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Awardees

2022 -
Grant Awardees - Program

Multi-omic reconstruction of flow across the distributed metabolism of early-branching Dracula ants

FISHER Brian Lee (USA)

Entomology - California Academy of Sciences - San Francisco - USA

LEBOEUF Adria (USA)

Department of Biology - University of Fribourg - Fribourg - SWITZERLAND

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 -
Grant Awardees - Program

Intracellular voltage control of directional cell migration

GOV Nir (ISRAEL)

Department of Chemical and Biological Physics - Weizmann Institute of Science - Rehovot - ISRAEL

KRISHNAN Yamuna (INDIA)

Department of Chemistry - Gordon Centre for Integrative Science - Chicago - USA

SAEZ Pablo (CHILE)

Department of Biochemistry and Molecular Cell Biology (IBMZ) / Cell Communication and Migration lab - University Medical Center Hamburg- Eppendorf | UKE - Hamburg - GERMANY

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 -
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 -
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 -
Grant Awardees - Program

Physical regulation of the genome

HOLT Liam (USA)

Dept. of Biochemistry & Molecular Pharmacology, Institute for Systems Genetics - New York University School of Medicine - New York - USA

LEVY Emmanuel (FRANCE)

Dept. of Structural Biology - Weizmann Institute of Science - Rehovot - ISRAEL

TAKINOUE Masahiro (JAPAN)

Department of Computer Science - Tokyo Institute of Technology - Yokohama - JAPAN

Textbook models for biological regulation emphasize active mechanisms of signal transduction and chemical signaling, such as protein phosphorylation. However, cells could also achieve control at a more fundamental level by directly sensing changes to the intracellular physical environment. The cell is highly crowded and far from thermodynamic equilibrium. Molecular crowding decreases molecular motion, and also drives interactions through depletion-attraction. We found that crowding is actively regulated in the cell and can tune phase separation. Active processes increase the effective temperature in the cell, helping to fluidize this extreme environment, and depletion of ATP can lead to glass transitions. Therefore, we hypothesize that the interplay between molecular crowding and active processes plays a global role in determining the rates of biochemical reactions. These effects strongly depend on length-scale, such that each biochemical process can potentially respond differently to physical perturbations depending on the size of molecules involved. Thus, the cell can evolve to increase the rates of some reactions and decrease the rates of others in response to changes in crowding or effective temperature. While appealing, the degree to which changes in the physical environment directly regulate biology has been challenging to test in vivo. Indeed mutation of endogenous molecules that impact the material properties or effective temperature of the nucleus necessarily interfere with host biology, leading to pleiotropic effects and making interpretation impossible. To solve this problem, we will: (i) reconstitute transcription within synthetic DNA nanostructure condensates in vitro (Takinoue lead); (ii) develop analogous protein condensates that anchor to specific DNA loci in vivo (Levy lead); and (iii) leverage large-scale genome engineering (Holt lead) to directly address the hypothesis that transcription can dynamically respond to changes in the physical properties of the environment. More generally, responsiveness of biochemistry to physical regulation could represent a primordial and universal level of regulation. Understanding the principles of physical regulation could help elucidate many unresolved conundrums in biology from cell-size control to mechanobiology and this knowledge would significantly improve our ability to engineer cellular systems.
2022 -
Grant Awardees - Program

Bridging robotics and pollination: Reconstructing a bee’s buzz through micro-robots

JAFFERIS Noah (USA)

Electrical and Computer Engineering - University of Massachusetts Lowell - Lowell - USA

VALLEJO-MARIN Mario (MEXICO)

