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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
2022
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Long-Term Fellowships - LTF
Biochemical and structural characterisation of the mycobacterial T4SS-like/T7SS conjugation system
HENNELL JAMES Rory (.)
. - University Medical Center Hamburg-Eppendorf - Hamburg - GERMANY
MARLOVITS Thomas (Host supervisor)
Bacterial conjugation allows the transfer of genetic material between bacterial strains and is associated with the spread of antibiotic resistance and virulence factors. Recent work has discovered a conjugable plasmid (pRAW) in Mycobacterium marinum and related plasmids that are present in up to 50% of natural Mycobacterium isolates, including the Non-Tuberculosis Mycobacteria which often cause infections in immune-compromised patients. Most bacterial conjugation systems use the Type IV Secretion System (T4SS). pRAW encodes a T4SS-like system and a Type VII Secretion System (T7SS) termed ESX-P1. The T4SS-like gene cluster lacks key genes and transposon mutagenesis experiments showed that both the T4SS-like genes and T7SS genes were required for successful conjugation, suggesting that they function together in conjugation.
In this project I will structurally and biochemically characterise the components of these T4SS-like and T7SS secretion systems through three main approaches: cryo-electron tomography of secretion systems in native cells, purification of secretion complexes from native cells for biochemical and cryoEM analysis, purification of recombinant secretion complexes from Mycobacterium smegmatis. This work will be carried out in the Marlovits laboratory, where there is expertise in structural biology in collaboration with the Bitter laboratory, where there is expertise in genetics of mycobacteria. Structural and biochemical studies of this complex will enhance our understanding of a fundamental biological process which may contribute to the spread of antibiotic resistance and virulence factors in bacteria that cause a significant disease burden worldwide.
2022
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Long-Term Fellowships - LTF
Cell-specific functional connectivity of cerebellar outputs for locomotor learning
HERENT Coralie (.)
. - Champalimaud Foundation (Fundação D. Anna de Sommer Champalimaud e Dr. Carlos Montez Champalimaud) - Lisbon - PORTUGAL
CAREY Megan (Host supervisor)
We constantly navigate a complex world filled with uneven terrains that alter our walking pattern. Learning to correct for predictable errors in a changing environment is crucial for smooth and coordinated locomotion. A striking example is the adaptability of locomotor patterns upon exposure to a split-belt treadmill, where opposite limbs move at different speeds. The host laboratory previously showed that mouse, like human, locomotor learning depends critically on the cerebellum and specifically, on neurons projecting to the cerebellar interposed nucleus (IP). Importantly, spatial and temporal components of learning (location and timing of paw placement) proceeded independently, suggesting that they might be dissociable at the circuit level. This proposal aims to identify and characterize the functional connectivity of cerebellar output circuits conveying corrective calibration signals that modify ongoing locomotor movements in space and time. Specifically, we will: 1) Use cutting-edge viral tools to map output circuits downstream of the IP and identify key candidates for spatiotemporal calibration signals; 2) Use high-resolution quantitative behavioral analysis and circuit manipulation to test specific functional roles of projection-defined subsets of IP neurons in locomotor learning; 3) Use optogenetically-guided multi-probe recordings of projection-specific IP neurons during learning to understand how the cerebellum transforms locomotor errors into spatiotemporal calibration of locomotor movements. Overall, this work will reveal unprecedented insights into neural circuits ensuring the adaptability of motor commands, directly relevant for human rehabilitative therapy.
2022
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Long-Term Fellowships - LTF
Evolutionary, expression, and functional characterization of ancient putative chemosensors
HIMMEL Nathaniel (.)
. - University of Lausanne - Lausanne - SWITZERLAND
BENTON Richard (Host supervisor)
Ligand-gated ion channels (e.g. TRPs, IRs/iGluRs) are critical in animal sensory systems to link recognition of external and internal cues to changes in physiology and behavior. Growing evidence indicates that many of these channel families have origins in the last common eukaryotic ancestor (~2 billion years ago), but their functions outside of Metazoa are poorly understood. Recently, homologs of insect chemosensory receptors (“Gustatory Receptor-like”, GRL) were identified by the host lab in several unicellular species, including chytrid fungi, protists, and alga, many of which are motile and are capable of chemotaxis, leading us to hypothesize that these putative channels function in external stimulus-guided behavioral or physiological responses. I propose to characterize ligand-gated ion channels in these understudied taxa, via three aims: (1) Bioinformatically identify and phylogenetically assess all animal ligand-gated ion channel family homologs across unicellular Eukaryota; (2) Determine channel expression and localization (starting with GRLs) across life stages of select unicellular taxa through RNA-sequencing and immunofluorescence; (3) Determine protein biochemical and functional properties both in vitro (through heterologous cell expression) and in vivo, starting with the chytrid Spizellomyces punctatus GRL1, capitalizing on new genetic tools for this species. My studies will expand our understanding of channel evolution and function across taxa, and potentially reveal molecular mechanisms of sensory-guided behavior and physiology in unicellular eukaryotes, offering insights into the early evolution of chemosensation.
