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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2022
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Grant Awardees - Program
Mapping gut-to-brain transmission of prion protein
AGUZZI Adriano (ITALY)
Institute of Neuropathology - University of Zurich - ZURICH - SWITZERLAND
THAISS Christoph (GERMANY)
Dept. of Microbiology - University of Pennsylvania - Philadelphia - USA
Prion diseases are incurable neurodegenerative conditions. They are caused by PrPSc, an infectious form of the cellular prion protein PrPC. Upon ingestion, PrPSc causes misfolding of PrPC and successively propagates to the brain, where it causes a universally fatal spongiform encephalopathy. Inhibition of gut-to-brain transmission should theoretically prevent disease, but the detailed circuit by which PrPSc reaches the brain remains incompletely defined. We have recently used polysynaptic tracing in combination with single-nucleus RNA-sequencing to comprehensively map neuronal gut-brain pathways from the intestinal epithelium to the brain. We made the surprising discovery that a single such pathway, leading from enteroendocrine cells to the brainstem via the enteric nervous system, is characterized by expression of the endogenous prion gene Prnp in each component of the circuit. In this project, we aim at (I) determining the physiological function of PrP in this gut-brain circuit, as well as (II) elucidating if this pathway transmits PrPSc from the intestine to the brain and whether its inhibition can prevent prion disease. To achieve these goals, we will join forces between a lab that has pioneered the study of prion transmission (Aguzzi) and a lab that specializes in the investigation of gut-brain communication (Thaiss).
2022
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Grant Awardees - Program
Spatial and deep neurolipidomics to reveal synapse diversity
AHRENDS Robert (GERMANY)
Analytical Chemistry - University Vienna - Vienna - AUSTRIA
VERHELST Steven (NETHERLANDS)
Department of Cellular and Molecular Medicine - KU Leuven -University of Leuven - Leuven - BELGIUM
ELLIS Shane (AUSTRALIA)
Molecular Horizons and School of Chemistry and Molecular Bioscience - University of Wollongong - Wollongong - AUSTRALIA
KREUTZ Michael (GERMANY)
Center for Molecular Neurobiology - University Medical Center Hamburg-Eppendorf - Hamburg - GERMANY
The astonishing capacity of the brain to process and store information crucially relies on properly functioning synapses. They provide the connecting entities within neural circuits and they properties define circuit function. The molecular composition of synapses can be very different, which has not been appreciated yet to the extent that would allow deeper insights into the molecular underpinnings of information processing in different circuits. While the role of proteins, as core components of the synaptic cell membrane and synaptic transmission has been addressed in certain detail it is unclear to what extent the molecular diversity of lipids can influence synaptic function. Based on new technologies allowing for the first time lipidomic studies at the level of different synapse types, the project aims at unveiling the molecular interactions between lipids and proteins. Newly developed analysis strategies as well as innovative lipid tagging and imaging approaches will enable us to determine the membrane composition of specific synapses with high resolution. This spatial lipidomics workflow will pave the way to studies on how aging and neurological diseases influence synaptic lipid composition with the prospect of therapeutic interventions.
2022
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Grant Awardees - Program
Unravelling the mechanisms of brain and behavioral elaboration in ecologically diverse butterflies
MONTGOMERY Stephen (UK)
School of Biological Sciences - University of Bristol - Bristol - UK
EL JUNDI Basil (GERMANY)
Department of Behavioral Physiology & Sociobiology - University of Wuerzburg - Wuerzburg - GERMANY
MARTIN Arnaud (FRANCE)
Department of Biological Sciences - The George Washington University - Washington - USA
BACQUET Caroline (CHILE)
Life Sciences - Universidad Regional Amazónica Ikiam - Tena - ECUADOR
How does the brain encode adaptive behavior? And how do neural systems facilitate behavioral elaboration? Answering these questions requires integrating evolutionary perspectives of ecology and neurobiology in taxa that display behavioral diversity and innovation. To do so, we need new investigative tools that allow us to look deeper into the brain, and to experimentally manipulate brain development and function. Developing new tools for specific groups of organisms is a major investment, and careful consideration should be given to which species to target. We present Heliconiini butterflies as a system where investment is clearly justified. The rich ecological diversity of Heliconiini has been studied for 150 years, but only recently has the extent of neuroanatomical variation been revealed, with some brain regions varying in size by over 25X. Our rich understanding of these taxa, combined with their experimental tractability presents new opportunities for an integrative understanding of neural variation. However, the current lack of established investigative tools inhibits our ability to understand this neural diversity. To address this, we will: 1) visualise and quantify neural diversity; 2) link neural activity to behavior in a nature-based virtual reality setup; 3) optimise genetic tools to manipulate brains and behavior; and 4) identify molecular controls of behavioral maturation. Developing this toolkit will unlock the potential of this system as a model for understanding brain and behavioral elaboration.
2022
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Grant Awardees - Program
Good vibes: how do plants recognise and respond to pollinator vibroacoustic signals?
