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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
2020
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Long-Term Fellowships - LTF
Investigation of the rules governing plasma cell transition between short and long-lived states
DE CARVALHO Renan (BRAZIL)
Laboratory of Lymphocyte Dynamics - The Rockefeller University - New York - USA
VICTORA Gabriel (Host supervisor)
Long-lived plasma cells (LLPCs) produce durable antibodies against a wide variety of pathogens, and are associated with long-lasting immune protection. LLPCs arise from T cell-dependent structures in secondary lymphoid organs known as germinal centers, whereby naïve B lymphocytes undergo rapid proliferation and mutate their Immunoglobulin genes. Cells that successfully generate high-affinity antibodies are selected to live, becoming either memory B cells or plasma cells (PCs), which in turn give rise to two main populations: short-lived plasma cells (SLPCs) and LLPCs. SLPCs are found in secondary lymphoid organs, bone marrow and mucosal tissues, where they eventually become LLPCs. Despite the importance of this cell type for protective responses throughout life, the factors driving each PC population is not fully understood. Moreover, a still unaddressed question in the field is why only a few clones of SLPCs convert into LLPCs, and the mechanisms driving this differentiation. Thus, this project aims to define the rules governing SLPC-LLPC transition. Through the combination of transgenic PC-reporter mice, cutting-edge techniques and tools available in Victora’s Lab, we will be able to specifically track SLPCs and LLPCs, providing important clues about their specific niches, clonal composition and patterns of gene expression. Taken together, the innovative approaches presented in the current proposal will faithfully address unsolved mysteries about the biology and dynamics of plasma cells, generating knowledge that will help to better understand the mechanisms driving tissue homeostasis, effective humoral responses and the development of better vaccine-based strategies.
2020
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Grant Awardees - Program
Integrating materials, behavior, robotics and architecture in giant filter-feeding sharks
DEAN Mason (USA)
Dept. of Zoology - Trinity College Dublin - Dublin - IRELAND
GOLDBOGEN Jeremy (USA)
Hopkins Marine Station, Dept. of Biology - Stanford University - Pacific grove - USA
HAUERT Sabine (SWITZERLAND)
Bristol Robotics Lab. - University of Bristol - Bristol - UK
HANNA Sean (UK)
Bartlett School of Architecture - University College London - London - UK
The largest animals of the past and present are suspension feeders, surviving by filtering and eating huge quantities of some of the smallest food in the ocean. This strategy has evolved repeatedly in a wide diversity of animals—from sponges to mammals—and is thought to be the most efficient feeding option for supporting the body mass of ocean giants like whales and the largest sharks. Despite the charisma and protected status of many large-bodied suspension feeders, we know surprisingly little about their ecologies and the tools they use to process water on industrial scales. This is largely due to challenges of studying these animals and their filters in the wild. We integrate a variety of disciplines and scales in the study of suspension feeding in the basking shark, a cosmopolitan species and the second largest fish, reaping >30 kg of plankton per day. We will use animal-borne tag sensors, drones and swarms of underwater robots to capture and dissect basking shark feeding events, to quantify the mechanics, behavior, and hydrodynamics of foraging. These data will be integrated with morphological and anatomical investigations of basking sharks’ fundamental filtering tools—stiff bristles called gill rakers, lining the throat by the tens of thousands—using advanced bioimaging and engineering techniques to quantify their geometries and materials. Behavioral and material data will converge in multi-scale optimization models of flow and filtration, in digital simulations and performance tests of 3D printed biomimics, building from fine-scale biological architectures to explore hypothetical shapes and arrangements, using machine learning to integrate model predictions from micron to meter scales. Seeing a high-performance biological system through the lenses of materials science, animal behavior, robotics and architecture, we gain a unique mechanistic window into the interaction of basking sharks with their environment, and the tools and energetics of a specialized ecology that has existed for millions of years. Exploiting this intersection of disciplines, we will learn how mineralized materials can be modified into high-throughput filters; create new integrated approaches and tools to characterize complex bio-architectures and monitor large aquatic animals in their habitats; and gain bioinspiration for new filter design in a wide range of applications.
