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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2023
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Grant Awardees - Program
From disorder to order: mechanism of specialised assemblies formation essential for muscle function
DJINOVIC-CARUGO Kristina (.)
European Molecular Biology Laboratory (EMBL-Grenoble) - Grenoble - FRANCE
HINSON John (.)
University of Connecticut, Farmington - . - .
RIES Jonas (.)
European Molecular Biology Laboratory (EMBL-Heidelberg) - . - .
ODA Toshiyuki (.)
University of Yamanashi - . - .
Muscle force production and mechanotransduction rely on the ordered assembly of functionally and molecularly specialised actin cytoskeletal complexes. The sarcomere - the basic contractile unit of myocytes - assembles from nascent actin-rich Z-bodies into paracrystalline multiprotein structures called Z-discs, which contain numerous proteins frequently mutated in inheritable muscle disorders such as familial myopathies and cardiomyopathies. Yet, the assembly rules and protein components regulating these complex structures remain largely unknown. The project aims to elucidate the assembly processes of multiprotein actin complexes essential for cardiomyocyte contractility and mechanotransduction. We will examine the hierarchy and interdependence of interactions of cytoskeletal complexes in intercalated and Z-discs (Objective 1), resolve the structure of cytoskeletal complexes in vitro in and in cellula at different stages of sarcomere biogenesis and assess the dynamics of cytoskeletal components in different stages of maturation (Objective 2). Finally, we will combine the data in a 4D multiscale molecular model and validate the model with structure-informed in cellula and in vitro assays (Objective 3). Capitalising on the team’s complementary and synergic expertise in cardiovascular development and disease, advanced imaging, structural biology and modelling, we will determine the biophysical and structural rules underlying complex assembly, molecular components and regulators, and combine the data in a 4D multiscale integrative molecular model. Of special interest is, how highly ordered cytoskeletal structures arise from disorder through maturation and specialisation of the actin cytoskeleton.
2023
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Grant Awardees - Program
Nuclei as mechanical sensors and actuators in epithelial folding
ERZBERGER Anna (.)
European Molecular Biology Laboratory (EMBL-Heidelberg) - Heidelberg - GERMANY
WANG Yu-Chiun (.)
- . - .
The nucleus is the largest and stiffest organelle in a cell. It functions not merely in cellular information processing, but also in the spatial organization of cells and tissues, as well as mechanotransduction impacting gene expression. Prior experimental investigations in nuclear mechanics are primarily in vitro or ex vivo, while most physical theories on tissue mechanics neglect the presence of nuclei. Thus, how large-scale in vivo tissue architecture is shaped by — and feeds back onto — nuclear properties is unclear. During epithelial folding (EF), nuclei characteristically relocalize along the apico-basal axis, raising the question if nuclear movements mechanically contribute to tissue deformation, and/or if the positioning or deformation of the nucleus senses and encodes tissue curvature information to subsequently modulate tissue architecture and cell state. We propose to investigate the coupled dynamics between cell shape, nuclear position and deformation, and address how nuclear distribution and mechanics orchestrates the transitions from the simple-columnar to the pseudostratified, or from the flat to the curved tissue architectures. Combining physics and biology, we will employ innovative, multi-scale theoretical approaches to account for parameters ranging from the subcellular to the tissue and embryo scales, and use the gastrulating Drosophila embryo to experimentally inform and verify our theoretical framework. Exploiting the prowess of Drosophila in quantitative imaging and controlled perturbation, and in particular, optogenetics, we will take a comparative approach to accentuate common mechanical principles of cell-nucleus coupling from the mechanistically distinct EFs that form during Drosophila gastrulation. Furthermore, we will propose lineage-specific feedback parameters to predict the way in which deformed or displaced nuclei influence long-timescale EF morphodynamics, and experimentally explore mechanosensitive changes of nuclear properties, chromatin states and transcription in search of corresponding mechanisms. We expect to uncover fundamental and scale-crossing principles of tissue self-organization driven by nucleo-cellular coupling, thereby testing the hypothesis that nuclei function as sensors and actuators for tissue deformation and differentiation.
2023
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Grant Awardees - Program
The role of lipid physical properties for the multifunctionality of insect cuticular hydrocarbons
FEDERLE Walter (.)
University of Cambridge - Cambridge - United Kingdom
MENZEL Florian (.)
Johannes Gutenberg University of Mainz - . - .
KANEKO Fumitoshi (.)
Graduate School of Science, Osaka University - . - .
Insects wear a multifunctional suit on their body surface - a thin film of cuticular lipids that fulfils many different biological tasks. This outermost layer has a complex chemical composition that varies greatly between species. It not only serves as a vital barrier against desiccation, but the lipids are also essential for chemical communication. Besides, cuticular lipids also have various biomechanical functions in surface adhesion, joint lubrication, and self-healing. How can this lipid layer perform so many functions at the same time? Why is the chemical composition of insect lipid films so complex, with up to 100 different compounds? What selection pressures explain the complex variation in the chemical composition of lipid films?
All the biological functions of cuticular lipids and possible trade-offs between them crucially depend on the physical properties of the films, which are still poorly understood. Current models assume that waterproofing is based on relatively solid lipids, while the other functions require lipids in a fluid state. We hypothesize that cuticular lipid layers can meet these conflicting requirements due to their complex phase behaviour and other physical properties, and that insects can tune these to different demands by varying lipid composition.
We will investigate four main questions: 1) What are the physical properties of cuticular lipid layers, and how are they influenced by their chemical composition? 2) How do cuticular lipid properties depend on temperature, and how do insects change their lipid layers when acclimating to different environmental conditions? 3) How do the physical properties of cuticular lipids affect their biological functions? 4) How do insect lipid properties correlate with their ecological niche?