BARBERO Francesca (ITALY)
Life Sciences and Systems Biology - Turin University - Turin - ITALY
OBERST Sebastian (AUSTRALIA)
Faculty of Engineering and IT, Centre for Audio, Acoustics and Vibration - University of Technology Sydney - Sydney - AUSTRALIA
MATUS Tomás (CHILE)
Program for Systems Biology of Molecular Interactions and Regulation/Group of 'Transcriptional Orchestration of Metabolism' - Institute for Integrative Systems Biology (I2SYSBIO), Joint Centre University of Valencia (UV), Spanish Research Council (CSIC) - Paterna, Valencia - SPAIN
A finely-tuned communication is crucial for maintaining plant-pollinator interactions. So far, this complex association has been investigated primarily by focusing on visual and olfactory cues. Recent studies have suggested vibroacoustic (VA) signals as an additional communication channel eliciting plant responses, however, the extent and ultimate roles of VAs in plant interactions are largely unexplored. In the context of plant-pollinator associations, VA signalling has only been scantily addressed, mainly in buzz-pollinated species, neglecting airborne components and without delving into the underlying molecular mechanisms involved. Our project aims at dissecting the molecular and physiological mechanisms of plant responses to distinct VAs emitted by approaching insects, using snapdragon as a model. Since Antirrhinum flower visitors have unequal efficiency as pollinators and emit characteristic VAs, we hypothesise that plants are able to recognise effective pollinators by sensing their specific VA signatures. We also postulate that VA-elicited snapdragon responses affect pollinator behaviours, with effects on pollen transfer, and consequently on plant reproductive fitness. Our project will test these hypotheses by a multidisciplinary approach combining ethology, plant molecular biology, and physics-informed data science. VAs of legitimate and illegitimate flower visitors will be recorded and engineered signals will be played back to test plant early and late electrophysiological, metabolic and transcriptomic responses. We will generate flower-shape and receptor-sensing mutants by CRISPR-Cas gene editing to analyse VA-sensing processes and structural features potentially evolved to enhance plant VA transmission. Behavioural assays will test flower visitors’ preferences to assess if plant responses triggered by VAs can be considered adaptive in the context of pollination. Multidisciplinary data will be interwoven in an evidence-based mathematical model tracing a roadmap to help understanding the origins of phyto-vibroacoustics: why vibroacoustic communication has evolved in plants. By tackling complex dynamics in plant-pollinator systems from a totally new angle, we endeavour to revolutionise our understanding of how plants interact with the biotic and abiotic components of the environment.
2022
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Grant Awardees - Program
Dynamics of multilayer epithelial structures: Integrative mechanical characterization of epidermis
DAS Tamal (INDIA)
TCIS, Collective Cellular Dynamics Lab - Tata Institute for Fundamental Research Hyderabad - Hyderabad - INDIA
SERWANE Friedhelm (GERMANY)
Department of Physics - LMU Munich - Munich - GERMANY
BI Dapeng (USA)
Physics - Northeastern University - Boston - USA
How single layer tissues transform into multilayer systems to become building blocks of organs and organisms is one of the unresolved riddles in biology. An intriguing example of this process is the formation of the most important barrier layer, the skin epidermis, which protects our body from the external environment and withstands large external stresses. During its development, the epidermis starts as a single layer of cells, which proliferate, move outward, and stack-up to build the multilayered epithelium. Understanding epidermal development is critical for understanding, preventing, and curing numerous skin defects, painful blistering, and skin cancers. To this end, skin epidermis development has traditionally been tackled via 3D imaging of fixed tissue, collected mainly from mouse embryos. With this scheme, however, the dynamics of epidermal development cannot be revealed. Besides, progress in research using animal models are limited by the time required to induce genetic perturbations and ethical considerations. Even where it is possible to pinpoint few molecular players using an animal model, the dynamic biophysical mechanism that dictates cell movements in a developing skin dermis remains unexplored. Funded by the HSFP, we will overcome these limitations by developing a stem cell-derived skin model, termed skin organoid. Furthermore, we will introduce a mechano-biological platform to measure tissue mechanics in 3D, and build a predictive 3D model of epidermis. In essence, our strategy is to build a bottom-up system that grants simple access to experimental parameters via biophysical measurements, genetic perturbations, and mathematical modeling, while retaining the physiological relevance. Taken together, owing to the interdisciplinary nature of our team, we plan to use a unique combination of disciplines and technologies, which will enable us to take a radically different approach for tackling the question of how a single layer epithelium transform into a multilayer tissue.