Dept. of Ecology and Genetics - University of Uppsala - Uppsala - SWEDEN

Bees provide essential services for pollination of both wild and agricultural systems, yet many wild bee populations are currently under threat. There are more than 20,000 species of bees worldwide and understanding how their morphological and ecological diversity translates to variation in function is of timely and urgent importance. Our project leverages a novel implementation of micro-robotics across a multispecies comparison of bees in two continents to disentangle the mechanistic function of buzz pollination, a type of pollination in which bees use powerful vibrations to shake pollen out of flowers. Approximately half of the 20,000 species of bees are thought to be able to buzz pollinate flowers of both wild and agricultural plants (e.g., tomato). These bees encompass an impressive range of morphological diversity, from sweat bees with body sizes of a few tens of milligrams in weight to large bumblebees and massive carpenter bees an order of magnitude heavier. Progress in the study of buzz pollination has been limited by the technical capacity to apply vibrations to flowers in a bee-like manner due to the reliance on large, cumbersome table shakers to mimic bee vibrations. Our project is set apart from previous work by using micro-robotic buzzers designed to capture the main properties of bee pollination buzzes using bee-scale vibrating and grasping mechanisms developed as part of the proposed work. This new approach will allow us to synthesise and apply vibrations capturing the diversity of buzzes produced by evolutionarily diverse types of bees sampled in the UK and North America. We will also investigate how these variations in the vibrations produced by the micro-robotic buzzers determine pollen release from buzz pollinated flowers, allowing us to link bee diversity, mechanical and vibrational properties, and pollen release function. Our project is built upon an international collaboration that brings together expertise in robotics and bee pollination to pursue a multidisciplinary use of micro-robotics for studying the functional diversity in a type of pollination involving thousands of bee and plant species around the world.
2022 -
Grant Awardees - Program

Regulation of neuronal physiology by the electromechanical effects of the action potential

LOIS Carlos (SPAIN)

biology and biological engineering - california institute of technology - Pasadena - USA

ROYLE Stephen (UK)

Centre for Mechanochemical Cell Biology - Warwick Medical School - Coventry - UK

SEZGIN Erdinc (TURKEY)

SciLifeLab - Karolinska Institute - Stockholm - SWEDEN

Cell signaling has traditionally been thought to exclusively depend on biochemical processes, but in recent years we have begun to appreciate how physical forces can control cell-cell communication. Mechanical forces generated by cells regulate many physiological processes, including selection of optimal antibodies by lymphocytes, sorting of chromosomes and organelles within the cell, and blood clotting in response to turbulence. Among all cells, neurons and muscle cells have special features because they have excitable membranes capable of generating large voltage fluctuations (~100 mV) known as action potentials. Over the past decades, researchers have accumulated evidence that action potentials generate membrane movements up to 100 angstroms. However, it remains unknown what are the biological consequences of this neuronal electromechanical force. The central hypothesis of this proposal is that the membrane motions associated with action potentials generate mechanical forces that regulate the intercellular communication between neurons and intracellular signaling events within individual neurons. To investigate how the mechanical force of action potentials regulates intercellular communication we will focus on the activation of the mechanoreceptor Notch, a key molecule involved in cell-cell interactions. To explore the effects of the neuronal electromechanical forces on intracellular signalling, we will focus on the regulation of membrane trafficking processes, including endocytosis and sorting of intracellular vesicles. To investigate these issues we have assembled a team with expertise on different aspects of cellular signalling including membrane biophysics, single-particle imaging in living cells, and neurophysiology. A central goal of the proposal is to take advantage of new technologies that can be used to investigate the regulation of cell physiology at several scales of biological complexity, spanning individual molecules, living cells, and transgenic animals. We anticipate that this research will provide unanticipated insights about how mechanical forces control intercellular and intracellular signaling events in neurons.
2022 -
Grant Awardees - Program

Super-resolution multifunctional scanning ion conductance microscopy: tapping the cell's energy grid

MACHESKY Laura (USA)

Migration, invasion and metastasis lab - CRUK Beatson Institute - Glasgow - UK

SASAKI Atsuo (JAPAN)

Department of Internal Medicine / Cancer Energy Metabolism Lab. - University of Cincinnati College of Medicine - Cincinnati - USA

TAKAHASHI Yasufumi (JAPAN)

Graduate School of Engineering Electronics - Nagoya university - Kanazawa - JAPAN