2020
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Long-Term Fellowships - LTF
Molecular and physical mechanisms of gamete binding and fusion in zebrafish
DENEKE Victoria (EL SALVADOR)
- Research Institute of Molecular Pathology - Vienna - AUSTRIA
PAULI Andrea (Host supervisor)
Fertilization is a dynamic process that involves the approach, binding and fusion of haploid gametes, the sperm and the egg. To date, only three proteins have been shown to be essential for fertilization in vertebrates: Izumo1, Juno, and CD9. In mammals, the binding of Izumo1 and Juno mediates sperm and egg interaction, yet many key regulators of fertilization have likely been missed, possibly due to redundant functions, since this process involves the coordination of multiple proteins. Therefore, it is instrumental to apply new tools to uncover new molecular regulators of fertilization. I propose to use a multifaceted approach that includes subcellular proteomics, quantitative in vivo imaging and genetics to gain a comprehensive understanding of the dynamics and molecular mechanisms regulating fertilization. Such approaches are technically challenging in the mammalian system, where fertilization occurs internally and access to a large number of eggs is limited. The zebrafish model provides many advantages for fertilization studies, since fertilization occurs externally, and many eggs and sperm can be collected from adults for proteomic studies. High resolution imaging studies are facilitated in the zebrafish (Danio rerio) system due to the presence of the micropyle, the single sperm entry site in the zebrafish egg. These features result in the ability to address long-standing questions in the field with emergent methodologies that will provide a new mechanistic and biophysical understanding of gamete binding and fusion.
2020
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Cross Disciplinary Fellowships - CDF
Reproducing affinity maturation dynamics in vitro
DUPIC Thomas (FRANCE)
Department of Organismic and Evolutionary Biology - Harvard University - Boston - USA
DESAI Michael (Host supervisor)
During an infection, antibodies undergo drastic improvements in their binding-affinity with the antigens. These changes are driven by affinity maturation, a process taking place in the germinal centers (micro-structures found in lymphoid organs). In these centers, the antibody-producing B-cells pass through multiple cycles of somatic hypermutation (division and mutation), and clonal selection (competition for antigen availability). This process is similar to Darwinian evolution and occurs in parallel with the actual evolution of the pathogens. While high-throughput sequencing has made the study of antibodies in-vivo much easier, the lymphoid organs, where affinity maturation takes place, do not lend themselves to longitudinal studies. In-vitro methods bypass these limitations, but they are often focused on the final product and discard the less efficient branches. This project aims to better understand affinity maturation with the help of an in-vitro experiment. The experiment, based on yeast display methods and FACS sorting, can measure the affinity of antibody's fragments in a high-throughput way. Coupled with barcoding, this allows us to study and evolve, in parallel, multiple branches of the evolutionary tree. The first part of the project consists in measuring the affinity of the clones in a given B-cell lineage, and estimate to which extent the affinity landscape associated with a specific antigen allows to predict the form of the immune response. This will be applied to studying how the evolution of the antigen impacts the development of antibodies.
2020
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Grant Awardees - Program
Cell-specific, photocontrollable neuropharmacology in the behaving mouse
MOUROT Alexandre (FRANCE)
Neuroscience Paris Seine - Sorbonne Université - UPMC - Paris - FRANCE
ELLIS-DAVIES Graham (USA)
Dept. of Neuroscience - Mount Sinai School of Medicine - New York - USA
The state of brain circuits is changed by neuromodulatory signals such as dopamine, serotonin or acetylcholine, which are released in spatially and temporally precise, phasic or tonic patterns depending on the physiological context. These neuromodulators act on multiple receptor classes, exerting diverse physiological effects through distinct signaling pathways. Obtaining a clearer picture of the function of neuromodulatory-driven signals in neural information processing and plasticity requires methods for remote-control of specific neurotransmitter receptors with high temporal precision in defined neurons and in behaving animals. We combine labs with expertise in synthetic chemistry and photochemistry (Ellis-Davies) and behavioral neuropharmacology (Mourot) in order to develop technologies to gain optical control over DA neuromodulation in the freely-moving mouse, for studies of neural circuits and behaviors associated with same-sex social interactions. Synthetic photochemical tools (caged and photoswitchable compounds) are, in principle, able to mimic the timing, amplitude and spread of naturally occurring neuronal signals. However, their in vivo use has been highly restricted, notably because these probes are stimulated by UV or visible light that penetrates tissue very poorly. To overcome this issue, we propose to use lanthanide-doped upconverting nanoparticles (UCNPs), which will be functionalized with caged/photoswitchable ligands for glutamate and dopamine receptors, enabling non-invasive control of the very receptors of the brain in behaving mice. We will further combine near-infrared photocontrol with chemo-genetic strategies to achieve optical control of receptors in defined neuronal targets. Leveraging UCNPs in this way will provide a platform for the interrogation of dopamine-related neuropsychiatric disorders in groups of animals in naturalistic environments, and will represent a milestone in our understanding of how dopamine impacts a variety of personality traits and same-sex interactions. The strategies developed here will be applicable to most receptors, neural circuits and animal models, thus our project bears enormous potential in changing the landscape of our understanding of neuromodulation, both in health and disease.