2022
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Grant Awardees - Program
Transition and reconstruction of Central Nervous System due to aging and disease
ZOU Yimin (USA)
Neurobiology - University of California, San Diego - La Jolla - USA
HJERLING-LEFFLER Jens (SWEDEN)
Dept. Medical Biochemistry and Biophysics - Karolinska Institutet - STOCKHOLM - SWEDEN
FUJIYAMA Fumino (JAPAN)
Laboratory of Histology and Cytology, Faculty of Medicine and Graduate School of Medicine - Hokkaido University - Sapporo - JAPAN
BOURNE James (AUSTRALIA)
Cellular and Cognitive Neurodevelopment - National institute for mental health - Bethesda - USA
What is aging? Getting old is not always bad, but it can be difficult both mentally and physically. Brain aging is a universal phenomenon in all mammalian species and continues to be a fundamental biological question. Although there has been much effort to understand brain aging and its many manifestations, including shrinkage and cognitive decline, it largely remains a mystery. With the increased life span of humans and neurodegenerative disorders on the rise, understanding normal aging will have a tremendous societal impact. Contrary to aging, much more is known about brain development. In the past several decades, tremendous progress has been made in deciphering the molecular program responsible for the development and maturation of neurons. Recent advances in genome science have led us to speculate that the very same factors that control fundamental developmental events are repurposed in adulthood to control synapse biology. It is known that the characteristic EEG rhythm decreases as aging. Therefore, we study the potential function of key factors and signalling molecules, which plays a pivotal role in developing the brain, on the formation, maintenance and function of the synapses formed by specific cortical neurons, which are essential for rhythm generation. We postulate that deregulation of these vital developmental factors might have a fundamental role in not only synaptic loss but also synaptic function when the cognitive decline starts in the aging brain. We will take a comparative approach to identify common mechanisms between the non-human primate model and a rodent model and test the functions of the aging program. This proposal relies on multilateral collaborations from distinct expertise in broad areas of neuroscience. Collaborations have made this proposal highly innovative as these questions are otherwise not accessible to researchers from each of the areas these investigators represent. When the issue of "what is aging" is clarified by our multidisciplinary team, it will be a great light not only for the mechanism of aging in healthy humans but also for the treatment and rehabilitation of diseases.
2022
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Grant Awardees - Program
Modeling electric fields at the heart of enzyme catalysis and function
WUTTKE Stefan (GERMANY)
Basque Center for Materials, Applications and Nanostructures - Ikerbasque Foundation - Leioa - SPAIN
BOXER Steven (USA)
Dept. of Chemistry - Stanford University - Stanford - USA
The synthesis and degradation of nearly all components of living systems are controlled by enzymes. Enzymes can accelerate the rate of biosynthetic processes to a remarkable degree while retaining a high level of specificity. We aim to understand the origin(s) of this rate enhancement by creating synthetic enzyme mimics. Our underlying hypothesis is that the active site elements of enzymes are organized to create large electric fields that interact non-covalently with the substrate bonds undergoing charge displacement during catalysis. If the field is large and oriented correctly, this interaction can make a substantial contribution to lowering the transition state free energy and accelerating the reaction. This concept is called electrostatic catalysis, and while some computational and experimental evidence exists to support this hypothesis, the non-covalent interactions at the heart of this concept have not been recapitulated or their fields measured in synthetic systems. This is a grand challenge at the interface of biology and chemistry. This proposal brings together a group that is expert in the synthesis of molecularly defined porous materials with a more biological group that has developed methods to measure electric fields within organized systems, specifically naturally occurring enzymes, and to connect those fields to the lowering of the activation free energy. By using metal-organic frameworks (MOFs) to precisely install the key functional groups of molecules in apposition to each other, the electric fields created by their non-covalent interactions will be measured for the first time. The synthetic scaffold offers a tremendous diversity of chemical functionality; specific MOF structures that mimic a wide range of enzyme active site geometries that lead to diverse function are proposed. While motivated by enzyme catalysis, electrostatic interactions due to non-covalent interactions are an essential feature of the assembly of living systems on all length-scales, so we expect this work to have both fundamental and applied impact in diverse fields. We build on this fundamental information to create enzyme-like architectures that should, if our hypothesis is correct, be capable of accelerating the rate of chemical transformations as is found in living systems.
2022
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Grant Awardees - Program
A bottom-up approach to understand how enzyme structural fluctuations accelerate multistep reactions
CHICA Roberto (CANADA)
Department of Chemistry and Biomolecular Sciences - University of Ottawa - Ottawa - CANADA
THOMPSON Michael (USA)
Department of Chemistry and Biochemistry - University of California, Merced - MERCED - USA
GREEN Anthony P. (UK)
Department of Chemistry - Manchester Institute of Biotechnology - Manchester - UK
Enzymes are a type of protein found within all living cells. Often called biocatalysts, enzymes speed up the rate of biochemical reactions to help support life. Their unique structure imparts certain characteristics and makes them reactive to specific substrates, analogous to a lock and key model. The structure of enzymes is amenable to change, however it is not clear how structural changes in enzymes affect their efficiency (speed of reaction). Our team of interdisciplinary experts is proposing a unique approach to study the effect of structural changes in enzymes on their behavior by using a combination of state-of-the-art time-resolved X-ray crystallography and substrate engineering. This study will allow us to evaluate the link between structural changes and the catalytic efficiency of enzymes for various complex and multistep chemical reactions. The knowledge accrued through these experiments will enable us to predict the role of structural fluctuations in enzyme catalysis, and set the stage for the rational design of efficient artificial enzymes for applications in medicine and industry.
