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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
Bacterial targeting of the host epitranscriptome
HARTLAND Elizabeth (.)
Monash University - Clayton - AUSTRALIA
ALLAIN Frédéric (.)
Swiss Federal Institute of Technology in Zurich (ETH Zurich/ETH Zürich) - . - .
HELM Mark (.)
Johannes Gutenberg University of Mainz - . - .
The post-transcriptional processing and modification of cellular RNA provides an additional level of gene regulation that is known as the epitranscriptome. However, despite current knowledge of RNA modifications, the functional significance of many epitranscriptomic changes within the cell is unknown. Here we will explore the impact of bacterial infection on the host epitranscriptome using methods to identify the direct and specific modification of host RNA by bacterial pathogens. Many host-interacting bacteria use specialised protein secretion systems to inject “effector” proteins into eukaryotic cells that target various cellular processes to promote bacterial survival. Although many bacterial effector proteins are known to mediate post-translational modifications of host proteins, effectors that directly modify host RNA and alter the epitranscriptome have not been described. We hypothesise that host-interacting bacteria harbour undiscovered RNA-binding effector proteins that post-transcriptionally target eukaryotic RNA with novel modifications. Such RNA modifying effectors would offer the potential to investigate the significance of RNA modifications in host cell responses and functional biology.
The specific aims are to: 1. Discover bacterial effector proteins that bind eukaryotic host RNA during infection using Legionella species as model intracellular bacteria by performing RNA-interactome capture (RIC) from host cell RNA. Epitope tagged RNA-binding effector proteins will then be used for cross-linking RNA immunoprecipitation (CLIP) of host RNA to identify RNA modifications using liquid-chromatography and mass spectrometry (LC-MS). 2. Define the host RNA targets of bacterial effectors and explore the structural basis of effector mediated RNA modifications using epitranscriptomics. Large-scale expression and purification of bacterial RNA-binding effectors with identified consensus RNA-modification motifs will be used for structural analysis of RNA-protein complexes. 3. Investigate the impact of effector-mediated host RNA modifications on the cellular response to infection by assessing bacterial mutant strains for intracellular replication defects and changes in host transcriptional responses to infection. The biodynamics of RNA-binding effectors and their modified host RNAs will be explored in vitro using novel liquid-liquid phase separation (LLPS).
2023
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Grant Awardees - Program
Understanding fundamental mechanisms governing insect cell membrane deformability
GEROLD Gisa (.)
University of Veterinary Medicine Hannover (TiHo) - Hannover - GERMANY
ARIOTTI Nicholas (.)
Institute for Molecular Bioscience - . - .
PERRIMON Norbert (.)
President and Fellows of Harvard College, Harvard Medical School - . - .
Insect cell membranes differ from mammalian membranes by deformability, lipid content, lipid distribution in microdomains and membrane leaflet asymmetry. Enveloped insect-borne viruses require intimate interactions with cellular membranes to enter cells, replicate their genomes in cells and bud from cells. Despite fundamental biophysical differences between insect and mammalian membranes, insect-borne viruses can productively infect cells from both phyla. Decades of studies on insect-borne viruses have not addressed the machinery of insect membrane deformation and its exploitation by viruses.
Here we hypothesize that insect-borne viruses have evolved to biophysically manipulate membranes from both phyla and/or hijack physiological membrane properties from both phyla. Whether genes involved in membrane dynamics or deformation are genetically similar in insects and mammals or whether insects and mammals achieve similar outcomes using distinct sets of genes remains elusive to date. Therefore, our objectives are to bundle the knowledge from three disciplines to unravel fundamental membrane processes in insect cells and compare these to mammalian cells.
Working at the interface of insect genetics, membrane biophysics and virology our newly formed team has assembled innovative technologies to break through this barrier in the field. Through the combined expertise of the PIs, we will: 1. Employ gene editing libraries in insect cells to identify host factors steering virus – membrane interactions; 2. Visualize membrane deformation at high-resolution upon genetic manipulation in uninfected and virus-infected insect cells using time-lapse imaging, high resolution imaging and biophysical probes; 3. Assess the impact of membrane deformation on permissiveness to insect-borne viruses by infection assays and sophisticated virological assays probing virus entry, genome replication at plasma membrane microdomains and virus budding from insect cells. 4. Compare the membrane deformation mechanisms in insect cells to those in mammalian cells.