2022
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Grant Awardees - Program
Molecular determinants of evolutionary conservation in disordered protein regions
HOLEHOUSE Alex (UK)
Dept. of Biochemistry and Molecular Biophysics - Washington University School of Medicine - St. Louis - USA
LEE Hyun (KOREA, REPUBLIC OF (SOUTH KOREA))
Biochemistry - University of Toronto - Toronto - CANADA
WEIJERS Dolf (NETHERLANDS)
Laboratory of Biochemistry - Wageningen University - Wageningen - NETHERLANDS
Intrinsically disordered regions (IDRs) are a ubiquitous class of protein domains found in the majority of eukaryotic proteins. Unlike folded regions, IDRs exist in a conformationally heterogeneous collection of states and lack a single canonical structure. IDRs play essential roles in a wide variety of cellular processes, from the immune response to transcriptional regulation to cell division. Despite their prevalence and crucial cellular roles, our understanding of how IDRs work and what they do in any given context is still in its infancy. Understanding a protein’s function is analogous to understanding that protein’s evolutionary constraints. Evolutionarily significant features are by definition important for protein function, either directly (i.e., catalytic residues in enzymes) or indirectly (i.e., protein stability in folded domains). Given our limited understanding of protein function, it should be of no surprise that our understanding of IDR evolution is also minimal. Rather than a problem, we propose this offers an incredible opportunity to take advantage of evolutionary selection as a design principle that selects for functionally important IDR features. To do this, we require a model system where IDRs are present, essential, and play similar roles across divergent evolutionary organisms. Plant AUXIN RESPONSE transcription FACTORs (ARFs) represent an evolutionarily ancient set of transcription factors that regulate almost every aspect of plant development. ARFs contain folded and well-characterized DNA binding domains, yet most also contain large IDRs that are poorly conserved by any kind of standard alignment-based metric. Importantly, ARF IDRs are critical for normal development. As a result, ARFs offer an unprecedented model to elucidate the determinants of functional selection on IDRs. Our project will integrate molecular biophysics, rational sequence design, and organismal physiology to uncover how changes in ARF IDRs conspire to determine evolutionary fitness.
2022
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Grant Awardees - Program
Physical regulation of the genome
HOLT Liam (USA)
Dept. of Biochemistry & Molecular Pharmacology, Institute for Systems Genetics - New York University School of Medicine - New York - USA
LEVY Emmanuel (FRANCE)
Dept. of Structural Biology - Weizmann Institute of Science - Rehovot - ISRAEL
TAKINOUE Masahiro (JAPAN)
Department of Computer Science - Tokyo Institute of Technology - Yokohama - JAPAN
Textbook models for biological regulation emphasize active mechanisms of signal transduction and chemical signaling, such as protein phosphorylation. However, cells could also achieve control at a more fundamental level by directly sensing changes to the intracellular physical environment. The cell is highly crowded and far from thermodynamic equilibrium. Molecular crowding decreases molecular motion, and also drives interactions through depletion-attraction. We found that crowding is actively regulated in the cell and can tune phase separation. Active processes increase the effective temperature in the cell, helping to fluidize this extreme environment, and depletion of ATP can lead to glass transitions. Therefore, we hypothesize that the interplay between molecular crowding and active processes plays a global role in determining the rates of biochemical reactions. These effects strongly depend on length-scale, such that each biochemical process can potentially respond differently to physical perturbations depending on the size of molecules involved. Thus, the cell can evolve to increase the rates of some reactions and decrease the rates of others in response to changes in crowding or effective temperature. While appealing, the degree to which changes in the physical environment directly regulate biology has been challenging to test in vivo. Indeed mutation of endogenous molecules that impact the material properties or effective temperature of the nucleus necessarily interfere with host biology, leading to pleiotropic effects and making interpretation impossible. To solve this problem, we will: (i) reconstitute transcription within synthetic DNA nanostructure condensates in vitro (Takinoue lead); (ii) develop analogous protein condensates that anchor to specific DNA loci in vivo (Levy lead); and (iii) leverage large-scale genome engineering (Holt lead) to directly address the hypothesis that transcription can dynamically respond to changes in the physical properties of the environment. More generally, responsiveness of biochemistry to physical regulation could represent a primordial and universal level of regulation. Understanding the principles of physical regulation could help elucidate many unresolved conundrums in biology from cell-size control to mechanobiology and this knowledge would significantly improve our ability to engineer cellular systems.