2020
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Long-Term Fellowships - LTF
From vision to camouflage: behavioural computations in the cuttlefish
EVANS Dominic (UK)
- Max Planck Institute for Brain Research - Frankfurt am Main - GERMANY
LAURENT Gilles (Host supervisor)
Understanding how vision guides behavior is a key goal of neural systems research. This project will use long-term behavioral assays and electrophysiology to investigate the perceptual rules and neural dynamics underlying camouflage behavior in the cuttlefish – an animal which uses vision and neural control of skin patterning to ‘match’ itself to the background visual scene. As the cuttlefish skin provides a readout of the animal’s perceptual state, this system presents an unparalleled opportunity to study visual processing and complex motor control in the behaving animal. Using large-scale high-resolution imaging techniques to record and reveal the dynamics of skin ‘pixels’ across the body, I aim to determine the behavioral rules and visuomotor computations that govern camouflage behavior. First, I will map the transformation of visual input into skin pattern output by systematically varying the visual scene of the animal’s home environment during long-term behavioral recordings. This will reveal which statistical properties of visual stimuli are reproduced in skin patterns, at single chromatophore resolution, and how chromatophore motor units are dynamically orchestrated to assume these patterns. Next, I will investigate the neural mechanisms of pattern generation using ex vivo electrophysiology in the pathway purported to control this behavior. I am convinced that the study of visually-guided body patterning behavior will yield fundamental principles of visual perception and complex sensorimotor processes in general.
2020
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Grant Awardees - Early Career
Large-scale mapping of intracellular dendritic dynamics during memory formation and replay
JAYANT Krishna (INDIA)
Dept. of Biomedical Engineering - Purdue University - West Lafayette - USA
EWELL Laura (USA)
Institute for Experimental Epileptology and Cognition Research - University of Bonn-Medical Center - Bonn - GERMANY
Dendrites govern feature selectivity in neurons by integrating and subsequently filtering thousands of synaptic inputs to decide overall spike output. A classic example of this relationship is observed in place cells (PCs) in the hippocampus, which spikes when an animal enters a specific position in space. Recent evidence based on two-photon imaging suggests place-related activity is driven by dendritic plateau potentials, however, the precise temporal relationship between such dendritic electrical activity and somatic output in vivo is still unknown. Moreover, coding in the hippocampus, occurs at the population level – sequences of PCs encode trajectories, and are replayed during consolidation. Replay occurs during transient high frequency LFP oscillations call sharp wave ripple (SWR). How is dendritic activity coordinated across SWR-sequences? What is the temporal structure of such signals? These questions remain unanswered because the small size of dendrites have precluded conventional electrophysiology to date. Here, we aim to map CA1 basal dendritic voltage dynamics in head-fixed and freely behaving animals using high-density transparent NanoElectrode Arrays (NEA) comprising of vertical metal-coated silicon NanoNeedles (dia ~100 nm; height ~60 um) and interleaved planar electrodes interfaced to custom CMOS amplifiers, and integrated onto a transparent glass cannula. This new device will enable optical, and, high-density intracellular and extracellular electrical recordings of dendritic dynamics during place field formation. We will additionally correlate intracellular (NanoNeedles), local-field-potential (LFP) (planar electrodes), and two-photon Ca2+ imaging through the transparent cannula to decode how basal dendritic activity shape PC sequences in head-fixed mice running on a circular track. Finally, once we have ascertained the NEA dendritic waveforms in head-fixed mice, we will map dendritic electrical activity in freely-moving animals performing a working memory task flanked by sleep sessions (to enable SWR recording). Using this novel NEA we will ascertain how the LFP and intracellular basal dendritic activity interact to encode place fields during memory formation and replay.