2022
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Grant Awardees - Program
Assembly, mechanics and growth of plant cell walls
COEN Enrico (UK)
Dept. of Cell and Developmental Biology - The John Innes Centre - Norwich - UK
COSGROVE Daniel J. (USA)
Biology - Pennsylvania State University - UNIVERSITY PARK - USA
DURAND-SMET Pauline (FRANCE)
Matter and complex systems - Université Paris Cité - Paris - FRANCE
SVAGAN (HANNER) Anna (SWEDEN)
Fibre and Polymer Technology - Royal Institute of Technology - Stockholm - SWEDEN
The shape and architecture of every plant depends on how its cells grow. The outer membrane of every plant cell is surrounded by a wall made of cellulose fibres embedded in a matrix, and neighbouring cells are stuck together so they cannot move. Despite these constraints, plants can generate remarkable shapes, from orchid flowers to tree canopies. These forms arise through a dynamic process in which the pressure within each cell causes the walls to stretch irreversibly, a process known as creep. Wall thickness is maintained through synthesis of new layers of fibers at the cell membrane, and partitioning walls are also added, preventing cells from becoming too large. Although the pressure in each cell acts equally in all directions, the wall fibers are not randomly arranged, causing cells to creep more in some orientations than others. The secret of plant shape therefore lies in how the cell walls are structured to yield with specific rates and orientations. Although much progress has been made in understanding how genes control these processes, we still lack a quantitative understanding of how growth of even a single plant cell is controlled. One difficulty is that cell wall properties depend on their history of formation, which is usually unknown. A further problem is that growth is modified by mechanical constraints and signals from neighbouring cells. This project aims to circumvent these problems by exploiting a simplified system in which the formation of a new wall can be followed from scratch. Protoplasts are single plant cells in which the walls have been digested away. Under the right conditions, protoplasts will regenerate their walls and exhibit oriented growth. Using the state-of-the-art techniques, we will quantify and perturb different components of the wall as it is made and measure its mechanical properties as it strengthens and begins to undergo creep. We will also synthesize simplified artificial plant cells and cellulose nanofiber networks to test hypotheses for how walls acquire their mechanical properties and the feedback mechanisms involved. By exploring hypotheses through computational modelling, we will evaluate which best predict experimental results and thus arrive at an integrated quantitative understanding of cell wall synthesis, assembly, mechanics and growth that underpins plant development.
2022
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Grant Awardees - Program
The social origins of rhythm
KING Stephanie (UK)
School of Biological Sciences - University of Bristol - Bristol - UK
MADSEN Peter Teglberg (DENMARK)
Dept. Of Biology, Section for Zoophysiology - Aarhus University - Aarhus - DENMARK
COOK Peter (USA)
Psychology - New College of Florida - Sarasota - USA
RAVIGNANI Andrea (ITALY)
Department Human Neurosciences - Sapienza University of Rome - Rome - ITALY
The enjoyment of music is ubiquitous across human societies and cultures. Among the (bio)cognitive underpinnings to process and enjoy music, rhythm plays a key role. In humans, musical beat processing intimately links perception and action when we entrain rhythmic movements to musical beats. In social settings, this leads to rhythmic actions within groups of people, such as dancing or marching in unison, but what selective pressures led to rhythmic behaviour to begin with, and why did the social use of rhythm evolve? The search for the origins of social rhythm is complicated because unlike other biological traits, rhythmic processing does not fossilize and humans only constitute one datapoint to build testable hypotheses on rhythm evolution. However, rhythmic processing is not unique to humans, with examples found across the animal kingdom. In this project, we will integrate approaches from field biology, comparative neuroscience, artificial intelligence, and speech sciences to test competing hypotheses on the evolutionary roots of rhythmic abilities. We will study a wide range of marine mammal species, known for their vocal flexibility but subject to differing social pressures, as a test-bench for evolutionary hypotheses on the origins of social rhythm in our own species.
2022
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Grant Awardees - Program
Bacterial genome editing systems as a driver of cancer mutations
GALUN Eithan (ISRAEL)
Director, Goldyne Savad Institute of Gene Therapy - Hadassah Hebrew University Hospital - Jerusalem - ISRAEL
DAGAN Tal (GERMANY)
Institute of Microbiology - Kiel University - Kiel - GERMANY
As life expectancy increases in the world, the likelihood that any individual will be diagnosed with cancer, or die from cancer related illness is high. Cancer development is associated with the occurrence of mutations, that develop in specific cell types in our body during aging. These mutations are the drivers of cancer development. Although we have a substantial knowledge as for the effect of mutations in specific genes on cancer propagation in the specific organs, we have no understanding why these specific genes are mutated and how mutations emerge. Our skin, gut and respiratory systems, are habitats to diverse bacteria that can interact with our organs. We know that bacteria can enter cells in our body in different organs. We also know that bacteria can secret different types of genetic cargo elements that can enter normal cells. The interaction between bacteria and human has been implicated in various states of health and disease. Here we aim to investigate whether bacteria and bacterial secreted elements may play a role in the emergence of cancer mutations. Our focus is on bacterial defense systems against their natural enemies: bacteriophages. To defend themselves against invading phages, bacteria evolved various mechanisms to cut and degrade phage DNA. Such systems have been adopted and utilized by scientists in order to engineer the genome of animals, plants and microorganisms with high precision. Bacteria that are associated with humans, also harbor such mechanisms; however, whether the DNA stored in our cells may be sensitive to bacterial defense systems is currently unknown. Can bacteria in the human microbiome manipulate our genome and initiate cancer development? In this program, two teams that never collaborated before, resolved to meet the challenges put forth by this hypothesis. The expertise of these teams are in very different scientific fields essential for investigating this project. The Dagan team in Kiel is a microbiological research group with knowledge in bacterial genetics and genomics, who will collaborate with the Galun team in Jerusalem that has the knowledge to establish cancer models in cell culture and mice. Together, the two teams will establish an experimental system to investigate the role of bacteria as drivers of mutagenesis in human tissues. Neither team alone is capable to conduct this program solely.