We will study the multifunctionality of insect cuticular lipid films by integrating physical chemistry, physiology and evolutionary ecology. By combining modern techniques for measuring physical properties of lipid layers with novel biological experiments on insects, we will determine how lipid composition, phase state and physical properties affect each function. With this we will gain novel insights into the functions of cuticular lipids, and better understand the adaptive value of the complex composition of cuticular lipids and how this multifunctional trait evolved.
2023
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Grant Awardees - Program
Social immunity in honeybee - SoBee
GALIZIA C Giovanni (.)
University of Konstanz (Universität Konstanz) - Konstanz - GERMANY
JENSEN Emil (.)
Technical University of Denmark - . - .
JENSEN Michael (.)
Technical University of Denmark - . - .
FIEHN Oliver (.)
The Regents of the University of California (University of California Davis) - . - .
Insects play crucial roles in pollination of the world’s crops. Yet insect populations are on decline, partially due to pesticide-intensive agriculture, climate change-induced disruptions, and diseases. With respect to disease, timely recognition of and response to, eminent contagions has proven essential for eusocial insects like honey bees (Apis mellifera). Without an adaptive immune system, honey bees rather rely on social immunity as part of maintaining hive hygiene, involving both removal of corpse from hives and altered social interactions. However, while there is a growing body of evidence linking disease-related odors to honey bee physiology and behavior, the causal molecular underpinnings of olfaction, or the sense of smell, driving behavioral disease defenses, like social immunity, in response to hive infestation, remains elusive. One key piece in decoding the sense of smell is to map the specificity and affinity of honey bee olfactory receptors (ORs). The honey bee genome encodes approx 170 ORs, yet odors consist of hundreds of small molecules. Adding to the complexity, the OR:odorant map is bow-tied, with many ORs detecting the same odorant, and some ORs detecting multiple odorants. Here we join expertise in entomology, synthetic biology, and chemistry to test the working hypothesis that the evolution of social immunity in honey bees is controlled by olfaction, or more specifically that certain ORs in worker bees are under strong selection, and even causal to olfaction-induced social immunity leading to survival and next-generation courtship. To address this hypothesis, the consortium on social immunity in honeybees (SoBee) will search bacterial and honey bee cues causal to recognizing infected sisters, by i) testing volatile organic compounds (VOCs) produced from metagenomic libraries of infectious bacteria against honey bee ORs expressed in a microbial olfaction platform, ii) performing metabolite profiling of honey bee glands and clonal isolates from metagenomic library screens to search for chemical cues correlating with social immunity, and, iii) testing glands in bioassays, bee brain activity, and conduct hygienic behavioral studies on honey bees. Thus, the project seeks to identify causal factors underlying social immunity with the ultimate goal to support sustainable honey bee disease mitigation and crop pollination.
2023
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Grant Awardees - Early Career
Exploration of the structure-function space of prebiotic to biological proteins – RENEWAL APP
FUJISHIMA Kosuke (.)
National University Corporation Tokyo Institute of Technology - Meguro-ku Tokyo - JAPAN
FRIED Stephen (.)
Johns Hopkins University JHURA - . - .
FREELAND Stephen (.)
University of Maryland Baltimore County - . - .
HLOUCHOVA Klara (.)
Charles University (Univerzita Karlova) - . - .
All life on Earth depends on proteins, now composed of a quasi-universal alphabet of 20 amino acids. The alphabet has been fixed in the Central Dogma for eons of evolutionary history, creating the impression that it is somehow “optimal” for folding sequences into complex structures and performing biochemical functions. The possibility however that the canonical amino acid alphabet is a “frozen accident” (to quote Francis Crick) has yet to be critically examined because whether alternative amino acids would lead to “bad” alphabets has not been empirically tested. Here, we propose to design “xeno-alphabets” composed primarily of non-canonical amino acids, and then to synthesize peptide libraries “written” in these new chemical languages. Our goal is to test whether alternative life (or evolutionary paths) could have produced successful proteins from entirely different building blocks and to learn about the chemical logic of the set found within life’s genetic code.
As the number of possible xeno-alphabets is infinite, chemoinformatic approaches will be used to propose representative xeno-alphabets that vary in their chemical distance from canonical and capture different regions of physicochemical property space. After designing such alphabets in silico, we will synthesize peptides composed of these letters using solid phase peptide synthesis (which will allow us to focus on evaluating the properties of the peptides, such as the ability to fold or bind with other biomolecules) or using wet-dry cycling (which will focus on the capacity of the building blocks to form peptides autonomously under prebiotically-relevant conditions).
In characterizing these peptide libraries, our principal aim will be to compare the structure-forming and functional potential of the alphabets (using a range of biophysical and biological methods) with the canonical set, to answer: How large is the chemical space that could support life as we know it (or don’t know it)?
We, therefore, propose a research program by which unique computational tools will be adapted to design xeno-alphabets, whose peptides will be tested with laboratory techniques – some of which draw from our previous experience but most require significant methodological innovation, including next-generation peptide sequencing.
2023
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Grant Awardees - Early Career
Switchable immunomodulation of mRNA transport and local translation in microglia by bioactive RNAs
MILOVANOVIC Dragomir (.)
German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen - DZNE) - Bonn - GERMANY
LEPPEK Kathrin (.)
University Hospital Bonn (Universitätsklinikum Bonn) - . - .
L. J. BROERE Daniël (.)
Universiteit Utrecht - . - .
FU Meng-Meng (.)
- . - .