2020
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Long-Term Fellowships - LTF
In situ characterization of eukaryotic sodium channels using cryoEM
FAN Xiao (CHINA, PEOPLE'S REPUBLIC OF)
Department of Molecular Biology - Princeton University - Princeton - USA
YAN Nieng (Host supervisor)
Voltage-gated sodium channels (VGSC, Nav) govern membrane excitability by initiating and propagating action potentials in nerve and muscle tissues. Mutations in Nav channels are directly linked to numerous human diseases, including epilepsy, arrhythmia, and pain. Understanding the gating mechanism of Nav channels is critical for both basic research and pharmaceutical applications. In recent years, several structures of Nav channels that were purified in detergent micelles were revealed by cryogenic electron microscopy (cryoEM). However, the structure of the resting state, which requires the presence of the transmembrane electric field, has been unattainable due to the technical challenges of maintaining the membrane potential during sample preparation. Here we propose an innovative way to prepare cryo-samples of Nav channels on in situ neuronal membranes and further elucidate their resting states by sub-tomogram averaging methods. Novel systems for sample preparation and data collection will be developed to obtain high-resolution structural information on Nav channels in distinct functional states in situ. The strategy can also be generalized to investigate other membrane proteins in a native membrane environment. Achieving the proposed aims will provide unprecedented insight into the Nav channel gating function, and provide useful tools for studying the structural biology of membrane proteins in general.
2020
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Long-Term Fellowships - LTF
Using visual proteomics to understand membrane dynamics in the malaria parasite P. falciparum
FERREIRA Josie (UK)
Centre for Structural Systems Biology - University of Hamburg - Hamburg - GERMANY
GILBERGER Tim (Host supervisor)
The malaria disease represents a significant global burden. Despite major advances in its treatment and control, rising resistance to front-line therapies makes the demand for innovative solutions more important than ever. To identify possible intervention points, we need a firm grasp on the processes that govern the parasites complex lifecycle. Central to the evolutionary success of the malaria parasite is the rapid invasion of erythrocytes and subsequent replication. During invasion, the parasite utilises intricate machinery coordinated by a sequence of receptor-ligand interactions, allowing the invagination of the erythrocyte membrane. Inside the erythrocyte, transient structures essential for invasion are rapidly disassembled. These include a double membrane structure termed the inner membrane complex. Despite their importance, our understanding of these transient structures is limited. I propose a correlative approach to understand receptor-ligand mediated erythrocyte invasion and subsequent disassembly of the inner membrane complex. I aim to directly visualise and analyse these processes in situ. This will be achieved using super-resolution fluorescence microscopy to guide specimen FIB-milling for electron cryo-tomography and subtomogram averaging. Simultaneously, studying the inner membrane complex over time in combination with mass spectrometry will allow me to identify and target key players in the disassembly process. Finally, using cryo-tomograms, I will generate a series of atlases of protein and organelle positions within the parasite and host cell. These will provide details of the alterations in the molecular landscape during and post invasion.
2020
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Long-Term Fellowships - LTF
Relevance of lipid droplet-mitochondria contact sites for brown adipose tissue function
FISCHER Alexander (GERMANY)
Department of Genetics and Complex Diseases - Harvard Medical School - Boston - USA
FARESE Robert (Host supervisor)
Brown adipose tissue (BAT) thermogenesis is essential for survival in cold temperatures. To meet the energetic demands of this process, BAT relies on efficient energy supply from the circulation as well as from intracellular triglyceride stores in lipid droplets. The fatty acids stored in triglycerides can be liberated by lipolysis and serve as fuel for mitochondrial thermogenesis. However, high intracellular levels of free fatty acids are detrimental for cellular survival, demanding for efficient transfer processes. Microscopical analyses indicate a tight interaction between mitochondria and lipid droplets, yet even the fundamental triggers leading to the initiation of contact site formation as well as their physiological role remain elusive. In this proposal, I therefore want to examine the hypothesis that molecular complexes mediating interactions between mitochondria and lipid droplets are formed in activated BAT, and that these contact sites are critical for BAT function. To achieve these goals, microscopical interaction studies will be employed to shed light on the conditions triggering contact site formation. The molecular machinery mediating the interaction will be identified using an APEX-proximity labelling approach. Genetic manipulation will be employed to examine the role of the proteins identified in this screen for initiation and maintenance of contact sites. The relevance of these proteins for BAT function will then be analyzed using CRISPR-Cas9 technology in primary adipocytes and mice. Conclusively, the proposed approaches will not only help understanding the mechanisms involved in organelle contact site formation but also define their physiological role.