These studies will provide insight into mechanisms driving insect versus mammalian membrane shape and function. Thereby, they will revolutionize our understanding of virus adaptation across fundamentally different species.
2023
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Grant Awardees - Program
Uncovering the real paleo diet: Novel isotope analytics of amino acids from fossil hominin teeth
NEUBAUER Cajetan (.)
University of Colorado Boulder - Boulder - United States
LÜDECKE Tina (.)
Max Planck Institute for Chemistry - . - .
BAKKOUR Rani (.)
Technical University of Munich (Technische Universität München, TUM) - . - .
Accumulating evidence suggests that fossil tooth enamel is remarkably efficient in preserving amino acids (AAs). Intact AAs in fossils have the potential to reveal paleodietary isotopic proxies that may enable unique insights into the lives of even our most ancient human ancestors. While isotope studies have been a great aid for examining how diet has shaped the evolution of key human traits (e.g., brain expansion, bipedalism), current isotope ratio mass spectrometry (IRMS) is fundamentally restricted to gases. However, improved sensitivity and the ability to measure intact biomolecules would permit access to the full spectrum of paleodietary information that is encoded in organic compounds preserved in enamel. While the application of classic IRMS methods for AA analysis of bone collagen have proven valuable for food web reconstruction in ecology and archaeology, the approach is limited to relatively recent (100kya) human prehistory. This project aims to employ a new analytical paradigm based on electrospray-Orbitrap MS to access ancient biomolecules. It will measure comprehensive (compound- and site-specific) isotopic information simultaneously in biomolecules with unprecedented sensitivities. Sensitivity of the electrospray-Orbitrap for isotopes is >10,000-fold higher than isotopic NMR and at least 10 to 100-fold better than the most sensitive IRMS today. This step change makes it conceivable to attempt measuring isotopes directly within intact fossilized polar molecules, including the minute quantities of AAs preserved in hominin enamel. Our team proposes a new analytical frontier: the quantification of paleodietary signatures encoded in intact molecules (“isotopocules”) that are millions of years old. Our US group has developed initial AA isotopocule measurements. Together with fossil preparation and affinity isolation methods pioneered by our two groups in Germany, this novel technique will be validated in a modern African ecosystem (Gorongosa National Park, Mozambique), then refined and applied to hominin fossils (>1Mya). This project will establish a framework to test hypotheses and ask more nuanced mechanistic questions about early hominin food acquisition and habits. The approach we propose has significant potential to be more broadly applied in paleontology, as well as environmental and health research.
2023
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Grant Awardees - Program
When the going gets tough: Trans-kingdom spore dormancy and revival mechanisms across scales
BALASUBRAMANIAN Mohan (.)
University of Warwick - Coventry - United Kingdom
O'SHAUGHNESSY Ben (.)
The Trustees of Columbia University in the City of New York - . - .
BEN YEHUDA Sigal (.)
The Hebrew University of Jerusalem, Jerusalem - . - .
JANSHOFF Andreas (.)
University of Göttingen (Georg-August-Universität Gottingen) - . - .
In response to adverse conditions, organisms across the tree of life retreat into remarkable dormant states as spores. Spores of bacteria, fungi, and plants are the most resilient cell types known, and can revive following prolonged dormancy, enabling long distance organismal dispersal with significant environmental impact. Yet, the dormant state and the rapid revival remain a cell biological and physical mystery. How are cellular organization and revivability preserved without energy from nutrients? What is the biophysical nature of the dormant cytosol and its role in dormancy? What metabolic processes are required for survival? What are the mechanisms of awakening? What role is played by the spore outer layers, and how do their mechanical properties evolve during germination? What factors govern long term spore fitness? How do environmental niches impact spore physical properties? Do common principles govern spore fitness across kingdoms?