Defects in microglia, the resident immune cells of the brain, have been implicated in neurological diseases, including Alzheimer’s, Parkinson’s, and multiple sclerosis. Microglia perform diverse functions, such as developmental synapse elimination, immune surveillance, and phagocytosis of pathogens and cellular debris. As highly ramified cells, microglia spatially regulate locally branched domains. In response to local signals, microglia can rapidly switch their shape from highly ramified to amoeboid. How this dramatic morphological change is achieved remains unclear. Recent transcriptome profiling of microglial processes uncovered a subset of local mRNAs encoding cytoskeletal protein. This suggests that mRNA transport and local translation may regulate microglia morphology. Though both of these mechanisms are well understood in neurons, they have not been studied extensively in microglia. In addition, few tools are available to manipulate mRNA transport and local translation with spatial precision. We will capitalize on our expertise in glial cell biology (Fu GLIA Lab), regulatory RNA structure, translation and therapeutics (Leppek RNA Lab), protein biochemistry and liquid condensates (Milovanovic CONDENSATE Lab), and synthetic organic chemistry (Broere SYNTHESIS Lab). We hypothesize that manipulating mRNA granules can lead to local changes in translation and morphology. We aim to: (i) identify key local mRNAs that affect microglial function using primary microglia cultures; (ii) characterize the mesoscale assembly of mRNAs and RNA-binding proteins (RBPs) inside condensates; (iii) leverage mRNA structure-function to design and develop a photoswitchable bio-active RNA tool (SMARTswitch); (iv) validate that SMARTswitch can manipulate local translation in microglia. Collectively, we will provide innovative synthetic RNA-based approaches to modulate local cellular functions and reprogram microglial responses.
2023
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Grant Awardees - Early Career
Experimentally evolving budding yeast cell size to test scaling laws in cell biology
FUMASONI Marco (.)
Fundacao Calouste Gulbenkian - Lisboa - PORTUGAL
GIOMETTO Andrea (.)
Cornell University - . - .
Genome and organelle sizes vary with cell volume following scaling laws that are thought to reflect physical and molecular constraints on life. Despite cell size spans over several orders of magnitude across the tree of life, individual species are able to maintain a characteristic, narrow range of volumes, following a handful of homeostatic principles. To cover a large range of sizes, scaling patterns were derived by comparing distantly related species, highlighting their conservation but limiting causal inference. On the other hand, much of the work on the mechanisms that maintain size homeostasis was done in single species, which typically cover cell size ranges that are too narrow to investigate scaling patterns. The molecular and physical links that govern size scaling patterns and homeostasis principles, and how they evolve to produce the variability we observe in nature have remained elusive. To overcome previous limitations, we will evolve and engineer a panel of much larger/smaller Saccharomyces cerevisiae cells, aiming at finding the physical or evolutionary limits for this species. We will track genomic and cellular changes associated with the altered size, identify causative mutations, and dissect the mechanisms they act on. Single cell measurements in a genetically amenable species over an unprecedented range of sizes will allow us to test the robustness of homeostasis principles and scaling laws in cell biology, and observe how evolution can alter physical constraints on cell, genome and organelle size.
2023
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Grant Awardees - Early Career
Unraveling the multi-layer relationship between archaeal symbionts and their viruses
QUAX Tessa (.)
Rijksuniversiteit Groningen - Groningen - NETHERLANDS
SAKAI Hiroyuki (.)
RIKEN BioResource Research Center (BRC) - . - .
GHOSAL Debnath (.)
University of Melbourne (Melbourne University) - . - .
GOOD Benjamin (.)
The Board of Trustees of the Leland Stanford Junior University - . - .
Associations between organisms and viruses are complex and encompass everything from beneficial to parasitic relationships. Here we will map the molecular mechanisms that underlie the interactions between crenarchaea, their DPANN archaeal symbionts and their viruses. Archaea are ubiquitous microorganisms in the environment, but the number of isolated species is modest and their cell biology remains underexplored. They are regarded direct ancestors of eukaryotes and important for understanding the origin and evolution of life. Current knowledge of microorganism–virus interactions relies primarily on laboratory studies of one virus and one cell. Yet, based on culture independent approaches, the fraction of microbial species that is involved in a symbiotic relationship is estimated to be considerable, although most are unculturable. Symbiotic microorganisms sustain relationships with another organism (called the host) over a considerable fraction of the life of the host. In addition, this relationship is beneficial for at least one of the organisms. Since symbionts often lack anti-viral defence systems, it has been hypothesized that symbionts can protect their host-cells from viral infection, by serving as decoy. However, empirical relevance of this hypothesis has not yet been tested.
Recently multiple fast-growing symbiotic archaea belonging to the phylum DPANN were isolated by HS, which now offers the exciting possibility to unravel molecular mechanisms underlying viral infection in a symbiotic system. The aerobic fast-growth allows us to apply to this system recently developed imaging techniques. We will combine virology, microbiology, microscopy and structural biology with mathematical modelling to connect the microscopic properties of the individual cells with the emergent behavior at the population level. This will allow us to assess if symbiotic DPANN serve as viral decoys.
Viruses of DPANN archaea are not studied, even though these archaea are widespread. With this project, we will generate unprecedented detail of their infection cycles, structure and the biology of their DPANN hosts, which will lay foundations for a novel field of research.
This project will be one of the first to study viral infection in a symbiotic system, and thus provide essential insights into the impact of viruses on symbiotic organisms, which are so widespread in nature.
2023
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Long-Term Fellowships - LTF
Unraveling limb size determinants using mouse-jerboa chimera
GOEL Isha (INDIA)
ARMI - Monash University - Clayton - AUSTRALIA
ROSELLO DIEZ Alberto (Host supervisor)
Background: From a tiny insect to a giant blue whale the diversity in the animal kingdom is truly remarkable. An understanding of this poorly explored variation in size of organisms can provide a more elaborate map of evolution and will be useful in commercial applications such as increasing meat production from specific body parts. Given the complexity of the animal body, it is more practical to start with one organ that can offer a high range of diversity among different species such as the limb. The differences in size and proportions demonstrating their adaptations during evolution open a door to the factors controlling organ size. Two main steps can be distinguished during limb growth: the patterning phase, in which the different limb segments are specified, and the post-patterning phase, where most of the elongation and differentiation take place.