2020
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Long-Term Fellowships - LTF
From social networks to neural networks: imaging social memory in the bat hippocampus
FORLI Angelo (ITALY)
Department of Bioengineering and the Helen Wills Neuroscience Institute - UC Berkeley - Berkeley - USA
YARTSEV Michael (Host supervisor)
From invertebrates to mammals, social behavior plays a fundamental role in the survival of species throughout the animal kingdom. In order to take advantage of past interactions with conspecifics, the brain has to encode, consolidate and recall social memories. Recent findings suggest that the hippocampal region CA2 is essential for social memory, but the nature and the stability of information stored in this circuit remains enigmatic. I will utilize the Egyptian fruit bat, a highly social mammal which develops long-term social networks within the colony, to ask how the long-term and dynamic representation of social information is encoded in CA2. I will adopt advanced behavioral measurements combined with machine learning methods to monitor and characterize social interactions and their associated vocalizations within a natural colony of bats over long periods. To investigate the existence and properties of social coding in CA2, I will take advantage of chronic wireless calcium-imaging in freely behaving and flying bats during behaviorally relevant social interactions as well as during sleep. By combining an ethological approach with cutting edge technologies for detailed measurements of long-term behavioral and neural dynamics, I will aim to uncover fundamental properties of social cognition in the mammalian brain.
2020
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Grant Awardees - Program
Evolution of conformational and kinetic ensembles during functional transitions
TOKURIKI Nobuhiko (JAPAN)
Michael Smith Labs - University of British Columbia - Vancouver - CANADA
OSUNA Silvia (SPAIN)
CompBioLab group, Institute of Computational Chemistry and Catalysis (IQCC) - University of Girona - Girona - SPAIN
FRASER James S. (USA)
Dept. of Bioengineering and Therapeutic Sciences - University of California San Francisco - San Francisco - USA
NOJI Hiroyuki (JAPAN)
Dept. of Applied Chemistry - University of Tokyo - Tokyo - JAPAN
Functional enzymes exist in an ensemble of conformations. Protein dynamics, including the transition between different conformational states, have been shown to play an important role in enzymatic functions. Additionally, conformational ensembles are thought to play a key role in enzyme evolution. For example, the evolution of a new catalytic function may depend on a shift in the conformational ensemble. This theoretical model is widely acknowledged, however, there is currently little experimental evidence linking conformational and catalytic ensembles with evolution. Thus, developing dynamic, high-resolution and single-molecule level views of enzymes is a pivotal step to advance our fundamental understanding of enzyme evolution.
In this proposal, we aim to capture a detailed resolution picture of conformational and catalytic changes across the evolutionary transitions between divergent enzyme functions. This will be achieved via the integration of diverse cutting-edge approaches, including: directed evolution (DE), single-molecule enzyme kinetics, dynamic structural biology, and computational simulations. We will characterize multiple series of enzyme intermediates that constitute complete adaptive transitions from one function to another. Conformational ensembles and motions will be characterized using serial femtosecond crystallography (SFX) combined with extensive molecular dynamic (MD) simulation. Catalytic fluctuations and heterogeneity will be experimentally measured using single-molecule enzymology techniques, and conformational changes in the reaction will be determined by kinetic-crystallography. Furthermore, we will identify the intramolecular amino acid networks that are associated with changes in conformational motions and ensembles. Finally, all experimental data will be integrated into an integrated computational model in order to describe the process of enzyme evolution as topology change in the conformational energy landscapes.
This work will lead to an unprecedented experimental and computational understanding of the interplay between conformational and catalytic ensembles of enzymes and their evolutionary dynamics. These in-depth molecular views of enzyme evolution will not only advance our basic scientific knowledge but also lead to technological advances for the design and generation novel enzymes in the laboratory.
2020
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Long-Term Fellowships - LTF
Investigating the ancestral role of animal-bacterial symbiosis in epithelial morphogenesis
GARCIA DE LAS BAYONAS Alain (FRANCE)
Department of Molecular and Cell Biology - University of California, Berkeley - Berkeley - USA
KING Nicole (Host supervisor)
Animal-bacterial interactions are widespread and regulate diverse vital processes, including nutrient uptake, immune system development and tissue morphogenesis. Although crucial for animal biology, little is known about the ancestry of animal-bacterial interactions or their influence on animal origins and evolution. As the closest living relatives of animals, choanoflagellates provide key insights for reconstructing animal origins. In the model choanoflagellate S. rosetta, molecules secreted by bacteria induce two life history events – multicellular development and mating (Alegado et al. 2012, Woznica et al. 2018). However, unlike in animals in which bacterial symbionts are stably enclosed within epithelial structures, the S. rosetta life cycle responds to diffusible cues from environmental bacteria. A new choanoflagellate species, S. monosierra, discovered by the host lab forms large spherical colonies containing a stable microbiome (Hake et al., in prep). Reducing the bacterial load reduces S. monosierra colony size without reducing cell number, suggesting the microbiome regulates colony morphogenesis.