To deliver a full mechanistic picture, we will combine advanced microscopy, spectroscopy, machine learning, biophysical modelling, and molecular/cell biological studies of bacterial and yeast spores, comparing dormant and nutrient-fed germinating spores. Using machine learning to analyse motions of fluorescently labelled endogenous molecules/complexes and exogenous tracer particles, we will quantify the scale-dependent relaxation kinetics of the dormant cytosol, characterize its material properties which are likely glassy as for other quiescent states, and measure entropy production to quantify metabolic activity. We will measure the cytosol-fluidizing effects of this metabolic activity using ATP uncaging, and test if this can trigger revival. Impedance spectroscopy will measure cytosol water content, a determinant of glassiness, and indentation-relaxation will probe mechanical stiffness of spore outer layers. We will encapsulate spore extracts in confined geometries (e.g. giant unilamellar vesicles) for convenient measurement and manipulation. Data from these studies will be used to develop a biophysical mathematical model of the dormant state, which will be experimentally tested. We will test the impact of diverse natural environments on our model organism spores, test if model spores and those isolated from the environment obey the same principles, and identify the parameters crucial for spore fitness.
2023
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Grant Awardees - Program
Mapping structural and functional connectivity of the distributed sensory system in chiton armor
LI Ling (.)
The University of Pennsylvania, Philadelphia, PA - Philadelphia - United States
BAUM Daniel (.)
Zuse Institute Berlin (ZIB) - . - .
SPEISER Daniel (.)
University of South Carolina - USC - . - .
Many organisms utilize a small number of sensory organs and a centralized nervous system (e.g., the paired eyes and complex brains of vertebrates) to acquire and process information. In contrast, other species have evolved distributed sensory networks (DSNs) consisting of dispersed but interconnected sensory elements to sense and respond to external stimuli. Here, we will explore a new research frontier on nature’s strategies for designing efficient and resilient DSNs by investigating a unique model system, i.e., chitons, via a synergistic interdisciplinary collaboration. Chitons are the only extant mollusks with living tissue embedded within their biomineralized protective shell plates. This innervated tissue (aesthetes) forms a complex three-dimensional (3D) interconnected network that fills thousands of long, narrow channels. These microchannels run through the shell plates and finally extend to the shell surface. It has been shown that the aesthetes perform several sensory functions, particularly photoreception. In addition, the aesthetes of certain chiton species include visual elements with different degree of complexities, ranging from simple photoreceptive organs to eyespots that contribute to spatial vision to image-forming eyes with mineralized lenses! Thousands of these visual sensory organs are distributed across the shell plates, making the system a unique ‘hard-wired’ (embedded in mineralized shells) DSN, through which the organisms collect and process visual information and finally respond. Current knowledge of chiton DSNs is primarily focused on overall behavioral responses of animals and the fine structures of individual sensory elements. We have very limited knowledge regarding the structure and function of the chiton DSNs on the system level. How are chiton DSNs wired up? How do they function? How resilient are chiton DSNs to damage? Our international, interdisciplinary team of material scientists, biologists, and applied mathematicians will address these three fundamental questions by establishing the complete ‘connectome’ of chiton DSNs and investigating its working mechanisms and system resilience. The knowledge gained from this research will transform our current understanding of natural DSNs, which may have significant impact on a number of areas, such as distributed sensing structures, living materials, resilient swarm systems, etc.
2023
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Grant Awardees - Program
SELFCURE: Evolutionary and cognitive processes underlying self-medication of immune-challenged bats
BECKER Daniel (.)
The Board of Regents of the University of Oklahoma (University of Oklahoma) - Norman - United States
PAGE Rachel (.)
Smithsonian Tropical Research Institute, Washington, DC - . - .
SIMON Ralph (.)
Nuremberg Zoo, Behavioral Ecology and Conservation Lab - . - .
Plant medicinal properties are used by a diverse range of animal taxa. Chimpanzees consume hairy Aspilia leaves when suffering from intestinal parasites, Kodiak bears use Ligustium roots against ectoparasites, and monarch butterflies prevent infection in their offspring by laying their eggs on milkweed, a plant toxic to protozoans. Self-medication behaviors provide an effective mechanism to minimize infection load. But despite its eco-evolutionary importance, we lack clear understanding of how behaviors associated with self-medication evolve. Importantly, animals may possess either an innate mechanism to search for medicinal food items, or they may learn individually or through others to associate specific foods with specific cures. Bats are a especially relevant group to study the mechanisms underlying self-medication. They harbor diverse parasites, feed on a wide variety of foods and, due to their cognitive capacities and extraordinary longevity, have high potential to learn to associate specific food resources with curative properties. Phyllostomid fruit bats in particular are ideal for investigation given the wide variety of plants that they have access to in the Neotropical rainforest.