Aim: We aim to generate jerboa iPSCs for the first time to study how they form limbs in host mouse embryos. We plan to compare the development of chimeric jerboa-mouse limbs with that of normal mouse limbs so that their intrinsic differences can be found.
Central hypothesis: Based on classic and recent studies, we hypothesize that final limb size is controlled by the signal balance during the patterning phase, whereas internal limb proportions are tuned by intrinsic differences in the tempo of the post patterning phase. This predicts that if early limb bud cells are placed within the signal environment of a different species, the limb bud cells will adapt the duration of their patterning phase, leading to a change in the limb size, while the internal proportions will be preserved. This decoupling between intrinsic and extrinsic processes will allow us to identify the key genes and networks involved in the control of limb size.
Experiments: The experiments will take place in three stages: 1) Preparation of jerboa iPSCs under the expert supervision of Dr. Rio Tsutsumi, Kyoto University. The jiPSCs will be chemically transformed in four stages and then characterized by RNA-seq and teratome assays for pluripotency. They will be modified for GFP expression 2) Preparation of hindlimb-less mouse model (Hoxb6-Cre; Ctnnb1(flox/flox)) and complementation of its blastocyst with jiPSCs. Litters will be collected to characterize the expression of segment markers Meis1/2, Hoxa11, Hoxa13 by in situ hybridisation, characterize bone length by micro-CT. Morphological and size analysis will be done according to protocols from the Cooper Lab 3) Relative RNA-seq and ATAC-seq analysis of transcriptome and accessible chromatin of limbs.
Conclusion: These experiments are designed to generate the first iPSC line from jerboa providing new resources for research. jiPSCs are expected to form most of the hindlimb in chimeric animals. The size and genetic analysis of the developed hindlimb will provide an insight into what aspects of limb growth are controlled by intrinsic mechanisms, and which aspects by extrinsic ones.
2023
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Grant Awardees - Program
Cellular and molecular basis of bilaterian symmetry
PAVLOPOULOS Anastasios (.)
FORTH Institute of Molecular Biology and Biotechnology (IMBB-FORTH) - Heraklion - GREECE
XIE Liangqi (Frank) (.)
Cleveland Clinic Foundation - . - .
GUIGNARD Léo (.)
Aix-Marseille University (Université d'Aix-Marseille) - . - .
One of the most pervasive, yet poorly understood, hallmarks of most metazoans is bilateral symmetry. The external left and right sides of bilaterians develop separately but somehow manage to produce symmetric matching halves, presumably via deterministic developmental programs, homeostatic buffering mechanisms or combinations thereof. We will probe these mechanisms in a crustacean embryonic epithelial monolayer that acquires a stereotypic, geometrically ordered and bilaterally symmetric tissue architecture composed of less than a thousand cells, while maintaining the capacity to restore left/right symmetry after unilateral cell ablations. Through live imaging with multi-view light-sheet fluorescence microscopy and image analysis of intact and ablated embryos, we will first decompose the shaping of each side into the individual cell contributions to quantify their levels of stereotypy and variability across sides, embryos and conditions during the normal emergence of bilateral symmetry and during its restoration after cell ablation. Guided by these cellular maps, we will then screen for spatially and temporally structured gene networks operating at the beginning, middle and end of the restoration process, using a genome-wide time-course profiling of gene expression and chromatin accessibility with established spatially resolved methods. To probe the regulatory rules of symmetry, we will also develop a new method for dual spatial transcriptomics and epigenomics by converting and amplifying the open chromatin DNA regions into polyadenylated RNA molecules that will be assayed together with cellular mRNA on existing platforms for spatial transcriptomics. We will devise novel computational frameworks to register the cellular atlases from the microscopy datasets with the molecular atlases from the multi-omics datasets in time and space, and to generate average, statistical representations from multiple input embryos. Data integration will enable us to measure at cellular resolution the intraindividual and interindividual variability between sides and across embryos, respectively, and to probe the qualitative and quantitative differences in the corrective molecular and cellular mechanisms that bilaterians have evolved to promote symmetry by buffering the effects of inherent developmental noise (developmental stability) and the effects of perturbation (canalization).
2023
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Long-Term Fellowships - LTF
Utilizing spatial transcriptomics for uncovering the hypoxic transcriptional landscape of tumors
GUSTAFSSON Johan (SWEDEN)
Cancer program - Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard ) - Cambridge - United States
GETZ Gad (Host supervisor)
The tumor microenvironment is characterized by a dense extracellular matrix in combination with leaky and irregular vasculature, creating acidic hypoxic tumor regions with small influx of oxygen and nutrients. Most therapies, such as radiation therapy, immune therapies, and chemotherapy are ineffective in these regions due to lack of oxygen, limited drug influx, immune exclusion, and low proliferation rate. Effective ways to target the cancer cells in hypoxic regions are lacking and means to address this problem could potentially improve the clinical outcome for many groups of patients.
An important step towards finding effective treatments targeting hypoxic regions is to understand their biology. The arrival of spatial transcriptomics has made possible high-resolution studies of the transcriptional landscape in tumors. In spatial transcriptomics, spots containing 1-10 cells are sequenced and associated with a physical coordinate from a thin tissue section, forming a spatial network of gene expression. Hypoxic regions can be identified using immunofluorescence staining for hypoxic markers, enabling identification of biological traits per level of hypoxia. In this project, we will collaborate with the Human Tumor Atlas Network (HTAN) to obtain spatial transcriptomics data overlayed with hypoxia staining from lung and breast cancer patient samples.
The first aim is to establish a method to determine the level of hypoxia per spot based on staining for hypoxic markers, but also from the transcriptomic profiles for use with datasets without staining information.