2022
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Grant Awardees - Program
Unravelling the code of mitochondrial-nuclear communication
LEFKIMMIATIS Konstantinos (GREECE)
Department of Molecular Medicine - University of Pavia - Pavia - ITALY
STÄDLER Brigitte (SWITZERLAND)
Interdisciplinary Nanoscience Center (iNANO) - Aarhus University - Aarhus - DENMARK
DASKALAKIS Nikolaos (GREECE)
NeuroGenomics & Translational Bioinformatics Laboratory - McLean Hospital/ Harvard Medical School - Belmont - USA
The energetic status of mitochondria often defines the outcomes of complex cellular responses. However, the modalities through which mitochondria-derived signals (retrograde signalling) are perceived by the nucleus and translated into specific transcriptional responses are poorly understood. A major roadblock in studying the crosstalk between these two organelles is our inability to isolate the messages they exchange from the background signalling events constantly taking place within the cell. We propose to overcome this issue with a bottom-up approach in which we will attempt to develop a synthetic, matrix-sustained two-organelle unit and use it as a platform to address a number of questions fundamental to mitochondrial and nuclear biology. By incorporating biosensors for small compounds that participate in mitochondria-nucleus crosstalk both, in the matrix and organelles, we will be able to identify the signalling molecules employed by these organelles under specific conditions (from nutrient availability to mitochondrial DNA damage). Similarly, by employing next generation single nucleus RNA sequencing we plan to identify the specific transcriptional signatures triggered by distinct mitochondrial changes in nuclei of the same background. We designed a collaborative research plan that builds across all three fields of expertise and combines cutting-edge techniques with conceptual perspectives. Städler, a materials chemistry expert, will develop the inter-organelle communication matrixes (IOCMs) and optimize the encapsulation of mitochondria and nuclei. Lefkimmiatis, a cell physiologist, will develop the biosensors, validate their functional incorporation in the support matrix and organelles, and will perform the imaging experiments for the identification of organelle-derived signals. Finally, Daskalakis, an expert in transcriptomics, will employ single nucleus RNA sequencing and bioinformatic analysis for recognizing the transcriptional signatures coupled to specific mitochondrial conditions. By working together, we will paint a comprehensive picture of how mitochondria and nuclei communicate as well as provide the scientific community with a platform that offers a controlled environment optimal for investigating complex communication pathways in the absence of background “signalling noise”.
2022
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Grant Awardees - Program
The walking fish: Integrating biomechanics, energetics and robotics to study water-land transition
DI SANTO Valentina (ITALY)
Department of Zoology - Stockholm University - Stockholm - SWEDEN
IIDA Fumiya (JAPAN)
Department of Engineering - University of Cambridge - Cambridge - UK
SHUBIN Neil (USA)
Department of Organismal Biology and Anatomy - The University of Chicago - Chicago - USA
The transition from water to land in vertebrates occurred over 370 million years ago, however many of the fundamental morphological and physiological traits necessary to life on land arose prior to the origin of land walking. Several groups of fully aquatic fishes walk underwater, raising the question of why and which traits fishes need to take advantage of this mode of locomotion. Unfortunately, no work to date has explored the energetic benefits of this fundamental behavior across different environments, hindering the capacity to test hypotheses on the performance of transitional forms found in the fossil record and to understand the ecology of many extant species. Moving over complex and three-dimensional structures of the natural environment requires adaptive locomotor behaviors, and it is unclear how fishes during their growth might take advantage of the complexity of the substrate of the oceans and littoral zones. How do walking fishes achieve these versatile locomotor behaviors when moving over substrates of different complexity? Is there an ontogenetic shift in walking performance? What is the cost of walking and how does it compare to swimming? Here, we propose a study on the effect of environmental plasticity of walking behavior and fin anatomy of a fish, Polypterus, reared under different substrate types (flat and 3D), underwater and semi-terrestrial. We will combine anatomical measurements, developmental biology, biomechanical and physiological analyses, and robotic platforms to show how energetically efficient it is for a fish to walk and swim over different substrates and media. Experimental data will guide the design of a robotic platform capable of both walking and swimming. We will develop the bioinspired soft robotic model (the “robofish”) to understand the relationship between mechanical features and how they interact with motor patterns to form adaptive behaviors over different substrates at different body sizes. The performance of the robofish will be compared to that of real fish across treatments, and this will form the basis to create a platform to compare locomotor efficiency and plasticity of extant and extinct species of fish and their closest relatives.