This proposal seeks to harness this new bacteria-containing choanoflagellate to investigate the ancestry of animal-bacterial symbiosis and its influence on epithelial morphogenesis. First, I will define the precise symbiotic bacteria that regulate S. monosierra colony size. Second, I will investigate the molecular cues and cellular mechanisms that underlie bacterial-dependent control of S. monosierra colony size. Last, I will explore choanoflagellate diversity to assess whether a stable microbiome was present in the last common ancestor of choanoflagellates and animals.
2020
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Long-Term Fellowships - LTF
Genomic characterization of regulatory elements associated with human breast milk production
GOLAN MAOR Yarden (ISRAEL)
Department of Bioengineering and Therapeutic Sciences - University of California - San Francisco - USA
AHITUV Nadav (Host supervisor)
Breast milk is the optimal dietary source for infants, as it supplies all the nutritional requirements for the first six months of life. However, over 50% of mothers express concerns about insufficient milk volume or poor milk quality as pertinent to their motivation to wean their infants before six months of exclusive lactation. Human breast-milk contains macro- and micronutrients as well as numerous bioactive compounds and several different cell types, including epithelial, myoepithelial, stem cells and leukocytes. The human mammary gland is distinct from other mammals in many aspects, including milk composition, gene expression and architecture. This renders commonly used mammalian animal models non-representative systems for studying the human lactation process. During my post-doctoral fellowship, I aim to characterize the breast-milk cells transcriptome (single-cell RNA sequence), regulome (ATAC-seq and Cut&Run), and variome (genotyping arrays) and link them to create a novel and important genomic lactation dataset. I will use samples collected under both physiological (e.g., colostrum, mature milk, and involution) and pathological (e.g., low milk production) conditions, to study the mechanisms underlying different lactation pathologies and to characterize how genetic variation influences lactation outcomes and infant growth. Collectively, the results of this study will significantly impact mother and infant health worldwide and expand our toolbox to improve breastfeeding medicine and help mothers dealing with breastfeeding issues and related diseases.
2020
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Cross Disciplinary Fellowships - CDF
Data-driven discovery of decentralised control mechanisms of action selection
GOSZTOLAI Adam (HUNGARY)
Neuroengineering Laboratory - Brain Mind Institute and Interfaculty Bioengineering Institute - Lausanne - SWITZERLAND
IJSPEERT Auke (Host supervisor)
In our lives, we are continuously generating a sequence of actions. What are the neural mechanisms that cause the selection of one action above all others? These mechanisms can provide key insights for designing artificial robotic controllers that are as flexible as their neurobiological counterparts. The dominant ‘feedforward’ model for action selection suggests that decisions are made in the brain, upon which a command signal is sent to downstream motor circuits. However, this model ignores the critical role that peripheral mechanosensory feedback signals likely play in action selection. Such a potentially paradigm-shifting ‘feedback-centric’ model of action selection, its dynamical mechanisms, and its neuronal instantiation have yet to be explored. As an HFSP Cross-Disciplinary Fellow in the laboratories of Pavan Ramdya (experimental neuroscience) and Auke Ijspeert (dynamical systems modelling), I will develop such a model through a combination of data-driven dynamical systems theory, optogenetics, and behavioral analysis in Drosophila melanogaster. I aim to discover how a variety of Drosophila limbed behaviors can be generated by a common modelling framework, whereby a set of neural oscillators are coupled through limb-mechanosensory feedback loops and driven by descending neurons. Using these models, I will predict and experimentally test how perturbing sensory feedback pathways affect action selection. Finally, I will cluster the distribution of model feedback topologies that explain different Drosophila behaviors to identify fundamental structure-function relationships and to reveal how one neural network can select and generate a remarkable diversity of actions.