The second aim is to identify regions within the hypoxia range with similar cellular behavior.
The third aim is to explore and understand the biology and identify potential drug targets in each hypoxic region. To this end, I intend to use methods such as differential expression analysis, gene set enrichment analysis, genome-scale metabolic modeling, and utilize gene essentiality information from the DepMap database.
The fourth aim is to collaborate with the PRISM lab at the Broad Institute, which performs high-throughput screening for drug targets in hundreds of cell lines. To validate our biological theories and provide potential drug targets for hypoxic regions, we will develop a hypoxic setup to test previously identified drug targets as well as perform screening of existing drug libraries for the hypoxic regions previously identified.
In this project, I will bring my metabolic systems biology knowledge into the Getz lab and learn about spatial transcriptomics and cancer biology. The results are envisioned to be an atlas over the transcriptional landscape in tumors defined per region of hypoxia and a list of potential drug targets for these regions. These could serve to find a complementary treatment to existing therapies, specifically targeting the hypoxic regions, which could lead to combination treatments with an increased survival chance for cancer patients.
2023
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Long-Term Fellowships - LTF
Investigating the mechanistic role of the gut microbiome in modulating depressive behavior in mice
GUZZETTA Katherine (USA)
D-BSSE - Eidgenoessische Technische Hochschule Zuerich (ETH Zürich) - Zurich - SWITZERLAND
PLATT Randall (Host supervisor)
Background: Depression is the leading cause of disability worldwide, creating immense psychological and economic burdens for individuals, families and society. Despite depression’s pervasiveness, the pathology and mechanism of action for treatments remain elusive, and roughly half of patients do not improve with antidepressant use. The high global prevalence, poor treatment efficacy and lack of mechanistic understanding has created a large knowledge gap that needs to be addressed to better understand the disease and help patients.
The gut microbiota is an emerging contributor to depression onset and recovery, and can regulate brain function, behavior, and mood of its host by altering the metabolome and immune system. Intriguingly, gut microbial composition is altered in depressed individuals, post-antidepressant treatment and by stress. However, the exact pathways by which these microbes act on the brain, including in depression, remain elusive largely due to an inability to mechanistically interrogate microbe-host interactions.
Overall aim: Uncover how the gut microbiota contributes to the development and recovery from stress-induced depressive behavior (initially in mice).
Hypothesis: The gut microbiota contributes to stress-induced depressive behavior and amelioration through microbe-host signaling (including modulating host serotonin levels and aryl hydrocarbon receptor immune signaling through microbial tryptophan metabolism), and manipulating these pathways is sufficient to augment depressive-like phenotypes in mice.
Experimental Approach: To reveal how stress and antidepressants impact the gut microbiome and physiology of mice, I will analyze behavior and physiology (gene expression, corticosterone/neurotransmitter levels, etc) and use contemporary multi-omics methods (metagenomics/transcriptomics) combined with the novel Record-seq technology recently created by the host laboratory (Schmidt, Nature, 2018; Schmidt, Science, 2022). My bioinformatics analysis will focus on understanding microbe-host pathways altered by stress and alleviated by antidepressant (fluoxetine or probiotic) consumption. I will then functionally validate key findings using CRISPR-based manipulation of top identified pathways in the gut microbiome (with host institutional knowledge) and microbiota transplantation to reveal novel mechanisms by which the gut microbiota contributes to anti-depressive or depressive-like behavior.
Conclusions: This research has the potential to shift paradigms for depression research by incorporating novel microbiome-based techniques and centering the gut microbiota in the pathophysiology of depression. This project will expand on my background of the microbiota-gut-brain axis and allow me to pursue new scientific disciplines and techniques, including CRISPR, microbial engineering, bioinformatics, and Record-seq. The use of cutting-edge non-invasive methods (Record-seq) also provides an entry point for follow-up clinical studies.
2023
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Long-Term Fellowships - LTF
Investigating the cross talk between glioma cells and oligodendrocytes in brain tumors
HAN Jichang (CHINA, PEOPLE'S REPUBLIC OF)
SCCC - Miller School of Medicine of the University of Miami - Coral Gables - United States
IAVARONE Antonio (Host supervisor)
Glioblastoma multiforme (GBM) is the most common high-grade glioma in adults and has an exceptionally dismal prognosis. Neuronal activity has recently emerged as a critical regulator of GBM progression by regulating membrane depolarization of glioma cells via neuron-glioma synapses or secreting neurotrophic factors from neurons. Oligodendrocytes can wrap around axonal segments, enabling fast saltatory conduction of action potentials and supporting axons' energy metabolism. Whether a functional interaction between oligodendrocytes and cancer cells drives GBM remains unknown. To better understand the interactions between tumor and non-tumor cells, the host lab analyzed larger scRNAseq dataset of GBM to uncover the ligand-receptor interactions from the tumor microenvironment (TME) using a recently developed single-cell tumor-host interaction (scTHI) tool and identified that the oligodendrocytes express high levels of NLGN1 that interacts with NRXN3 expressed by neuronal tumor cells.
We propose a model wherein oligodendrocytes directly interact with the tumor cells through ligand-receptor interactions and generate oligodendrocyte-glioma myelin sheaths to promote cancer development. This proposal will uncover the functional downstream consequences of the newly identified ligand-receptor interactions and how they drive glioma progression. A key innovative component of our proposal will be to interrogate the ability of glioma cells to form functional myelin sheaths with oligodendrocytes thus hijacking the normal activities of oligodendrocytes.
