requires a precise measurement of the Hubble parameter, H0, which is my goal using the time delay (TD) method in strongly lensed quasars. The TD method exploits well-known physics on galaxy-scales. It is one of the very few techniques that can yield H0 to <2% using a single methodology. It involves no calibration, and is truly independent of any other cosmological probe. Capitalizing on the successful pathfinders COSMOGRAIL (PI: Courbin) and H0LiCOW (PI: Suyu, CoI: Courbin) time has come to fully exploit TDs with an observational, modeling and technical boost, organized in 2 phases. Phase I will secure H0 to 2% using the current chain of analysis, with feasible enhancements beyond the current state-of the-art. This will confirm or refute the tension seen between H0 values with different cosmological probes. Phase II targets 1% precision, improving the FoM of Stage-IV cosmological surveys by 40%. The 4 proposed Work Packages can transform the field within the next 5 years by 1- implementing the first high-cadence photometric monitoring of lensed quasars to measure 50 new TDs, 2- providing new flexible non-parameteric lens models based on sparse regularization of the reconstructed source and lens mass/light distributions, 3- providing a modular end-to-end simulation framework to mock lensed systems from hydro-simulations and to evaluate in detail the impact model degeneracies on H0, 4- discovering new suitable lensed quasars in current surveys.