Using state-of-the-art tracking techniques, AI-based individual recognition, and targeted and -omics approaches for characterizing immunity and parasites, we propose to investigate the mechanisms underlying self-medication in phyllostomid bats. First, we will determine the immune state, parasite diversity, and nutritional diversity of wild bat populations and investigate potential links between immunity, infection, and certain food plants. Next, by testing immune-challenged and control-treated individual bats on natural and artificially-created medicinal food preferences, we will shed light on the role of learning vs innate mechanisms in self-medication. By tracking groups of bats through a rainforest site that has been studied long-term with fully mapped fruiting tree species, we have the unique opportunity to assess whether immune-challenged individuals switch to a diet with medicinal compounds. Finally, by tracking experimentally immune-challenged and experimentally cured bats trained on artificial sonar beacons indicating the presence of medicinal foods in the wild, we will assess how information regarding self-medication can spread through a bat social network.
2023
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Grant Awardees - Program
Evolution at the plant apex: identifying steps enabling a major organismal radiation.
HARRISON Jill (.)
University of Bristol - Bristol - United Kingdom
HETHERINGTON Alexander (.)
University of Edinburgh - . - .
FUJINAMI Rieko (.)
Kyoto University of Education - . - .
BEECKMAN Tom (.)
Ghent University (Universiteit Gent) - . - .
The origin and rise to dominance of vascular plants massively impacted the Earth System and led to an explosive radiation in biodiversity, but how vascular plants originated and diversified to form lycophytes, ferns and seed plants with complex shoot and root systems is unknown. Answers to these questions hinge on apical growth, a key innovation enabling persistent stem cell activity in plants’ growing tips. Like living mosses, the earliest land plants lacked apical growth, and were short lived with tiny stems terminating in the development of spore-producing sporangia. We hypothesise that the origin of apical growth involved the relocation of sporangia from terminal to lateral positions, and the juxtaposition of stem cell and proliferative regions, as seen in the apices of living vascular plants. However, mosses and vascular plants are distantly related with widely divergent forms, and ancestral patterns of apical growth shown by ancient pro-vascular and vascular plant fossils are unknown. Moreover, living vascular plants have diverse patterns of apical growth, and the changes enabling shoot and root evolution are unknown. To test our hypothesis, we propose an innovative research plan that combines morphological data from fossils and living plants at either side of the origin of apical growth with developmental and genetic data from mosses, lycophytes, ferns, and seed plants through four interlinked work packages.
WP1 will use a forward genetic screen in a moss and establish functional reverse genetic analysis in a lycophyte to identify genes involved in the origin of apical growth.
WP2 will determine structure of fossil apices preserved during the emergence of vascular plants to identify ancestral patterns of apical growth.
WP3 will evaluate cell proliferation patterns in a moss and a range of vascular plants and compare apical organizations between living plants and fossils to identify stepwise changes during the evolution of apical growth.
WP4 will use transcriptomic and reverse genetic methods to identify conservation and divergence in the genetic networks for apical growth.
As an integrated whole, the research will lead to a step change in our understanding of apical growth, a key innovation enabling the radiation of today’s dominant vascular plant flora.
2023
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Grant Awardees - Program
Physics goes wild: studying the evolution of iridescence and its perception in Amazonian butterflies
DEBAT Vincent (.)
French National Museum of Natural History (Muséum national d'histoire naturelle, MNHN) - Paris - FRANCE
BELUŠIC Gregor (.)
University of Ljubljana (Slovenia) - . - .
GIRALDO Marco (.)
University of Antioquia (Universidad de Antioquia) - . - .
BRISCOE Adriana (.)
The Regents of the University of California (Irvine) - . - .
Iridescence is a fascinating optical property induced by complex nanostructures that evolved multiple times in a wide diversity of organisms. Yet, how iridescence is perceived and how it co-evolves with visual perception is unknown. Here, we aim at identifying the selective forces shaping the evolution of wing iridescence and its perception in the emblematic Morpho butterflies.