2022
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Grant Awardees - Program
Bridging biophysics and evolution: impact of intermediate filament evolution on tissue mechanics
TOMANCAK Pavel (CZECH REPUBLIC)
Max Planck Institute of Molecular Cell Biology and Genetics - Max Planck Society - Dresden - GERMANY
HEISENBERG Carl-Philipp (GERMANY)
Heisenberg Lab - IST Austria - Klosterneuburg - AUSTRIA
HEJNOL Andreas (GERMANY)
Department of Biologial Sciences/Comparative Developmental Biology - Friedrich Schiller University Jena - Jena - GERMANY
EXTAVOUR Cassandra (CANADA)
Dept. of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA
Interactions between mechanical and biochemical processes determine the shape of living matter. However, we do not understand how this interaction evolves to give rise to the large diversity of shapes of life. Our team will take a comparative approach at the interface between evolutionary developmental biology and biophysics to identify conserved and divergent mechanochemical interaction principles determining animal shape. Specifically, we will elucidate how the biochemical evolution of intermediate filaments (IFs) impacts the mechanical and morphogenetic properties of epithelial tissues undergoing spreading in different model and non-model organisms across the tree of life. Epithelial spreading, whereby a sheet of connected cells stretches to increase its surface area, is a common phenomenon in various developmental and disease-related processes, such as gastrulation, oogenesis and wound healing. IFs are generally thought to function in this process by providing epithelia with mechanical support, and to protect them from damage by external and internal forces. Our preliminary observations suggest that different mechanical properties of spreading epithelia in arthropods and vertebrates are associated to the presence of IFs in vertebrates, and their loss in arthropods. We thus hypothesize that the diversification of IFs is responsible for the evolution of species-specific mechanical properties of epithelial tissues determining their spreading behavior. We will test this hypothesis by strategically sampling species across animal phylogeny and determine how changes in IF biochemistry cause changes in epithelial mechanics and spreading. Finally, we will challenge this hypothesis by ambitious experiments where entire IF molecular machineries will be added to the genomes that do not have it, and examine the impact on epithelial tissue mechanics and morphogenesis. Our major innovation is bridging evolutionary biology and tissue biomechanics. This transdisciplinary approach will elucidate the physical basis for the genotype-phenotype relationship, revealing how mechanochemical processes evolve to yield diverse animal shapes. Our proposal combines the strengths of traditionally separate disciplines to investigate the morphogenetic role of IFs, central yet understudied cytoskeletal elements, across phylogeny.
2022
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Grant Awardees - Program
The evolution of sperm cell shape and motion
HUMPHRIES Stuart (UK)
Physical Ecology lab., College of Science, School of Life Sciences - Lincoln Institute for Advanced Studies - Lincoln - UK
SNOOK Rhonda (USA)
Dept. of Zoology - Stockholm University - Stockholm - SWEDEN
FAUCI Lisa (USA)
Dept. of Mathematics - Tulane University - New Orleans - USA
Across the tree of life, sperm show an unrivalled diversity of shapes and sizes greater than any other cell type. The reasons for such diversity remain elusive. Most work has focussed on simple sperm shape found in externally fertilizing invertebrates and internally fertilizing vertebrates, yet most diversity is found in internally fertilizing invertebrates, especially insects. Therefore to truly understand how and why different sperm shapes have evolved, we need to shift away from these historically studied animals and focus on the evolution of insect sperm. In this project we will test how sperm shape and size variation has evolved and more specifically, how it allows sperm to perform their ultimate function – fertilisation. To do so, we will unite researchers from three differing disciplines: biophysics, evolutionary ecology, and mathematics. A biophysics approach will allow us to test how the sperm swim, and determine how the reproductive fluid and reproductive tracts they move in shape these movements. An evolutionary ecology focus will allow us to test how both large- and small-scale evolutionary variation in sperm shape is linked to coevolution with the fertilization environment of the female. The fundamental integration of mathematics across and within our projects will provide synthesis of empirical work and generate new predictions of how the combination of sperm shape and motion, reproductive tract structure, and competition between multiple sperm affect reproductive performance. Only by combining these three disciplines can we truly understand this sperm diversity for the first time. Novel experimental devices, microscale measurements of fluid properties, genetic studies and computational modelling will allow us to chart the evolution of sperm shape, understand how sperm form and female reproductive tracts evolved together, and to link all of these to predict and understand how sperm performance is determined.
