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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2023
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Grant Awardees - Program
From diffuse to localised signalling: The origin of synaptic neurotransmission in animals
WATANABE Shigeki (.)
Johns Hopkins University School of Medicine - Baltimore - United States
IKMI Aissam (.)
European Molecular Biology Laboratory (EMBL-Heidelberg) - . - .
MUSSER Jacob (.)
Yale University - . - .
The evolution of the nervous system is one of the remaining great mysteries of animal evolution. A key step was evolution of the chemical synapse, which enabled the transition from ciliomotor-based movement by diffusive signals to muscle-based locomotion driven by ultrafast localised signals. However, current understanding of this transition is mostly limited to determining the distribution of synaptic genes in early animal genomes, revealing most predate synapses. There are two competing hypotheses for how chemical synapses evolved. The first, termed the “chemical brain hypothesis”, proposes animal behaviour was initially controlled by paracrine cell networks using volume (non-synaptic) signalling. The second, termed the “protosynaptic hypothesis”, proposes that synaptic architecture already existed prior to the origin of true nervous systems, and facilitated some form of directional signalling. To test these hypotheses, we integrate expertise in synaptic dynamics and physiology, functional proteomics, and transgenesis techniques in early animals to uncover how synaptic signalling is achieved in the first animals without synapses (sponges) and those with synapses (cnidarians). To accomplish this, we will reconstruct the ancestral dynamics and localisation of synaptic protein complexes, discover the origins of ultrafast mechanisms for synaptic exo- and endocytosis, and determine the role of electrical potentials in propagating the first synaptic signals. In summary, our study aims to reveal the mechanisms underlying the origin of synaptic transmission with broad implications for the evolution of animal behaviours.
2023
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Grant Awardees - Program
Shiny signalling: the production, detection and neurobiological processing of brilliant colours
VAN DER KOOI Casper J. (.)
University of Groningen - Groningen - NETHERLANDS
KINOSHITA Michiyo (.)
The Graduate University for Advanced Studies, SOKENDAI - . - .
KEMP Darrell (.)
Macquarie University - . - .
Why do some organisms have shiny colours and others do not? Shiny colours are displayed across a suite of plants and animals, including the flowers of buttercups, orchids and tulips, the wings of butterflies, and the surfaces of beetles. The visual appearance of these organisms is dominated by a flash, which entails a bright pulse of polarised light with a strong angular dependence. The dynamic nature of such “flashy” effects presents a paradox in visual ecology, because although flash effects likely enhance long-range signal visibility, they may undermine the ability to locate objects at close range. This may help explain why colours with a matte appearance prevail in nature, yet the repeated independent evolution of shiny colours implies a fundamental, possibly universal adaptive benefit for signal dynamicity per se. Our project will constitute the most integrative cross-taxon approach to understanding the basis of this adaptive benefit conducted to date.
We will achieve an integrative understanding of the ecological significance of flashy colours by: (1) characterising the optical properties of sexually deceptive flowers and relating these to their insect models; (2) quantifying how flower gloss determines the long-distance visibility and short-distance discriminability of flowers to insect pollinators; (3) determining the behavioural significance of flashy colours in insect visual ecology; and (4) elucidating how the insect brain processes bright flashes. Hence, we will trace the full pathway from how such signals are generated to how they ultimately elicit fitness effects in their relevant viewers. This breadth of insight is only possible by integrating our collective expertise in biophysics (van der Kooi), behavioural ecology (Kemp) and neurobiology (Kinoshita), which is precisely why this project promises unprecedented insight into a (literally) brilliant phenomenon that has fascinated researchers for centuries.
2023
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Grant Awardees - Program
Intracellular selection and dynamics of mitochondrial ageing
OSMAN Christof (.)
Ludwig Maximilian University Munich (Ludwig-Maximilians-Universität München, LMU) - Munich - GERMANY
KRIEG Michael (.)
ICFO – The Institute of Photonic Sciences - . - .
SHRAIMAN Boris (.)
The Regents of the University of California, Santa Barbara - . - .
Eukaryotic cells contain multiple mitochondrial genome (mtDNA) copies, which encode proteins required for mitochondrial energy production. Maintaining intact mtDNA is critical for cellular and organismal health and its deterioration has been linked to cellular aging. mtDNA is known to mutate at an elevated rate, but extensive evidence also suggests the existence of processes, acting on cellular and subcellular levels, that eliminate damaged mtDNA thus acting to rejuvenate mitochondria. Yet mtDNA integrity declines during ageing, but the timecourse of its decay and the underlying mechanisms remain largely unknown, because of challenges presented by the complex and quantitative nature of involved phenotypes. This project will address these challenges through a multidisciplinary approach that applies yeast as a model organism and combines novel mtDNA-based reporters, special purpose optofluidic devices and advanced mathematical modelling. Our goal is to understand (a) the link between mtDNA decay and physiological changes associated with the ageing process at the single cell level; (b) the mutational events that drive mtDNA decay with single cell sequence resolution and (c) the processes that facilitate intracellular selection against mutant mtDNA and their role in suppressing mtDNA decay during ageing.