The genus Morpho is ideal to study the evolutionary drivers of iridescence, because striking variation in iridescence occurs within and among its 30 species, associated with contrasted ecologies. We will test two main hypotheses: (1) Morpho iridescence evolves under selection by predators, the blue flashes produced during escape flight increasing their difficulty of capture. (2) Iridescence facilitates species and mate recognition, in part dependent on the light environment. These hypotheses imply a co-evolution of Morpho coloration with flight and color vision.
To test these hypotheses, we will combine the skills of experts from complementary scientific disciplines. (1) Physics: we will quantify iridescence and polarization in both sexes for the whole genus, through microspectrophotometry, imaging scatterometry and spectrogoniometry. (2) Behavioral ecology: we will use state-of-the-art videographic and kinematic analyses to quantify flight behavior during escape, courtship and male-male competition and assess its effect on dynamic color signals. (3) Molecular biology: we will assess the evolution of opsins throughout the genus and assess their expression in both sexes in blue and non-blue Morpho species, using RNA-seq, immunohistochemistry and in situ hybridization. (4) Electro- and optophysiology: sensitivity of the photoreceptors will be assessed using single cell recordings; optical pupillograms will characterize retinal mosaic structure, and recordings of optic lobes will identify the neuronal pathways involved in iridescent color vision.
This original interdisciplinary approach will allow us to decipher the factors shaping the evolution of iridescence and polarization in Morphos, from the joint perspective of signal production and reception. Filling this knowledge gap will be a major contribution to our understanding of the diversity of structural colors in the living world.
2023
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Grant Awardees - Program
New Kids on the Block: how DeNovo emerged micropeptides rewire cellular networks
CARVUNIS Anne-Ruxandra (.)
University of Pittsburgh - Pittsburgh - United States
BRUN Christine (.)
Inserm Délégation régionale Provence Côte d'Azur - . - .
BORNBERG-BAUER Erich (.)
University of Münster (Westfälische Wilhelms-Universität Münster) - . - .
De novo genes emerge in non-coding DNA and code for entirely novel de novo proteins (DNPs) with evolutionarily unexplored sequences, structures and functions. DNPs have been recognized recently and are intensely studied as they describe a hitherto unknown mode of molecular innovation and may reveal species specific functional differences. However, most studies so far ignore that DNPs do not emerge or evolve in isolation, but in the context of an already established complex system. This project will study how DNPs integrate and potentially reshape pre-existing protein interaction networks and, conversely, how networks adapt in response to these “new kids on the block”.
Most DNPs may not be retained over several speciation events or even fixed in the whole human population, yet lurk in our cells and may pose disease risks. We focus on short proteins that have very recently emerged or are currently spreading in the human lineage. We will deploy an array of computational and experimental approaches to identify human DNPs and map their protein interaction landscapes throughout evolution . We will first define a comprehensive set of thoroughly verified human DNPs. Next, we will determine their evolutionary history by comparative genomics and reconstruct, wherever possible, their most likely ancestral sequences. We will computationally predict biophysical properties such as structure, intrinsic disorder and aggregation propensity of DNPs. Potential protein binding motifs and likely interactors of DNPs will be predicted and confirmed experimentally using yeast-2-hybrid and phage display. By combining evolutionary analyses of DNPs and their interactors with graph theoretical modeling of network behavior in response to DNP addition, we will learn if DNPs preferentially attach to proteins of the network with particular topological, functional or evolutionary properties. Our experiments and analyses will lead to understanding if DNPs evolved to adapt to the interaction network, if the existing network adapted or, alternatively, if the network has evolved resilience towards incoming additions. Overall, we aim to dissect the molecular bases and derive corresponding rules governing how DNPs integrate cellular networks to engender novel beneficial functions or novel disease risks that are specific to humans.
2023
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Grant Awardees - Program
Autonomous evolution of synthetic cells under non-equilibrium conditions
BRAUN Dieter (.)
Ludwig Maximilian University Munich (Ludwig-Maximilians-Universität München, LMU) - Munich - GERMANY
MATSUURA Tomoaki (.)
National University Corporation Tokyo Institute of Technology - . - .
GÖPFRICH Kerstin (.)
Max Planck Institute for Medical Research (Max-Planck-Institut für Medizinische Forschung) - . - .