2020
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Long-Term Fellowships - LTF
A radical approach to histidine bioconjugation
GREEN Ori (ISRAEL)
The Department of Chemistry and Applied Biosciences - ETH Zurich - Zurich - SWITZERLAND
MORANDI Bill (Host supervisor)
Site-selective modifications of proteins at a predetermined location have been proven to be very useful to gather information and explore composite biological processes. In addition, these reactions give opportunities for researchers in academia and industry to prepare functional protein based materials for various applications in our daily life. Today, the chemical toolbox for site selective modifications is quite developed for targeting highly reactive amino acids residues such as cysteine and lysine, however targeting less reactive amino acids is much more challenging and therefore examples are rarer. Among the unreactive amino acids, histidine site selective modification is highly desirable. Although several reports exist for this modification there is no concrete general approach for selectively modifying histidine residues. This fact motivated us in this research proposal. Herein, we propose to develop a general strategy to selectively modify histidine residues on proteins without the need of complex genetic manipulations. We plan to leverage the exquisite functional and water group tolerance of Minisci type radical reactions to address this challenge. The bioorthogonality and feasibility of the developed reaction will be tested for drug development and fluorescent labelling of enzymes. We believe that the success of this selective histidine modification will have tremendous impact in the biomedical sciences.
2020
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Grant Awardees - Program
High-throughput single-molecule evolution
GRIFFITHS Andrew David (FRANCE)
Lab. of Biochemistry - CBI - UMR 8231 - ESPCI Paris Tech - Paris - FRANCE
VAN OIJEN Antoine (NETHERLANDS)
School of Chemistry and Molecular Bioscience - University of Wollongong - Wollongong - AUSTRALIA
Directed evolution is a technique to investigate evolutionary dynamics and evolve nucleic acids and proteins for research, diagnostic and therapeutic applications. It uses cycles of mutation and screening or selection to mimic Darwinian Evolution. The aim of these experiments is to screen or select large libraries of molecule variants with different sequences (‘genotypes’) and retain those sequences having the required properties (or required ‘phenotypes’).
At the moment one essential limitation of Directed Evolution methods is that the properties of each variant in the library are assessed based on bulk samples, i.e. on the average activity of a large numbers of copies of the same molecule. While these copies are identical at the sequence level, they may still exhibit different phenotypes, for example due to the fact that the same sequence can assume multiple three dimensional structures. These ‘heterogeneous’ phenotypes can play important roles in evolutionary dynamics, but at the moment there is no convenient Directed Evolution tool to address them.
Here we combine expertise from the fields of directed evolution and single-molecule microscopy to develop a novel approach that allows us to perform directed evolution while looking at the behaviour of single-molecules. The method can be used to perform accurate phenotypic characterization measuring multiple aspects of the phenotype in parallel, something that can be challenging with conventional approaches. For example it can be used to study how a molecule with a specific sequence can sometimes play a role in different chemical reactions, how to achieve ‘specialization’ and what the consequences of specialization are in terms of efficiency. As discussed above, the method can also reveal the existence of phenotypic heterogeneity in molecules with identical sequence. This approach will allow us to address several biological questions that cannot be addressed with conventional methods. These include, the evolution of heterogeneous phenotypes in populations of RNA molecules under selection for binding, the role of heterogeneity in defining the evolutionary potential of antibodies and the correlation between rate and accuracy in DNA polymerases. It will also provide a potent route to develop biomolecules for biomedical and industrial applications, notably in the field of single-molecule technologies.
2020
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Long-Term Fellowships - LTF
Cryo-EM visualization of sister chromatid cohesion establishment at the replication fork
HENRIKUS Sarah (GERMANY)
Macromolecular Machines - The Francis Crick Institute - London - UK
COSTA Alessandro (Host supervisor)
Loss or imbalance of chromosomes can trigger various pathologies, threatening healthy cell proliferation. During the cell cycle, each chromosome is replicated, generating sister chromatids. Before cell division, duplicated chromosomes must be equally segregated and transmitted to daughter cells. Chromosome segregation is organized by cohesin, which topologically links chromatids from their synthesis onwards. Despite its vital importance, the molecular basis of sister chromatid cohesion establishment at the replication fork remains mostly elusive. A clear model is lacking of how cohesin transitions from interactions with one parental duplex DNA at the front of the replisome to two duplicated DNA strands behind the replisome.
Detailed analysis of cohesin assembly at the fork is critical for the formation of a structural framework for cohesion establishment. This proposal aims to address two fundamental questions. First, I seek to describe the conformational changes that cohesin undergoes when it transitions from encircling one to two DNA molecules. Second, I aim to capture cohesin interacting with the replication fork. To tackle these questions, I will use in vitro reconstituted systems combined with cryo-EM imaging. Leveraging my expertise in chemistry and single-molecule techniques, I will develop a new DNA-affinity cryo-EM grid. This new tool will allow me to visualize cohesin and the replication machinery in a DNA-bound state, building on in vitro reconstituted systems available in the Costa and Uhlmann labs. With this multidisciplinary approach, I aim to characterize the elusive molecular intermediates of sister chromatid cohesion establishment.