2022
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Long-Term Fellowships - LTF
Characterizing how pioneer transcription factors and chromatin structure regulate genome activation
HOPPE Caroline (.)
. - Yale University - New Haven - United States
GIRALDEZ Antonio (Host supervisor)
Zygotic genome activation (ZGA) is a universal step in animal development that involves massive chromatin remodeling and results in priming of cis-regulatory regions and transcriptional activation. In a function conserved across species, pioneer transcription factors (TFs) bind nucleosomal DNA to facilitate opening of regulatory regions to other TFs. In zebrafish, it relies on Nanog, Pou5f3 and SoxB1, yet the specific roles of pioneer TFs and the causal relationship between chromatin architecture and genome activation remain unknown. Further, we lack a holistic understanding of how global chromatin structure is spatially organized and remodeled during genome activation. We will integrate cutting-edge imaging and genomic approaches, including super-resolution, and expansion microscopy to study global chromatin architecture at unprecedented resolution and address these questions at single-cell resolution in zebrafish embryos. We will investigate spatiotemporal behavior of pioneer TF hubs during ZGA, determine interactions of pioneer factors at single molecule resolution and elucidate how promoter-enhancer interactions are modulated in response to pioneer activity.
This is a significant shift in both discipline and methodology from my previous research; I will use a new model organism and develop genomic and chromatin probing techniques while leveraging my microscopy expertise, which is a new dimension for the lab. We expect to elucidate the structure/function relationship of chromatin and pioneer factor dynamics, uncover fundamental mechanisms and provide a framework for dynamic chromatin interactions that will be relevant in other contexts.
2022
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Grant Awardees - Program
Bridging robotics and pollination: Reconstructing a bee’s buzz through micro-robots
VALLEJO-MARIN Mario (MEXICO)
Dept. of Ecology and Genetics - University of Uppsala - Uppsala - SWEDEN
JAFFERIS Noah (USA)
Electrical and Computer Engineering - University of Massachusetts Lowell - Lowell - USA
Bees provide essential services for pollination of both wild and agricultural systems, yet many wild bee populations are currently under threat. There are more than 20,000 species of bees worldwide and understanding how their morphological and ecological diversity translates to variation in function is of timely and urgent importance. Our project leverages a novel implementation of micro-robotics across a multispecies comparison of bees in two continents to disentangle the mechanistic function of buzz pollination, a type of pollination in which bees use powerful vibrations to shake pollen out of flowers. Approximately half of the 20,000 species of bees are thought to be able to buzz pollinate flowers of both wild and agricultural plants (e.g., tomato). These bees encompass an impressive range of morphological diversity, from sweat bees with body sizes of a few tens of milligrams in weight to large bumblebees and massive carpenter bees an order of magnitude heavier. Progress in the study of buzz pollination has been limited by the technical capacity to apply vibrations to flowers in a bee-like manner due to the reliance on large, cumbersome table shakers to mimic bee vibrations. Our project is set apart from previous work by using micro-robotic buzzers designed to capture the main properties of bee pollination buzzes using bee-scale vibrating and grasping mechanisms developed as part of the proposed work. This new approach will allow us to synthesise and apply vibrations capturing the diversity of buzzes produced by evolutionarily diverse types of bees sampled in the UK and North America. We will also investigate how these variations in the vibrations produced by the micro-robotic buzzers determine pollen release from buzz pollinated flowers, allowing us to link bee diversity, mechanical and vibrational properties, and pollen release function. Our project is built upon an international collaboration that brings together expertise in robotics and bee pollination to pursue a multidisciplinary use of micro-robotics for studying the functional diversity in a type of pollination involving thousands of bee and plant species around the world.
2022
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Long-Term Fellowships - LTF
NAMUH -- A human genomic perspective on the evolution of chromosomal inversions
JAY Paul (.)