A diverse range of cutting-edge techniques will be used to address these goals. To distinguish and verify the interactions between tumor and non-tumor cell types in GBM, I will deploy spatial transcriptomic technology and multiplexed error-robust fluorescence in situ hybridization (MERFISH). For these analyses, a panel of genes will be designed based on the host lab scRNA-seq data and cell-type/state annotations, to decipher spatial and functional organization. I will also investigate the ultrastructure of oligodendrocyte-glioma myelin sheaths in mouse models and patient tumors by enhanced focused ion beam scanning electron microscopy (FIB-SEM) technology enabling high-throughput, large volume, and high-resolution 3D imaging. Finally, to elucidate the molecular mechanisms of ligand-receptor interactions governing tumor growth or oligodendrocyte recruitment in glioma, I propose to examine the gene expression profiling and gene set enrichment analysis of ligand-null (CRISPR-KO) versus parental ligand-wild-type in cell lines or genetically engineered mouse models of gliomas.
The outcome of this work will unravel the regulation and functional impact of the crosstalk between glioma cells and oligodendrocytes in GBM and provide the key knowledge for the design of innovative therapies. It will also provide the paradigm-shift discovery and functional characterization of myelination as driver of GBM progression.
2023
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Grant Awardees - Early Career
Dark oxygen production: Assessing an overlooked microbial process in Earth's hidden ecosystems
RUFF S. Emil (.)
Marine Biological Laboratory - Woods Hole - United States
KRAFT Beate (.)
University of Southern Denmark (Syddansk Universitet, SDU) - . - .
HEMINGWAY Jordon (.)
Swiss Federal Institue of Technology - . - .
Most gaseous oxygen (O2) on Earth is produced via oxygenic photosynthesis. However, new evidence indicates that O2 is also produced in permanently dark ecosystems. This so-called “dark oxygen production” (DOP) can proceed via abiotic chemical reactions or via microbial dismutation of chlorite and nitric oxide—metabolisms fundamentally different from photosynthesis. Recent work suggests that microbial DOP is widespread in groundwater ecosystems, yet definitive evidence is lacking to date. Our team has the abilities, instruments, and expertise to provide such evidence and elucidate the origins, processes, and production rates of groundwater O2. We hypothesize that microbial DOP is a globally relevant process in groundwater ecosystems today, and that groundwater aquifers represent model systems to study O2 production and consumption in the deep geologic past, as well as in subsurface ecosystems of other celestial bodies.
We propose an international, multi-disciplinary project to provide comprehensive insights into the geochemistry, microbiology, and ecology of DOP. Our combined expertise leverages three key technological advances: (1) triple- and clumped-oxygen isotope analyses, which can unambiguously link O2 to biological DOP origins (led by PI Hemingway), (2) determination of DOP rates and fluxes at unprecedented resolution using nanomolar O2 concentration measurements (led by PI Kraft), and (3) high-throughput analyses of O2-producing enzymes and pathways present in complex communities using genome sequencing and protein mass spectrometry (led by PI Ruff). We will apply these techniques to a sample set from diverse aquifers spanning a broad range of ecosystems in Canada, Finland, Germany, Switzerland, and the USA. We expect several key outcomes. First, we will determine the first ever triple- and clumped-oxygen isotope signatures of DOP by different biotic and abiotic sources, values that are needed to decipher natural signals. Second, we will use stable isotope-labelling to determine rates of microbial DOP in groundwaters, critical measurements that are lacking to date. Finally, we will conduct the first global survey of key microbial lineages and genes to understand the diversity, abundance, and activity of microbes involved in DOP. These insights are crucial to understand groundwater aquifers, which represent Earth’s largest source of drinking water.
2023
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Long-Term Fellowships - LTF
Disentangling microbiome effects on plant adaptation
HERNANDEZ-TERAN Alejandra (MEXICO)
EEB - The Regents of the University of California (Irvine) - Irvine - United States
REBOLLEDA-GOMEZ Maria (Host supervisor)
It is increasingly clear that microbes can influence host health and fitness. In particular, microbes affect important developmental transitions like metamorphosis in mosquitoes and flowering time. The timing of these transitions is central for organisms responses in changing environments. However, we do not know which microbes alter such traits and how they do it, or whether it is adaptive for the microbes or a consequence of their metabolism.
Through integration of life-history models, microbial physiology, community selection, and plant evolutionary ecology, my goal is to understand microbial effects on plant developmental timing. The ultimate goal is to generate predictive models of when are microbes more likely to impact plant development, which microbial functions are involved, and how are these interactions going to change with an increasingly variable environment. One intriguing hypothesis is that since microbes are indicators of environmental and ecological conditions, they can provide accurate information about optimal phenology to the plant hosts while integrating to noisy variation. I will use flowering time in Arabidopsis thaliana as a experimental system to determine how microbial community function might change with changes in temperature.
Recently, Dr. Rebolleda-Gomez developed a predictive model microbial community change across temperatures in simple carbon sources. In collaboration with members of the lab, I will extend these models to more complex communities. Using this data I will be able to analyse the information and reliability of changes in microbial functions over time (compared to the temperature series alone) to evaluate the quality of microbes as cues. These mathematical approaches are new to me, but as part of my postdoctoral formation at UCI I will benefit from the expertise in microbial ecology of Dr. Rebolleda-Gomez and time series analyses of Dr. Symons (a close collaborator). Using recently developed theory on community level selection, I will select from different substrates, microbes that significantly affect flowering time and inoculate A. thaliana lines with different flowering plasticity. I will test the effect of such communities in different thermal conditions to determine when and why plants respond to microbes. Using omics approaches, I will characterize from the selected microbial communities the metabolic functions that are associated with either late or early flowering time. Finally, I will incorporate our insights into predictive life-history models to evaluate possible effects of microbes on plant adaptation to climate change. Altogether, this project will allow me to gain insights into the mechanisms by which microbial communities affect plant phenology, and to hypothesize about the evolutionary implications. This fellowship will allow me to learn the mathematical and experimental tools necessary to generate predictive models of microbiome effects on plant development.