2022
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Grant Awardees - Program
Multi-omic reconstruction of flow across the distributed metabolism of early-branching Dracula ants
LEBOEUF Adria (USA)
Department of Biology - University of Fribourg - Fribourg - SWITZERLAND
FISHER Brian Lee (USA)
Entomology - California Academy of Sciences - San Francisco - USA
TEUSINK Bas (NETHERLANDS)
Amsterdam Institute of Molecular and Life Science (AIMMS) - VU University Amsterdam - Amsterdam - NETHERLANDS
Many successes in life are based on collaboration – this extends to the molecular level, where life is fueled by the chemical processes collectively called metabolism. Microorganisms exchange nutrients through cross-feeding, and multicellular organisms are made up of tissues with different metabolic roles and needs. Social insects, where the notion of self is distributed over multiple individuals, take this collaboration still further: Many ant colonies engage in social exchanges of experimentally accessible fluids that contain both exogenously sourced and endogenously produced materials. Larvae of many social insects have been purported to be a ‘digestive caste.’ They are fed exogenously sourced food by adults and return a nutritious fluid whose metabolic functions remain unestablished. The mode of transmission from larvae to adults varies across ant species: In some, larvae voluntarily secrete fluids, while in early-branching ‘Dracula’ ants, adults non-destructively drink larval hemolymph. Such socially exchanged fluids can be analysed to monitor the fluxes of distributed metabolism, making ant colonies apt model systems to study the molecular mechanisms of inter-system communication and division of metabolic labor. We address three key questions (i) what is being exchanged? (ii) what are the functional implications of these exchanges? and (iii) how did these modes of exchange evolve? We combine behavior observations with detailed molecular analyses of four species representing different social feeding modes and evolutionary lineages. We perform proteomics and metabolomics on each colony-tissue and exchanged fluid. Based on genomes and gene expression, we reconstruct metabolic networks for advanced multi-omic data integration to identify active pathways. Novel community-scale metabolic modeling will be used to probe colony-level functionality of social exchange. Critical pathways will be validated with fluorescent metabolite probes in an automated colony- and transmission-tracking system and by genetic or feeding perturbations. This project offers new ways to view social behavior, evolutionary biology, metabolism and the physics of collective behavior. Ultimately, this work will innovate by elucidating the functional role of distributed metabolism, probing its evolution, and providing new tools to study community-level metabolic interactions.
2022
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Grant Awardees - Program
Intracellular voltage control of directional cell migration
SAEZ Pablo (CHILE)
Department of Biochemistry and Molecular Cell Biology (IBMZ) / Cell Communication and Migration lab - University Medical Center Hamburg- Eppendorf | UKE - Hamburg - GERMANY
KRISHNAN Yamuna (INDIA)
Department of Chemistry - Gordon Centre for Integrative Science - Chicago - USA
GOV Nir (ISRAEL)
Department of Chemical and Biological Physics - Weizmann Institute of Science - Rehovot - ISRAEL
Cell migration is pivotal to wound healing, the immune response, and cancer. When a cell moves within a tissue it experiences a complex landscape, facing barriers as well as other cells in set topologies. When cells are moving towards a designated target - referred to as directional migration - they are attracted by specific chemical cues. These cues compel cells to adopt a preferred path along which they often face obstacles that generate bifurcating arms, of which one emerges as the winning direction. One way that cells sense barriers is by activating ion channels on their surface, which changes the membrane potential (MP) across the cell membrane. Due to the lack of tools it was so far impossible to expose the links between MP and directional migration. Ion channels on organelles can also contribute to changes in MP. Migrating cells use polarity as a navigation system, which in turn, is reflected in the organization of organelles - raising exciting questions. How do single cells choose a direction of migration? Do changes in MP at the cell surface and in organelles regulate this decision? Is there a cell-surface-to-organelle axis of communication that drives this decision? We propose to study how cells choose a direction between competing arms formed during movement. We posit that when a moving cell faces a bifurcation, ion channel activity at the plasma membrane changes MP, modifies the local actin flow, thereby contributing to the process of favoring an arm that sets the direction (similar to the front wheel and handle of a bicycle), while organelles at the cell rear respond and contribute to the forward movement (analogous to the back wheel of a bicycle). To test this idea, we will use new technologies that measure MP on the cell surface and in organelles of cells while they are migrating and choosing a direction. The data obtained will be integrated into a theoretical model, which we expect will describe and predict the direction of migration. Indeed, the ability to predict cell migration is an essential precursor to controlling its movement. Controlling cell movement can lead to accelerated wound healing, prevention of metastasis or sculpting of the immune response.
2022
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Grant Awardees - Program
Trichomes: uncovering principles of forming complex 3-dimensional shapes by cellular morphogenesis
GROSSNIKLAUS Ueli (SWITZERLAND)
Institute of Plant and Microbial Biology - University of Zurich - ZURICH - SWITZERLAND
KONDO Shigeru (JAPAN)
Frontier Bioscience - Osaka University - Suita - JAPAN
While experimental and theoretical studies have provided a deep understanding of the three-dimensional formation of tissues and organs, it largely remains a mystery how a single cell acquires its particular shape. One reason is that the complexity of cellular morphogenesis makes a mathematical description difficult because, in contrast to tissues, cells cannot be used as units in the mathematical model. Furthermore, the many processes that occur simultaneously in a single cell and influence each other, necessitate multi-component, interrelated models. Finally, locally restricted manipulations in specific regions of the cell are required to test certain aspects of the models for cellular morphogenesis. It is thus clear that solving such a complex problem depends on advances in both theory and experiment, requiring a research environment where theoreticians and experimentalists work closely together. We will tackle this problem through cooperation of the Grossniklaus and Kondo groups, specializing in plant developmental biology and mathematical modeling, respectively. The Grossniklaus group will use cell biological, biophysical, and photochemical approaches to investigate the individual processes of trichome morphogenesis. The Kondo group will perform simulations to understand how individual phenomena are integrated to produce the complex morphology of trichomes. Through this interdisciplinary collaboration, we will shed light onto the fundamental principles of cellular morphogenesis.