. - Københavns Universitet (University of Copenhagen, UCPH) - Copenhagen - DENMARK
NIELSEN Rasmus (Host supervisor)
Chromosomal inversions are ubiquitous in genomes. In many species, they are associated with complex traits, such as sexual dimorphism and social organization, but also with detrimental effects and genetic diseases. I have previously shown that inversions could tend to be involved in complex polymorphisms because they capture deleterious mutations. However, despite their well-documented biological importance, our understanding of the evolution of inversions is limited because of the difficulty of detecting them. I propose to take advantage of the abundance of recently sequenced present-day and ancient human genomes to dissect the evolution of chromosomal inversions. I will use cutting-edge methods, based on the detection of specific patterns of genetic diversity, to localize inversions in thousands of humans from periods back to 10kya. Using large-scale biomedical databases, I will test the association between these inversions and many evolutionary relevant characters, such as mortality or genetic diseases. I will test predictions regarding the evolution of inversions by following their frequency over time and by contrasting with other types of mutations. By comparing the genetic diversity in many inverted and non-inverted segments, I will untangle the selective forces acting on inversions, shedding new light on why they arise and how they evolve upon formation. Besides the insights into the consequences of inversions in humans, these in-depth analyses of the evolution of chromosomal inversions may yield groundbreaking fundamental results that will benefit many fields of biology, such as evolution, ecology, medicine and conservation genetics.
2022
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Cross Disciplinary Fellowships - CDF
Development of wireless focused ultrasound system for sono-optogenetics in freely behaving animals
JEONG Jinmo (.)
. - The University of Texas at Austin - Austin - United States
WANG Huiliang (Host supervisor)
Optogenetic techniques have been applied to modulate genetically-targeted neurons and find their wide applications in neuroscience research field to understand the link between brain function and behavior. However, traditional optogenetic methods use optical fibers for light delivery, which could cause brain damages due to the invasive fiber implantation surgery. Recently, my host supervisor Dr. Huiliang Wang has co-developed a technology called Sono-opotogenetics that uses mechanoluminescent nanoparticles to convert focused ultrasound (FUS) to light for optogenetic stimulation. This technology does not require invasive surgery hence it is minimally-invasive to the animals. However, the FUS system used in this work requires head-fixation of the mice. Therefore, it could not be used for neuroscience studies in freely-behaving mice.
Through the Human Frontier Science Program, I am aiming to develop a wireless, wearable ultrasound transducers for sono-optogenetic neuromodulation in freely-behaving mice. I will plan to fabricate flexible ultrasound transducers utilizing my micro-fabrication skills. I have gained over my PhD study in Korea and integrate with a wireless communication system.
The proposed wearable focused ultrasound system together with sono-optogenetics technology, is expected to allow us to perform non-invasive sono-optogenetic stimulation in freely moving animals. For example, it could be a powerful genetically-targeted neuromodulation tools in cognitive or memory behavioral studies with freely moving animal in complex-structured mazes.
2022
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Long-Term Fellowships - LTF
Metabolism as an integrator that coordinates morphogenesis in the developing mammalian embryo
JUNYENT ESPINOSA Sergi (.)
. - California Institute of Technology - Pasadena - United States
ZERNICKA-GOETZ Magdalena (Host supervisor)
During embryo implantation, the pluripotent epiblast (source of all adult tissues) must coordinate growth, cell fate transitions and the emergence of embryo shape. However, the programs that integrate these processes remain undetermined. Metabolic networks, acting as hubs of all cellular activity, hold the potential to be key. In vitro, metabolic networks enable proliferation and correct cell fate acquisition of pluripotent embryonic cells. Yet, longstanding limitations for studying embryos during implantation have meant that the role of metabolism in embryo morphogenesis, and its precise regulation in space and time, remain unknown. The host lab has recently developed cutting-edge in vitro culture platforms that allow the investigation of the peri-implantation morphogenetic process in natural embryos, and its reconstruction using stem cell-based embryo models. I propose to combine these state-of-the-art embryological tools with time-resolved metabolic analysis using biosensors and single-cell metabolomic approaches; to determine how dynamic metabolic flux coordinates embryo growth and morphogenesis; and to map and model the dynamics of glycolytic flow and key intermediary metabolites during precise stages of epiblast remodelling. Together this will allow me to uncover mechanistic links between metabolic rewiring and cell fate transitions in the developing epiblast. I will then assess how these processes adapt during normal regulation of embryo size, and with maternal malnutrition, where nutrients powering metabolism are drastically reduced. This project will be first to resolve how metabolism and morphogenesis are coordinated in the development of a mammalian embryo.