Fascinating biology originates from the Darwinian evolution of cellular life. Mechanisms to create the evolvability of cellular systems remain a fundamental open question. We will reveal how out-of-equilibrium conditions could be used as a driving force to create an autonomously evolvable synthetic cell. While providing highly efficient ways to evolve synthetic protocells in the future, the approach will also address how cells could have emerged in the first place. We will use thermal gradients at air-water interfaces and freeze-thaw cycles to assemble and replicate cells. Selection will be performed based on the ability of the cell to express either peptide-based or RNA-based dimerizing transmembrane units and associate and sediment. The autonomous nature of the process will allow us to select only cells that could incorporate a functional transcription and translation system.
We will proceed along three subprojects:
i. Autonomous vesicle assembly. Components essential for transcription and translation will be encapsulated into unilamellar lipid vesicles through thermal trapping at a heated air-water interface and accumulation by freeze-thaw-cycles. This will demonstrate the autonomous out-of-equilibrium emergence of both biomolecule accumulation and encapsulation to recreate cellular compartments.
ii. Transmembrane domain for the selection by sedimentation. Based on the information encoded on the DNA, synthetic cells will display either an RNA-based or a protein-based surface molecule to trigger aggregation and subsequent sedimentation. This function will be first established in GUVs and then moved to systems which select the aggregated cells by autonomous sedimentation, providing the selective signal that the transcription/translation system was functional.
iii. Autonomous amplification of the sedimented cells. Sedimented cells will be brought back to the next rounds of evolution by picking the sedimented colonies, replicating the DNA, refeeding the transcription/translation system and recreating the vesicle compartments. Besides establishing the processes in tubes, the selection and refeeding will be continuously performed in a heated air-water interface microfluidics or a thermally oscillated freeze-thaw cycle. The whole-cell selection and reformation of cells will create an autonomous evolution of proto-cellular systems.
2023
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Grant Awardees - Program
The Architecture of Photosynthesis
GEITMANN Anja (.)
The Royal Institution for the Advancement of Learning/McGill University - Montreal - CANADA
DEAR John (.)
Imperial College of Science, Technology and Medicine - . - .
PEZZULLA Matteo (.)
Aarhus University (Aarhus Universitet, AU) - . - .
BRODERSEN Craig (.)
Yale University - . - .
Photosynthesis is the metabolic process that sustains all life on Earth. Understanding how vascular plants reconcile leaf structural optimization for both light capture and photosynthetic gas exchange with architectural stability required to withstand gravity and wind has been an intractable challenge. While the anatomy of the inner leaf tissues should optimize gas exchange through a porous microstructure that augments the net absorptive interface, such an optimization should also come with a cost to the architectural stability of thin planar leaves. This interdisciplinary project leverages a combination of expertise in cell biology, ecophysiology, and mechanical engineering to investigate the functional trade-off between gas exchange and leaf mechanics. Based on engineering concepts, the biomechanics of plant leaves and the porous properties of its inner tissues will be analyzed at multiple length scales to gain insight into evolutionary pressures that have shaped laminar leaves over millions of years. Our approach will reconcile how and why leaves are structured the way they are and identify the critical design principles of highly productive species capable of sustaining maximum photosynthetic performance. We also aim to understand the construction costs and minimal investments needed to produce a laminar leaf that is biomechanically robust while still meeting the demands to serve as the cellular scaffold for photosynthesis. Collectively, the data and new methodology developed in this collaborative project will 1) provide novel insight into the evolutionary trajectory of land plants, 2) identify the key design elements of the internal three-dimensional cellular geometry, 3) facilitate the interdisciplinary exchange of ideas, tools, and theory to make a major advancement in our understanding of plant biomechanics and materials science, and 4) identify a set of key traits that could be used for the development of next-generation biomimetic materials with inspiration from nature, as well as new crop varieties that are more efficient in terms of resource allocation, photosynthetic performance, and resilience.
2023
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Grant Awardees - Program
Decoding the gelatinous origins of brain evolution
WOLF Fred (.)
University of Göttingen (Georg-August-Universität Gottingen) - Göttingen - GERMANY
BURKHARDT Pawel (.)
UNIVERSITY OF BERGEN - . - .