Cells show a remarkable resiliency when energy-starved, maintaining their ability to migrate to a new energy-rich environment, where they can re-purpose their cytoskeleton to take up nutrients via macropinocytosis. ATP and GTP are the major energy currencies of the cell, driving motor activity, cytoskeletal polymer dynamics and signaling. While the cell generally maintains robust global levels of ATP and GTP in nutrient-starved conditions, it is the local concentrations and ratios of ATP/ADP and GTP/GDP that drive motility and signaling. Multiple parameters control ATP/GTP flux, including: -Diffusion -Biosynthesis vs consumption -Shuttling and compartmentation However, how the cell meets energy demand is largely unclear, because we lack tools to measure multiple parameters simultaneously at sub-cellular resolution over time in live cells. Our multidisciplinary team, with expertise in motility (Machesky), metabolism (Sasaki), and Scanning Ion Conductance Microscopy (SICM) (Takahashi) will address this unmet need. SICM offers advantages of measurements without perturbation, correlation with high-resolution confocal imaging and simultaneous measurement of multiple parameters. Our team will thus engineer the first live single-cell multiscale platform, using cellular feedback to guide sampling and stimuli, providing the means to acquire a holistic view of cellular energy flux. We have two main objectives, each with new technology driven by our biological questions. Objective 1. Develop metabolic and protein mapping SICM to discover how cells use membraneless compartmentation to control metabolite supply and demand at the leading edge. We will establish how diffusion, biosynthesis and consumption generate and maintain intracellular nucleotide gradients using subcellular metabolic sampling SICM. We also probe subcellular localization and organization of metabolic enzymes, using femtoliter scale subcellular protein proximity labelling. Objective 2. Develop cell-to-machine feedback loop controlled SICM to determine how a cell decides to walk or to eat Using cell feedback guided SICM, we discover how mechanosensing via plasma membrane tension, integrins and the cytoskeleton, as well as nutrient sensing, allowing the cell to either locomote or use its cytoskeleton to perform nutrient uptake via macropinocytosis.
2022 -
Grant Awardees - Program

Mental 3D space-time travel in fission-fusion animal societies

MOSS Cynthia (USA)

Dept. of Psychological and Brain Sciences - Johns Hopkins University - Baltimore - USA

PEREMANS Herbert (BELGIUM)

Dept. of Engineering Management - University of Antwerp - Antwerp - BELGIUM

VON BAYERN Auguste (GERMANY)

Dept. of Behavioural Ecology and Evolutionary Genetics - Max-Planck-Institute for Ornithology - Seewiesen - GERMANY

WAHLBERG Magnus (SWEDEN)

Marine Biological Research Center - Dept. of Biology - Kerteminde - DENMARK

Flying and swimming animals can move freely in three-dimensional space, but their ability to use past information to inform future decisions remains largely unknown. Time flows in one direction, and no living creatures can physically move backwards into the past or forwards into the future. Animals can, however, use memories to adapt their behavior in future events. For humans, it is even possible to mentally travel backwards and forwards in time; we can ‘see’ ourselves in past situations and foresee ourselves in future ones. Mental time-travel is regarded as a fundamental property of human success, enabling us to organize societies and travel to the moon. Here we study to what degree other animals possess mental time travel abilities. We study dolphins, bats and parrots, which all travel and forage in 3-D space and live in large groups where they are constantly engage in social interactions, both cooperation and competition. Any degree of mental time travel abilities would be advantageous for them to anticipate the best solutions in the execution of future tasks. We investigate how our model species perceive time, and any evidence for them making use of episodic memory and perform future planning. By using similar experimental approaches for all model species, we compare mental time travel in animals living in vastly different environments and exposed to a large variety of challenges. By comparing the performance of our model species, we can decipher the underlying evolutionary mechanisms and requirements for mental time travel. We will use the results of our investigations to construct robots that exhibit different degrees of mental time travel functions. By studying the success rate with which robots solve problems, and by manipulating the robots’ abilities to mentally travel in time and collaborate, we will aim to pinpoint which mental time travel traits are most pertinent for solving different types of problems. The robot studies not only inform us about how our model species function, but may also inspire the development of robots that successfully solve difficult problems requiring complex decision-making, such as responding appropriately in emergency situation and executing complex construction operations.
2022 -
Grant Awardees - Program