2022
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Long-Term Fellowships - LTF
Neuronal heme sensing in metabolic adaptation to infection
KITOKO Jamil (.)
. - Fundacao Calouste Gulbenkian - Lisboa - PORTUGAL
SOARES Miguel (Host supervisor)
Sickness behavior is an evolutionarily conserved response to infection, whereby anorexia promotes a protective hypometabolic state. Presumably, this neurometabolic response evolved to restrict pathogens from accessing vital nutrients, such as iron. In mammals, iron is predominantly found within heme, the vast majority of which constitutes the prosthetic groups of hemoglobin, within red blood cells (RBCs). Multiple pathogens evolved to damage RBCs as a strategy to access host iron. This is associated however, with the generation of extracellular labile heme, which can act as a proinflammatory alarmin. Recent data from the host laboratory shows that labile heme elicits sickness behavior and the development of a hypometabolic state, similar to induced by infection with different classes of pathogens. Here I hypothesize that neurons sense labile heme, either directly or indirectly (i.e., via its proinflammatory effects on macrophages), eliciting sickness behavior and the associated organismal hypometabolic state. While intracellular heme can be sensed directly by neurons in the brain, via the Rev-erba/ß family of nuclear receptors, whether this is also the case for extracellular labile heme or whether this occurs indirectly via macrophages is not known and shall be established. I propose to: 1) Characterize brain neuronal activity upon heme administration to mice, using cutting-edge whole-brain clearing, mapping techniques and molecular profiling; 2) Determine critical components of heme-induced neuronal activation using pharmacological approaches to regulate sickness behavior and organismal metabolism, as monitored by state-of-the-art metabolic phenotyping systems.
2022
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Cross Disciplinary Fellowships - CDF
An extreme approach to biomineralization: biomineral selection by extremophiles
KNOLL Pamela (.)
. - University of Edinburgh - Edinburgh - United Kingdom
COCKELL Charles (Host supervisor)
CARTWRIGHT Julyan (Host supervisor)
In biomineralization, organisms actively build structures (e.g., bones) or initiate a reaction from the secretion of precipitation-inducing chemicals (e.g., stromatolites). Even within extreme temperature and pH environments, bacteria-induced mineral precipitation uses enzyme-mediated reactions and/or controls the surrounding metal redox state to create dense mats of mineral filaments. While inorganic reactions are capable of mimicking these morphologies, such as laboratory grown chemical gardens, biominerals are often composed of mineral phases that are seldom selected in inorganic precipitation. Complicating the understanding of mineral selection in extremophiles versus similar inorganic counterparts is the large variation between their environmental conditions during precipitation. Using temperature/pressure vessels, I will investigate biominerals formed by thermoacidophiles and thermoalkaliphiles and compare their crystal products to those of chemical gardens formed under the same conditions. The goal is to understand the distinction between precipitation in living versus nonliving systems including the modification of crystal structure and habit within the silica-rich environments where both structures are found as well as the effect of metabolic processes on existing inorganic and biomineral structures. Tackling knowledge gaps in extremophiles will provide insights into the mechanisms for biomineralization and survival of these organisms in mineral-rich environments (at toxic levels for most organisms). This work can also pave the way to understanding how life could withstand the harsh conditions of early Earth and current conditions on other planetary bodies.
2022
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Long-Term Fellowships - LTF
Systematic characterization of SNPs in CREs associated with congenital heart disease
LINDENHOFER Dominik (.)
. - European Molecular Biology Laboratory (EMBL-Heidelberg) - Heidelberg - GERMANY
STEINMETZ Lars (Host supervisor)
Genome wide association studies (GWAS) produced a wealth of information on associations between distinct genetic loci and human diseases. Over 90 percent of predicted variants for common diseases are located in the non-coding genome mainly affecting cis-regulatory elements (CREs) like enhancers. Single nucleotide polymorphisms (SNPs) in enhancers can affect gene expression and contribute to disease mechanisms, but for the majority of SNPs their functional contribution to disease is not understood. Current high-throughput methods to study enhancers use CRISPRi to perturb them entirely. This neglects the differential influence of individual SNPs at CREs on disease-relevant gene expression. I aim to establish a method to modify SNPs in CREs in high-throughput using precision genome editing with a targeted scDNA-scRNAseq readout to link variable genomic editing outcomes with disease-relevant gene expression. Screening at this scale will require to advance methods for precision genome editing in mammalian cells, while the single-cell multiomic readout is crucial to precisely link genotype with gene expression profiles due to differential editing efficiencies at distinct loci.