2020
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Long-Term Fellowships - LTF
Charting the evolutionary history of a sex-specific innovation at the single-cell level
HOPKINS Benjamin (UK)
Department of Ecology and Evolution - University of California - Davis - USA
KOPP Artyom (Host supervisor)
Development is the critical link between genetic and morphological change. Thus, to understand how organisms come to differ in appearance we must understand how the developmental pathways that build them evolve. We know that changes in these pathways can drive the evolutionary loss or modification of traits. But we have so far failed to explain how new developmental pathways evolve. This is the greatest gap in our understanding of morphological diversification: innovations, such as wings, horns, and feathers, all need to evolve before they can be modified. This problem is further confounded in the most extreme parts of organismal design, sex-specific traits, which require not just the acquisition of a new developmental pathway but its limitation to a single sex. In this proposal, I develop a new analytical approach, which repurposes emerging biomedical methods, to identify for the first time the developmental genetic processes by which a novel trait, the recently-evolved Drosophila sex comb, has evolved. Combining time-series, single-cell RNA-sequencing with developmental genetic manipulations, I will use a comparative, multi-species approach to (a) reconstruct the developmental pathway that builds sex combs, (b) identify the developmental genetic changes that have driven morphological diversification, (c) elucidate how the novel pathway integrates sex-determination machinery, and (d) assess the evolvability of this innovation. Ultimately, this approach represents a new way of doing ‘evo-devo’ research – an approach that simultaneously charts trait evolution across levels of biological organisation, from gene to tissue, to understand the diversification of life.
2020
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Grant Awardees - Program
The extracellular space of the brain: a multi-modal analysis from nano-structure to in vivo function
NÄGERL Valentin (GERMANY)
Interdisciplinary Institute for Neuroscience - University of Bordeaux - Bordeaux - FRANCE
HRABETOVA Sabina (USA)
Dept. of Cell Biology - SUNY Downstate Medical Center - Brooklyn - USA
NEDERGAARD Maiken (DENMARK)
Center for Translational Neuromedicine - University of Copenhagen, Panum - Copenhagen - DENMARK
NISHIZAWA Seiichi (JAPAN)
Dept. of Chemistry, Graduate School of Science - Tohoku University - Sendai - JAPAN
The extracellular space (ECS) forms an important but understudied frontier in neuroscience. It consists of the narrow gaps that surround all brain cells, which are filled with interstitial fluid and extracellular matrix molecules, occupying around one fifth of the volume of the brain. Even though all extracellular signaling molecules and nutrients must transit through the ECS to reach their targets, we know very little about the shape and dynamics of this brain compartment, or its influence on brain function. Although the ECS has received much less attention than neuronal and glial networks, it plays a fundamental functional role in brain health and disease, serving as a reservoir of ions for electrical activity and providing an essential microenvironment for the well-being of cells and brain homeostasis. Based on pioneering theoretical and biophysical studies, we know the diffusivity and geometry of the ECS are major determinants of how molecules (endogenous substances or medical drugs) can spread around the brain or get cleared from it. However, mapping the biophysical landscape of the ECS with enough spatial resolution in live brain tissue has been impossible to accomplish until now for lack of appropriate tools.
Bringing together a team of leading researchers, this multidisciplinary project will study key properties of the ECS, focusing on its dynamic organization, its role in material transport (in brain perivascular spaces and parenchyma) and its impact on brain function at the cellular and systems level. To this end, we will develop several innovative investigative tools that will allow us to image and manipulate key aspects of the ECS, and to study its structure and function in brain slices, in vivo and in silico.
Specifically, we will (1) engineer novel chemical tools to label hyaluronan (HA) and to manipulate its biological activity, (2) develop super-resolution microscopy technology to study impact of ECS on synaptic function in brain slices and to enable ECS visualization in the intact brain in vivo, (3) make biophysical measurements to quantify diffusion of molecules through the ECS, (4) investigate ECS control of ‘glymphatic’ function in the sleep-wake cycle, (5) construct morphologically realistic mathematical models to simulate substance transport through the ECS. This combination of methodologies will enable us to better understand how this brain compartment influences brain physiology, focusing on single neuron function and sleep.