The origin of first brains was key in animal evolution as it allowed them to rapidly integrate environmental cues, coordinate responses to threats or opportunities, and form internal models of the world to make decisions and guide behavior. However, the evolutionary origin of animal brains remains mysterious. Ctenophores are marine organisms and strong candidates for one of the first animal lineages developing an elementary brain to navigate through the ocean. Intriguingly, ctenophores possess a unique type of neuronal integration center called the aboral organ that in juvenile animals contains about 80 nerve cells and functions as a multi-sensory integration center controlling complex behaviors. The ctenophore aboral organ presumably evolved independently of centralized nervous systems in bilaterians and likely preserves biophysical and molecular mechanisms characteristic of the first nervous systems. Ctenophores therefore offer a unique opportunity to elucidate the cellular mechanisms, behavioral capacities, and adaptive values relevant to the evolutionary invention of animal nervous systems. Here, we propose to uncover the neural circuit basis of ecologically important behaviors of a fierce planktonic predator, Mnemiopsis leidyi, a ctenophore that can disrupt entire marine ecosystems when displaced or out of control, contributes to the production of “ocean snow”, transferring carbon to the abyss, and harbors perhaps the most alien brain of any predatory animal on the planet. We will build on recent breakthroughs in organismal biology, molecular neuroscience, connectomics, neural circuit inference and neurotechnology to establish a data-driven account of Mnemiopsis’ neural brain circuits and behavior, to all-optically read and interrogate the state of its brain, and to test and validate computational models of its neuronal processing by cellular-resolution whole-brain imaging. Dense behavioral videography data in free-ranging animals will be used to construct data-driven quantitative models of 3D animal postural and movement dynamics during hunting, propulsion and steering. Together, these studies will allow us to understand Mnemiopsis’ brain and behavior by bridging levels from the molecular and biophysical architecture of nerve cells to ecologically important behaviors and shed new light on the very origin of biological brains.
2023
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Grant Awardees - Program
Evolution of protein multifunctionality
FEUDA Roberto (.)
University of Leicester - Leicester - United Kingdom
CHANG Belinda (.)
University of Toronto, Department of Cell & Systems Biology - . - .
MENON Anant (.)
Weill Medical College of Cornell University - . - .
GOEPFERT Martin (.)
University of Göttingen (Georg-August-Universität Gottingen) - . - .
Like moonlighting people, proteins can have several seemingly unrelated functions. How multiple functions can coexist within the sequence of a single polypeptide chain remains an open question, especially if the individual functions are not separated as in a Swiss army knife but intermingled such that selection for one function might compromise others. Merging expertise in evolutionary genomics, biochemistry, biophysics, and physiology, implemented via in silico, in vitro and in vivo approaches, we now propose to elucidate fundamental principles underlying protein moonlighting using the Drosophila melanogaster opsin protein Rh1 as a prototype. Rh1 (i) initiates visual transduction in photoreceptor cells, (ii) organizes cilia in mechanoreceptor cells, (iii) acts as a chemoreceptor protein in taste receptor cells, (iv) functions in the sensory discrimination of environmental temperature, and (v) acts as a phospholipid scramblase, contributing to membrane lipid homeostasis. We will use two approaches to scan for variants that may be important for Rh1 multifunctionality, which will then be investigated experimentally. First, we will investigate natural variation of the Rh1 sequence across populations/species and identify targets of selection. Second, we will conduct deep scanning mutagenesis experiments of Rh1 to identify all allowable variants which permit proper protein maturation and visual signaling. Allowable mutations not found in nature may be important for non-visual functions. Natural and allowable sequence variants will be quantitatively phenotyped using in vitro and in vivo analyses to determine their effects on the photo-, mechano-, chemo-, and thermosensory functions of Rh1, its scramblase activity, spectral tuning, and downstream signaling. These genetic and functional data will then be used to (i) link multiple aspects of Rh1 functions to specific amino-acid residues, (ii) determine to what extent the diverse functions make use of common residues, (iii) reveal whether the respective residues are conserved or vary in nature, (iv) elucidate the functional consequences of this variation and finally, (v) illuminate the evolutionary constraints associated with moonlighting by opsins. Thus, we will obtain a molecular understanding of how hyper-diverse functions are realized and maintained in super-multifunctional proteins.
2023
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Grant Awardees - Program
Deciphering the role of dynamics in vascular network remodeling and determination
KATIFORI Eleni (.)
University of Pennsylvania, Philadelphia, PA - Philadelphia - United States
JONES Elizabeth (.)
Catholic University of Leuven (Katholieke Universiteit Leuven, KU Leuven) - . - .