I will use this method to systematically test SNPs in CREs associated with congenital heart disease (CHD), a disorder resulting in structural heart abnormalities at birth. CHD is highly heritable and GWAS identified hundreds of CHD-associated SNPs at risk loci in non-coding regions with their function remaining elusive. Screening for these SNPs in human heart organoids will allow us to determine associated gene expression changes systematically and how they contribute to the disease mechanism of CHD.
2022
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Grant Awardees - Program
Regulation of neuronal physiology by the electromechanical effects of the action potential
LOIS Carlos (SPAIN)
biology and biological engineering - california institute of technology - Pasadena - USA
SEZGIN Erdinc (TURKEY)
SciLifeLab - Karolinska Institute - Stockholm - SWEDEN
ROYLE Stephen (UK)
Centre for Mechanochemical Cell Biology - Warwick Medical School - Coventry - UK
Cell signaling has traditionally been thought to exclusively depend on biochemical processes, but in recent years we have begun to appreciate how physical forces can control cell-cell communication. Mechanical forces generated by cells regulate many physiological processes, including selection of optimal antibodies by lymphocytes, sorting of chromosomes and organelles within the cell, and blood clotting in response to turbulence. Among all cells, neurons and muscle cells have special features because they have excitable membranes capable of generating large voltage fluctuations (~100 mV) known as action potentials. Over the past decades, researchers have accumulated evidence that action potentials generate membrane movements up to 100 angstroms. However, it remains unknown what are the biological consequences of this neuronal electromechanical force. The central hypothesis of this proposal is that the membrane motions associated with action potentials generate mechanical forces that regulate the intercellular communication between neurons and intracellular signaling events within individual neurons. To investigate how the mechanical force of action potentials regulates intercellular communication we will focus on the activation of the mechanoreceptor Notch, a key molecule involved in cell-cell interactions. To explore the effects of the neuronal electromechanical forces on intracellular signalling, we will focus on the regulation of membrane trafficking processes, including endocytosis and sorting of intracellular vesicles. To investigate these issues we have assembled a team with expertise on different aspects of cellular signalling including membrane biophysics, single-particle imaging in living cells, and neurophysiology. A central goal of the proposal is to take advantage of new technologies that can be used to investigate the regulation of cell physiology at several scales of biological complexity, spanning individual molecules, living cells, and transgenic animals. We anticipate that this research will provide unanticipated insights about how mechanical forces control intercellular and intracellular signaling events in neurons.
2022
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Grant Awardees - Program
Super-resolution multifunctional scanning ion conductance microscopy: tapping the cell's energy grid
MACHESKY Laura (USA)
Migration, invasion and metastasis lab - CRUK Beatson Institute - Glasgow - UK
SASAKI Atsuo (JAPAN)
Department of Internal Medicine / Cancer Energy Metabolism Lab. - University of Cincinnati College of Medicine - Cincinnati - USA
TAKAHASHI Yasufumi (JAPAN)
Graduate School of Engineering Electronics - Nagoya university - Kanazawa - JAPAN
Cells show a remarkable resiliency when energy-starved, maintaining their ability to migrate to a new energy-rich environment, where they can re-purpose their cytoskeleton to take up nutrients via macropinocytosis. ATP and GTP are the major energy currencies of the cell, driving motor activity, cytoskeletal polymer dynamics and signaling. While the cell generally maintains robust global levels of ATP and GTP in nutrient-starved conditions, it is the local concentrations and ratios of ATP/ADP and GTP/GDP that drive motility and signaling. Multiple parameters control ATP/GTP flux, including: -Diffusion -Biosynthesis vs consumption -Shuttling and compartmentation However, how the cell meets energy demand is largely unclear, because we lack tools to measure multiple parameters simultaneously at sub-cellular resolution over time in live cells. Our multidisciplinary team, with expertise in motility (Machesky), metabolism (Sasaki), and Scanning Ion Conductance Microscopy (SICM) (Takahashi) will address this unmet need. SICM offers advantages of measurements without perturbation, correlation with high-resolution confocal imaging and simultaneous measurement of multiple parameters. Our team will thus engineer the first live single-cell multiscale platform, using cellular feedback to guide sampling and stimuli, providing the means to acquire a holistic view of cellular energy flux. We have two main objectives, each with new technology driven by our biological questions. Objective 1. Develop metabolic and protein mapping SICM to discover how cells use membraneless compartmentation to control metabolite supply and demand at the leading edge. We will establish how diffusion, biosynthesis and consumption generate and maintain intracellular nucleotide gradients using subcellular metabolic sampling SICM. We also probe subcellular localization and organization of metabolic enzymes, using femtoliter scale subcellular protein proximity labelling. Objective 2. Develop cell-to-machine feedback loop controlled SICM to determine how a cell decides to walk or to eat Using cell feedback guided SICM, we discover how mechanosensing via plasma membrane tension, integrins and the cytoskeleton, as well as nutrient sensing, allowing the cell to either locomote or use its cytoskeleton to perform nutrient uptake via macropinocytosis.