2022
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Grant Awardees - Program
Molecular determinants of evolutionary conservation in disordered protein regions
HOLEHOUSE Alex (UK)
Dept. of Biochemistry and Molecular Biophysics - Washington University School of Medicine - St. Louis - USA
LEE Hyun (KOREA, REPUBLIC OF (SOUTH KOREA))
Biochemistry - University of Toronto - Toronto - CANADA
WEIJERS Dolf (NETHERLANDS)
Laboratory of Biochemistry - Wageningen University - Wageningen - NETHERLANDS
Intrinsically disordered regions (IDRs) are a ubiquitous class of protein domains found in the majority of eukaryotic proteins. Unlike folded regions, IDRs exist in a conformationally heterogeneous collection of states and lack a single canonical structure. IDRs play essential roles in a wide variety of cellular processes, from the immune response to transcriptional regulation to cell division. Despite their prevalence and crucial cellular roles, our understanding of how IDRs work and what they do in any given context is still in its infancy. Understanding a protein’s function is analogous to understanding that protein’s evolutionary constraints. Evolutionarily significant features are by definition important for protein function, either directly (i.e., catalytic residues in enzymes) or indirectly (i.e., protein stability in folded domains). Given our limited understanding of protein function, it should be of no surprise that our understanding of IDR evolution is also minimal. Rather than a problem, we propose this offers an incredible opportunity to take advantage of evolutionary selection as a design principle that selects for functionally important IDR features. To do this, we require a model system where IDRs are present, essential, and play similar roles across divergent evolutionary organisms. Plant AUXIN RESPONSE transcription FACTORs (ARFs) represent an evolutionarily ancient set of transcription factors that regulate almost every aspect of plant development. ARFs contain folded and well-characterized DNA binding domains, yet most also contain large IDRs that are poorly conserved by any kind of standard alignment-based metric. Importantly, ARF IDRs are critical for normal development. As a result, ARFs offer an unprecedented model to elucidate the determinants of functional selection on IDRs. Our project will integrate molecular biophysics, rational sequence design, and organismal physiology to uncover how changes in ARF IDRs conspire to determine evolutionary fitness.
2022
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Grant Awardees - Program
Physical regulation of the genome
HOLT Liam (USA)
Dept. of Biochemistry & Molecular Pharmacology, Institute for Systems Genetics - New York University School of Medicine - New York - USA
LEVY Emmanuel (FRANCE)
Dept. of Structural Biology - Weizmann Institute of Science - Rehovot - ISRAEL
TAKINOUE Masahiro (JAPAN)
Department of Computer Science - Tokyo Institute of Technology - Yokohama - JAPAN
Textbook models for biological regulation emphasize active mechanisms of signal transduction and chemical signaling, such as protein phosphorylation. However, cells could also achieve control at a more fundamental level by directly sensing changes to the intracellular physical environment. The cell is highly crowded and far from thermodynamic equilibrium. Molecular crowding decreases molecular motion, and also drives interactions through depletion-attraction. We found that crowding is actively regulated in the cell and can tune phase separation. Active processes increase the effective temperature in the cell, helping to fluidize this extreme environment, and depletion of ATP can lead to glass transitions. Therefore, we hypothesize that the interplay between molecular crowding and active processes plays a global role in determining the rates of biochemical reactions. These effects strongly depend on length-scale, such that each biochemical process can potentially respond differently to physical perturbations depending on the size of molecules involved. Thus, the cell can evolve to increase the rates of some reactions and decrease the rates of others in response to changes in crowding or effective temperature. While appealing, the degree to which changes in the physical environment directly regulate biology has been challenging to test in vivo. Indeed mutation of endogenous molecules that impact the material properties or effective temperature of the nucleus necessarily interfere with host biology, leading to pleiotropic effects and making interpretation impossible. To solve this problem, we will: (i) reconstitute transcription within synthetic DNA nanostructure condensates in vitro (Takinoue lead); (ii) develop analogous protein condensates that anchor to specific DNA loci in vivo (Levy lead); and (iii) leverage large-scale genome engineering (Holt lead) to directly address the hypothesis that transcription can dynamically respond to changes in the physical properties of the environment. More generally, responsiveness of biochemistry to physical regulation could represent a primordial and universal level of regulation. Understanding the principles of physical regulation could help elucidate many unresolved conundrums in biology from cell-size control to mechanobiology and this knowledge would significantly improve our ability to engineer cellular systems.