CORNELISSEN Annemiek (.)
Laboratoire Matière et Systemes Complexes, CNRS, UMR 7057 - . - .
Vascular networks in animals are constantly in flux, remodeling their topology and architecture during development and adulthood, to respond and adapt to different stimuli and environmental conditions. The resulting topologies are typically complex, involving several levels of hierarchy, and display features that can be inconsistent with steady flow adaptation models, like suppression of vascular shunting. In this project, we will explore how these biological transport networks are built and maintained. In particular, we will combine our expertise in theoretical and computational fluid dynamics, soft matter physics, and experimental developmental biology of two very different animal classes, mammals and jellyfish, to understand how pulsatility and other dynamics influences the long-term adaptation and remodeling of the vascular system. Pulsatility is present in all living organisms and yet our understanding of the role this stimulus plays is minimal. We propose that pulsatility is vital to the organism, playing an essential role in preserving vascular loops and preventing shunting.
To do this, we will first build computation models that calculate the flow dynamics in complex elastic networks. We will test these models with real in vivo measurements of whole mouse embryos and jellyfish. We will then use experiment and computation to study how short-term dynamics in the flow and variations in the pumping force that propels the fluid are propagated by fluid structure interactions of the elastic vascular walls. We will investigate mechanisms, both on the physiological and genetic level, including gain-of-function and loss-function models. The earlier is obtained by increasing vessel stiffness, both in jellyfish and mouse, thereby generating faster and larger pulse waves. The latter takes advantage of recently developed mechanical assist devices for the heart that create continuous flow in the vasculature. Our final aim is to to understand the role of wave reflection and additive/subtractive effects of the pulse wave forms and perform a comparative analysis of our findings in jellyfish and mouse, to eventually uncover the fundamental biological rules that shape vascular network architectures.
2023
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Grant Awardees - Program
Electrogenetic control of bacterial metabolism, communication, and biofilm formation
MALVANKAR Nikhil (.)
Yale University - New Haven - United States
CRAIG Lisa (.)
Simon Fraser University - . - .
FRANCETIC Olivera (.)
Institut Pasteur, Paris - . - .
SALGUEIRO Carlos (.)
Faculdade Ciências e Tecnologia, Universidade Nova de Lisboa - . - .
Electrogenetics is an emerging biotechnology platform that uses electric fields to control gene expression. Current electrogenetic methods rely on diffusive ions which become ineffective due to high fluid flow present in most environments. To achieve fast and directional electron transport, soil microbes including Geobacter have evolved long thin proteinaceous “nanowires” capable of ultra-fast delivery of excess metabolic electrons to external mineral acceptors or to other microbes in a process called Direct Interspecies Electron Transfer (DIET). DIET is crucial to prevent toxic electron build-up in the anaerobic habitats where Geobacter lives in biofilm communities with other microbe species. Crucially, many archaea capture these electrons via DIET and use them to produce methane (methanogens) or to degrade methane (methanotrophs). Nanowires and DIET thus have a major impact on the global levels of methane, a greenhouse gas 30 times more potent than CO2 in trapping heat. Despite their global importance, the conditions and mechanisms driving nanowire biogenesis and function in DIET are poorly understood. Recently, PI Malvankar showed that nanowires are polymers of cytochromes that are secreted to the Geobacter cell surface via an unusual type IV pilus machine. Electric fields induce nanowire production by upregulating expression of genes involved in their biogenesis. Thus, the Geobacter system is an ideal model to study electrogenetics. To elucidate how the electric fields control nanowire biogenesis and signalling, we will identify Geobacter genes upregulated during DIET in co-cultures of Geobacter donor and acceptor species. We will deploy solid-state physics, spectroelectrochemistry, biochemistry, structural biology and genetics to characterize nanowire secretion and assembly, electron wiring and transport in DIET, and its effects on gene expression. By reconstituting nanowire secretion and assembly in Escherichia coli we can characterize their biogenesis and function. This information can be used to design nanowire-based electrogenetics systems that form conductive biomaterials, generate energy (biofuels) and produce biological products. Importantly the Geobacter system can be paired with methane-utilizing microbes to investigate electrogenetics in these species, with the long term goal of controlling DIET to reduce atmospheric carbon levels.
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 - 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).