2022
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Long-Term Fellowships - LTF
Understanding ancient woolly mammoth gene function through multiplex gene editing
MAJEWSKI Dorothy (.)
. - President and Fellows of Harvard College, Harvard Medical School - Boston - United States
CHURCH George (Host supervisor)
The ability to sequence ancient DNA from extinct species is a relatively recent development in evolutionary biology with the potential to provide direct information on evolutionary pressures spanning tens of thousands of years. However, our ability to functionally characterize these genes is limited to predictions based on orthologues in living ancestors. Using multiplex gene editing techniques currently being developed in the Church lab at Harvard University, I will modify Asian elephant cell lines with multiple candidate mutations simultaneously based on the related woolly mammoth genome. Functional characterization of mammoth genes in the context of elephant tissues can provide insight into cold-resistance adaptations selected for by harsh environmental conditions. Several loci of interest from the mammoth genome will be targeted based on sequence comparison with the elephant genome, specifically aiming to find orthologous proteins altered from a common ancestor over the course of speciation. Multiplex gene editing methods will be optimized for the elephant cell lines, both in immortalized somatic cells and eventually induced pluripotent stem cells. Functional analysis will be performed by a combination of cell-based and biochemical approaches. The technology to modify many genes simultaneously will create a foundation for the long term goal of generating Asian elephant – woolly mammoth hybrid embryos, a part of de-extinction efforts to fill lost ecological niches that can be applied to several species in the future.
2022
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Long-Term Fellowships - LTF
Feeding or folding? Untangling the ecology of spatial patterning in microbial consortia
MEACOCK Oliver (.)
. - University of Lausanne - Lausanne - SWITZERLAND
MITRI Sara (Host supervisor)
The ecology of microbial communities is characterised by a rich interplay between metabolic and mechanical processes. In sessile communities, these processes typically play out through changes in the spatial structure of the system, such as the strong intermixing of strains that rely on each other’s secretions, or the buckling of a biofilm due to growth-induced forces. However, as species in naturally-occurring communities can differ widely in both their metabolic and physical properties, it has thus far proven difficult to disentangle the contributions of these two types of process during the emergence of spatial structure in multi-species consortia.
To address this, I propose a three-pronged course of research, using the Mitri group’s recently characterised four species consortium as a testbed. In stream one, I will develop microfluidic techniques to physically separate different species while allowing chemical exchange between them, isolating those spatial patterns driven purely by metabolic mechanisms. In stream two, I will adapt pre-existing ecological theory to uncover the underlying metabolic interactions necessary to explain these patterns, as well as investigate patterning’s importance in enabling the community to perform a user-defined function such as toxin degradation. Finally, in stream three, I will reintroduce the previously excluded mechanical interactions in a controlled manner, engineering the emergent patterns to improve the community’s ability to fulfil its target function. This project will combine my proven analytical capabilities with the ecological insights of my host group to bring a fresh, more predictive perspective to microbial ecology.
2022
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Long-Term Fellowships - LTF
Neural basis of relative aversive value coding in mice
MIRANDA Magdalena (.)
. - Institute for Functional Genomics (Institut de Génomique Fonctionnelle, IGF-CNRS) - Montpellier - FRANCE
TROUCHE Stéphanie (Host supervisor)
Absolute (good or bad), but also relative (better or worse), values can be assigned to an experience to guide appropriate actions (approach or avoidance). While previous work mainly focused on appetitive relative value coding, a detailed understanding of the neural mechanisms allowing animals to compare relative aversive value is at its infancy. Additionally, the extent to which value computed during learning is affected by specific internal states to alter value-based decisions remains elusive. The paraventricular thalamus (PVT) is modulated by hypothalamic inputs and also integrates positive and negative emotional states. Moreover, through its glutamatergic projections to the Nucleus Accumbens (NAc), the PVT is therefore ideally positioned to impact value coding and appropriate behavior selection. In this project I will use a novel behavioral task combined with optogenetics and in vivo physiology to examine the neural mechanisms for absolute versus relative value assignment during learning in mice and how internal state affect value signals. By monitoring and manipulating the neural activity simultaneously with dopamine kinetics from genetically defined neuronal populations in behaving mice, this project will investigate 1) the role of the PVT-NAc pathway, 2) the physiological changes of the DA release in the NAc and 3) the effect of acute changes in internal state (e.g. thirst) during both relative and absolute aversive learning and choice. This project therefore aims to build the first functional circuit model in mice for relative aversive value coding and highlights how internal states integrated in the PVT modulate value coding and value-based decisions.