Specifically, we will use mtDNA-based fluorescent reporters for mtDNA copy number and expression to infer mtDNA health throughout the ageing process while monitoring the decline of physiological parameters in single cells. To do so, we will develop a novel device that combines optofluidics with advanced fluorescence microscopy to monitor, select and sort single cells during the ageing process and eventually subject them to whole genome amplification and sequencing in a highly parallelized manner to determine mtDNA sequence changes. This will allow us to monitor mitochondrial function and mtDNA variation with cell age and between ancestrally related cell lineages. Resulting data will be analyzed quantitatively with the help of mathematical models of mtDNA propagation within cells, including effects of mutation, selection and random drift, which will enable us to specifically address the role of intracellular purifying selection in extending the mitochondrial healthspan of a cell. Our findings will provide broad fundamental insight into mitochondrial biology.
2023
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Grant Awardees - Program
Exploring the evolution and physiology of the olfactory-immune system connection
MUKHERJEE Tina (.)
Institute For Stem Cell Science and Regenerative Medicine, inStem - Bangalore - INDIA
MATTHEWS Ben (.)
University of British Columbia - . - .
RECKER Mario (.)
University of Exeter - . - .
TRINDADE MARQUES João (.)
Universidade Federal de Minas Gerais, Instituto de Ciencias Biologicas - . - .
Aedes aegypti mosquitoes, the major vector for many important diseases, such as Zika and dengue, exist as two separate subspecies, one domestic and another sylvatic, that differ in their olfactory system. Notably, the adaptation to human blood feeding (anthropophilia) in the domestic subspecies is linked to the expression and specificity of an odorant receptor and correlates with increased ability to acquire and transmit viruses, commonly referred to as vector competence. While evolution of immune modulation by the olfactory system is poorly understood, recent findings in fruit flies have alluded to a role of olfaction in promoting anti-pathogenic immunity. We hypothesize that the olfactory and immune systems are connected in Ae. aegypti mosquitoes and that the changes leading to anthropophilia also affected antiviral immunity, resulting in higher susceptibility to and increased transmission of viral infections. In this proposal, we will use a multi-disciplinary approach to identify and functionally characterize the connection between the olfactory and immune systems in the context of antiviral defenses in Ae. aegypti mosquitoes and in the Drosophila model system. We will further investigate the association between olfactory-linked immune modulation and anthropophilic preferences in Ae. aegypti mosquito subspecies and its consequence for arboviral disease epidemiology. Combining comparative genetic, olfactory, virological and immunological analyses, synthesized in an evolutionary modelling framework, this innovative program of work will address a major gap in our understanding of the impact of environmental odor sensing on the immune system and antiviral defense. As such it will shed new light on the evolution of vector competence in Ae. aegypti and could lead to the development of novel strategies to control the transmission of mosquito-borne viruses.
2023
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Grant Awardees - Program
Unraveling the mechanism of schistosome egg migration in a complex host environment
OKEYO Kennedy (.)
Purdue University, West Lafayette, IN - West Lafayette - United States
OCHOLA Lucy (.)
Strathmore University -CREATES - . - .
Schistosomes, the parasitic trematodes which cause the chronic infection schistosomiasis –a major neglected tropical disease affecting more than 200 million people worldwide, have a complex life-cycle involving infection of an aquatic snail intermediate host and a definitive mammalian host. Despite lacking apparent locomotory mechanism, schistosome eggs are able to transit through gastrointestinal tissues into the lumen for excretion, a journey that clearly presents an evolutionary challenge to the parasites. How the eggs are able to translocate in the gut remains unresolved puzzle. In this study, we aim to clarify the migratory mechanism of schistosome eggs from the perspective of tissue mechanics. We posit that anisotropic cell clustering and fibroblast-dependent changes in tissue mechanics following immune reaction to egg deposition may confer a propulsive advantage to the eggs, enabling them to tactfully transit through the host tissues. To clarify the role of fibroblasts in this process, we aim to develop both in vitro and in vivo models, and use them to track fibroblast migration spatiotemporally. First, we will establish a 3D microphysiological system that recapitulates the gastrointestinal tissue where egg migration takes place in vivo. Next, we will deploy the technique of 3D traction force microscopy integrated with atomic force microscopy to map the forces generated around a migrating egg, and correlate them with fibroblast dynamics. Finally, by integrating data from timelapse live cell imaging, cell migration tracking, force mapping, immunological characterization and genetic profiling, we will characterize fibroblasts movement and contractile force generation during granuloma formation and egg migration. Ultimately, we will develop a quantitative mechanistic model of egg migration based on tissue mechanics. Clarifying the egg propulsion mechanism will complement past and on-going biological studies, leading to a better understanding of how schistosomes adapt and exploit the symbiotic relationship with the host to continue their complex life cycle. In addition, since fibroblasts are gaining scientific attention for their role in aiding cancer development, clarifying their role in the propulsion of Schistosoma eggs will deepen our understanding of fibroblast contribution to the development of other diseases such as cancer and tuberculosis (TB).
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.