2023
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Long-Term Fellowships - LTF
Growth and folding of a wing origami
HIROKAWA Soichi (USA)
Faculté des Sciences - Developmental Biology Institute of Marseille (Institut de Biologie du Développement Marseille, IBDM) - Marseilles - FRANCE
LECUIT Thomas (Host supervisor)
Tissue folding is widespread in morphogenesis. It often arises due to geometric frustration associated with growth mismatch. One of the big questions is how organisms take advantage of the local mechanics, differential growth, and physical and geometric boundary conditions of tissues to drive this folding. One such example may be found in the final stages of Drosophila wing development. During metamorphosis, the wing elongates along the body of the fly as a planar sheet before anchoring to the hard cuticle layer encasing it. From 30 hours into metamorphosis up to 96 hours when metamorphosis ends, the wing has grown by more than an order of magnitude in surface area. The wing manages to continue to grow in the confined space over these 66 hours by folding. During this period, as the wing continues to grow, it also becomes thinner and develops more folds. However, the driving mechanism for this folding phenomenon and the level of variability in the shape change across individual wings are not known. We propose to study how the physical and geometric constraints on the wing and the differential growth of the cellular layer and its attached extracellular matrix (ECM) allows the wing to fold. This project will be an incorporation of live imaging in 3D through the highly robust Gal4-UAS system to identify geometric changes to the wing as it develops folds and will require an analysis of 3D-reconstructed images to identify the patterns of shapes that emerge and the recurrence or variability of these patterns across wings of different individuals. A key piece to better understanding the role of this differential growth between the cells and the ECM as well as the constraints on the folding process will involve genetic and physical perturbation of the wings to further study how making alterations to the development of the wing changes its folding pattern. These include using recently developed optogenetic systems to spatially control changes to local cellular growth rates and the use of genetic mutants to examine how the changing the expression level of genes and the distribution of their resultant proteins affect the boundary or growth conditions on the wing and thus affect the folding pattern. We will also examine how the wings unfold at various time points during development by removing the boundary that encases them and watch how they unravel. We expect these experiments and the concurrent analyses will allow us to understand how boundary conditions that confine the wing and the differential growth and material properties between cell and ECM combine to allow the fly to continue to develop its wings under spatial confinement.
2023
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Long-Term Fellowships - LTF
Rock-paper-scissors dynamics between mobile genetic elements
HUISMAN Jana Sanne (NETHERLANDS)
Physics - Massachusetts Institute of Technology - MIT - Cambridge - United States
GORE Jeff (Host supervisor)
The ecology of bacteria is directly tied to the ecology of the mobile genetic elements (MGEs) that infect them. These elements act as parasites or symbionts, spreading horizontally between bacteria and shaping the genetic repertoire of their hosts. MGEs can be beneficial when carrying traits like metabolic pathways, virulence genes, or antibiotic resistance, which allow their host bacteria to thrive in new environments. Yet, they are also costly due to the expression of the encoded genes. Additionally, evidence is emerging of extensive interaction and competition between MGEs. Many MGEs co-circulate in natural bacterial populations and co-carriage within the same bacterial host is common. However, little is known about “coexistence conditions” for MGEs: how can diverse MGEs be maintained in the same population? And how does this affect the bacterial community in which they circulate?
We aim to address these questions for plasmids, a type of MGE frequently implicated in the spread of antibiotic resistance. Plasmids commonly code for genes that prevent further infection by similar plasmids (“superinfection”). We hypothesize this naturally leads to non-transitive interactions between plasmids that compete for the same bacterial hosts, and that this can maintain a diversity of plasmids even in the absence of selection for plasmid-borne traits. Non-transitive interactions work like the game “rock-paper-scissors”: each strain both inhibits and is inhibit by other members of the community. Such interactions have been proposed as a prime driver of species diversity, yet experimental realizations thus far remain restricted to bacteriocins or antibiotics, with limited extension to explaining MGE diversity.
We intend to study these dynamics in an experimental system using Escherichia coli strains that differ only in their carriage of two competing antibiotic resistance plasmids: (i) “F0” carries no plasmid and grows fast, (ii) “ML” carries a non-conjugative plasmid with medium cost, and (iii) “SC” carries a costly conjugative plasmid and grows slowest. As a result, F0 outcompetes ML due to growth, ML outcompetes SC due to growth and immunity to superinfection, and SC outcompetes F0 since the conjugative plasmid transforms F0 into SC. We will use pairwise and 3-way competition experiments to study the stable states of this system over multiple growth-dilution cycles. By varying parameters of the experiment, like growth rate, dilution, dispersal, and relative costs, we can probe the conditions for plasmid coexistence over a range of scenarios. Mathematical modelling will help scale these transitivity rules to a broad diversity of co-circulating plasmids and predict their influence on the stability of more complex bacterial communities.
Understanding such plasmid diversity and maintenance is directly relevant for the study of bacterial colonization and infection of human and animal hosts, as well as the spread of antibiotic resistance.
2023
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Grant Awardees - Program
From diffuse to localised signalling: The origin of synaptic neurotransmission in animals
WATANABE Shigeki (.)
Johns Hopkins University School of Medicine - Baltimore - United States
IKMI Aissam (.)
European Molecular Biology Laboratory (EMBL-Heidelberg) - . - .
MUSSER Jacob (.)
Yale University - . - .