2022
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Long-Term Fellowships - LTF
Delineating control of translation upon iron starvation
MOLENAARS Marte (.)
. - New York University Grossman School of Medicine - New York - United States
POSSEMATO Richard (Host supervisor)
Iron is the most abundant transition metal in biological systems. Iron and iron-containing cofactors support essential processes like energy metabolism or DNA replication. As with many essential nutrients, cells have mechanisms to sense shortages and alter metabolically intensive processes like translation. My over-arching goal is to gain mechanistic understanding of the translational program dedicated to cope with the iron deprivation. Known mechanisms for iron sensing involve Iron regulatory proteins (IRP) 1 and 2, which have RNA binding domains that bind iron-responsive elements (IRE) upon iron starvation. Known IRP targets are involved in iron metabolism: IRPs bind the 3`UTR of mRNA related to iron uptake or the 5`UTR of mRNAs related to iron storage to stabilize or inhibit translation, respectively. Interestingly, I have found that (1) iron starvation rapidly inhibits mammalian translation globally and (2) novel IRP-bound mRNA species are selectively affected. Here, I will determine how iron sensing pathways regulate translation globally, and delineate which mRNAs are directly regulated by IRPs. Using polysome profiling I will define how mRNA translation rates are affected by iron starvation and determine whether these effects are dependent upon IRPs or other common translational control mechanisms such as mTORC1. I will isolate polysomal RNA and perform RIP-seq of IRP-bound mRNAs upon induction of the iron starvation response pharmacologically or genetically to identify novel transcripts regulated by the IRP system. These findings will have an impact on diseases where iron metabolism is dysregulated, such as Friedrich’s Ataxia, iron storage diseases, or cancer.
2022
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Grant Awardees - Program
Mental 3D space-time travel in fission-fusion animal societies
WAHLBERG Magnus (SWEDEN)
Marine Biological Research Center - Dept. of Biology - Kerteminde - DENMARK
MOSS Cynthia (USA)
Dept. of Psychological and Brain Sciences - Johns Hopkins University - Baltimore - USA
PEREMANS Herbert (BELGIUM)
Dept. of Engineering Management - University of Antwerp - Antwerp - BELGIUM
VON BAYERN Auguste (GERMANY)
Dept. of Behavioural Ecology and Evolutionary Genetics - Max-Planck-Institute for Ornithology - Seewiesen - GERMANY
Flying and swimming animals can move freely in three-dimensional space, but their ability to use past information to inform future decisions remains largely unknown. Time flows in one direction, and no living creatures can physically move backwards into the past or forwards into the future. Animals can, however, use memories to adapt their behavior in future events. For humans, it is even possible to mentally travel backwards and forwards in time; we can ‘see’ ourselves in past situations and foresee ourselves in future ones. Mental time-travel is regarded as a fundamental property of human success, enabling us to organize societies and travel to the moon. Here we study to what degree other animals possess mental time travel abilities. We study dolphins, bats and parrots, which all travel and forage in 3-D space and live in large groups where they are constantly engage in social interactions, both cooperation and competition. Any degree of mental time travel abilities would be advantageous for them to anticipate the best solutions in the execution of future tasks. We investigate how our model species perceive time, and any evidence for them making use of episodic memory and perform future planning. By using similar experimental approaches for all model species, we compare mental time travel in animals living in vastly different environments and exposed to a large variety of challenges. By comparing the performance of our model species, we can decipher the underlying evolutionary mechanisms and requirements for mental time travel. We will use the results of our investigations to construct robots that exhibit different degrees of mental time travel functions. By studying the success rate with which robots solve problems, and by manipulating the robots’ abilities to mentally travel in time and collaborate, we will aim to pinpoint which mental time travel traits are most pertinent for solving different types of problems. The robot studies not only inform us about how our model species function, but may also inspire the development of robots that successfully solve difficult problems requiring complex decision-making, such as responding appropriately in emergency situation and executing complex construction operations.