The evolution of the nervous system is one of the remaining great mysteries of animal evolution. A key step was evolution of the chemical synapse, which enabled the transition from ciliomotor-based movement by diffusive signals to muscle-based locomotion driven by ultrafast localised signals. However, current understanding of this transition is mostly limited to determining the distribution of synaptic genes in early animal genomes, revealing most predate synapses. There are two competing hypotheses for how chemical synapses evolved. The first, termed the “chemical brain hypothesis”, proposes animal behaviour was initially controlled by paracrine cell networks using volume (non-synaptic) signalling. The second, termed the “protosynaptic hypothesis”, proposes that synaptic architecture already existed prior to the origin of true nervous systems, and facilitated some form of directional signalling. To test these hypotheses, we integrate expertise in synaptic dynamics and physiology, functional proteomics, and transgenesis techniques in early animals to uncover how synaptic signalling is achieved in the first animals without synapses (sponges) and those with synapses (cnidarians). To accomplish this, we will reconstruct the ancestral dynamics and localisation of synaptic protein complexes, discover the origins of ultrafast mechanisms for synaptic exo- and endocytosis, and determine the role of electrical potentials in propagating the first synaptic signals. In summary, our study aims to reveal the mechanisms underlying the origin of synaptic transmission with broad implications for the evolution of animal behaviours.
2023
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Long-Term Fellowships - LTF
Mapping the spatiotemporal organization and mechanosensitivity of gamma delta T cell synapses
JUKIC Nebojsa (CROATIA)
Autonomous Matter - Institute for Atomic and Molecular Physics (AMOLF) - Amsterdam - NETHERLANDS
GANZINGER Kristina (Host supervisor)
TANS Sander (Host supervisor)
Background: The spatiotemporal organization of T-cell receptors (TCRs) is critical to target cell recognition that underlies a novel class of cancer therapies. While dynamic receptor reorganization was observed in canonical T-cells, less is known about the recognition mechanisms of gamma delta (gd) T-cells, which are emerging as attractive candidates. Specifically, the spatiotemporal organization of their receptors upon immune synapse (IS) formation, their mechanosensitivity, and possibly crucial membrane deformations remain largely unexplored. While high-resolution fluorescence microscopy of T-cells contacting supported lipid bilayers (SLBs) presenting target proteins has been crucial to dissect canonical T-cell organization and signaling, SLBs containing select antigens and adhesion molecules cannot be used to probe gd T-cells as not all factors involved in antigen presentation are known for gdTCRs.
Aims: Combining my expertise in membrane biophysics and SLB fabrication on non-rigid substrates with the host’s expertise in biophysics, high-resolution fluorescence microscopy and T-cell immunology, we will reveal the spatiotemporal organization of gdTCRs upon immune synapse formation between T-cells and tumor cell-derived SLBs. In brief, we will:
A0. Establish experimental platform - mechanically tunable, tumor cell-derived SLB
A1. Map the spatiotemporal (re)organization of gdTCRs upon IS formation
A2. Assess effect of surface rigidity on organization of gdTCRs and gd T-cell activation
Hypotheses: I conjecture that gd T-cell receptors undergo specific spatiotemporal organization to allow antigen recognition in infection and tumorigenesis. Clustering of TCRs in canonical T-cells and exclusion of phosphatases from the IS amplify the signal from antigen-binding events, but dynamic TCR reorganization in gd T-cells remains unexplored. Intriguingly, receptor organization may interplay with membrane deformation and mechanosensitivity, which may both be critical to T-cell activation. I will study this by modulating support rigidity, with which I have ample experience.
Experimental approach:
E0: Develop polymer-based supports for fluorescence microscopy. Harvest plasma membrane vesicles from tumor cell cultures. Optimize SLB formation.
E1: Total internal reflection fluorescence microscopy - single molecule tracking of synaptic components upon gd T-cell contacting tumor cell-derived SLB.
E2: Measure force of gd T-cell–SLB interaction as a function of SLB rigidity using atomic force microscopy-based single-cell force spectroscopy and acoustic force spectroscopy.
Conclusions: I will observe the spatiotemporal organization of gdTCRs upon immune synapse formation at the molecular level, gaining insight into their activation mechanism – an unresolved question that has stymied progress in gdT-cell application in immunotherapy. I expect my novel, tumor-cell derived experimental platform to open up a range of new avenues in gdTCR research.
2023
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Grant Awardees - Program
Shiny signalling: the production, detection and neurobiological processing of brilliant colours
VAN DER KOOI Casper J. (.)
University of Groningen - Groningen - NETHERLANDS
KINOSHITA Michiyo (.)
The Graduate University for Advanced Studies, SOKENDAI - . - .
KEMP Darrell (.)
Macquarie University - . - .
Why do some organisms have shiny colours and others do not? Shiny colours are displayed across a suite of plants and animals, including the flowers of buttercups, orchids and tulips, the wings of butterflies, and the surfaces of beetles. The visual appearance of these organisms is dominated by a flash, which entails a bright pulse of polarised light with a strong angular dependence. The dynamic nature of such “flashy” effects presents a paradox in visual ecology, because although flash effects likely enhance long-range signal visibility, they may undermine the ability to locate objects at close range. This may help explain why colours with a matte appearance prevail in nature, yet the repeated independent evolution of shiny colours implies a fundamental, possibly universal adaptive benefit for signal dynamicity per se. Our project will constitute the most integrative cross-taxon approach to understanding the basis of this adaptive benefit conducted to date.
We will achieve an integrative understanding of the ecological significance of flashy colours by: (1) characterising the optical properties of sexually deceptive flowers and relating these to their insect models; (2) quantifying how flower gloss determines the long-distance visibility and short-distance discriminability of flowers to insect pollinators; (3) determining the behavioural significance of flashy colours in insect visual ecology; and (4) elucidating how the insect brain processes bright flashes. Hence, we will trace the full pathway from how such signals are generated to how they ultimately elicit fitness effects in their relevant viewers. This breadth of insight is only possible by integrating our collective expertise in biophysics (van der Kooi), behavioural ecology (Kemp) and neurobiology (Kinoshita), which is precisely why this project promises unprecedented insight into a (literally) brilliant phenomenon that has fascinated researchers for centuries.