New ways to generate color: light manipulation by crystal-forming pigments

PALMER Benjamin (UK)

Department of Chemistry - Ben-Gurion University of the Negev - Rehovot - ISRAEL

STUART-FOX Devi (AUSTRALIA)

School of Biosciences - The University of Melbourne - Melbourne - AUSTRALIA

TZIKA Athanasia (GREECE)

Department of Genetics and Evolution - University of Geneva - Geneva - SWITZERLAND

Recently discovered organic crystals in the eyes of shrimp exhibit remarkable optical properties, never observed in synthetic materials. Intriguingly, the same crystal-forming pteridine pigments are abundant in the skin of many vertebrates. Pteridines are the dominant class of pigment within the xanthophore pigment cells of reptiles, amphibians and fish; yet the optical properties of crystalline pteridines remain completely unexplored. How do these pigments contribute to vivid skin colors and what is the mechanism of molecular self-assembly? We seek to answer these questions by integrating comparative biology, materials chemistry, optics, molecular evo-devo and transcriptomics, and exploiting opportunities provided by reptilian models. In Aim 1, we will characterize the ultrastructure of pigment cells and the chemical, material and optical properties of crystalline pteridine pigments for multiple dragon lizard species and color forms of the corn snake. We will relate the optical properties of pteridine crystals within xanthophore pigment cells to those of guanine crystals within iridophore pigment cells. Aim 1 will enable us to integrate pigment-structure interactions at different scales of structural organization (cellular ultrastructure and subcellular optics) to produce a comprehensive model of skin color generation in reptiles. By discovering the special optical properties that arise from the crystallinity of certain pigments and their ordered assembly, we will reveal new ways that vertebrates generate vivid colors. In Aim 2, we will elucidate the formation and molecular control of crystalline materials within pigment cells throughout ontogeny in bearded dragons and corn snakes. Currently, we do not know what proteins control crystal nucleation, growth or assembly or which proteins are involved in transport of molecular precursors. Understanding the link between gene and crystal ‘phenotype’ would reveal how organisms exquisitely regulate the formation and properties of molecular crystals. This new and exciting connection between molecular biology and materials science could pave the way for the development of genetic tools to design new synthetic molecular crystals.
2021 -
Grant Awardees - Program

Maintenance, homeostasis and heredity of mitochondria and their genomes

BADRINARAYANAN Anjana (INDIA)

National Centre for Biological Sciences - TIFR - Bangalore - INDIA

MANLEY Suliana (USA)

Dept. of Institute of Physics - Ecole Polytechnique Federale de Lausanne (EPFL) - Lausanne - SWITZERLAND

MARSHALL Wallace (USA)

Dept. of Biochemistry and Biophysics - University of California San Francisco - San Francisco - USA

PAULSSON Johan (SWEDEN)

Dept. of Systems Biology, HMS - Harvard University - Boston - USA

Mitochondria are central to modern eukaryotic life. As self-reproducing organelles with their own DNA, they must prevent damage and fluctuations in copy number from accumulating, while their network is locally sculpted through fission and fusion. Yet, even the most basic mechanisms of control are largely unknown, leaving many key questions unanswered. What mechanisms exist to ensure inheritance of genetic material between mitochondria, and mitochondria between cells in the face of segregation errors and noise? Self-replication is dynamically unstable in the absence of feedback control, and multilevel segregation requires multilevel control. How does the mitochondrial genome maintain its integrity? Genotypic selection of a heteroplasmic population of mitochondria post-mutation reflects a process similar to the neutrally stable dynamics behind mutual exclusion in ecological systems. How do mitochondria within a single cell maintain or modulate their size distribution or overall network size? Local decisions to divide or fuse must propagate up to the scale of the network. These decisions should adapt in response to damage, to protect the viability of the network. At present, these questions remain open, in part because they transcend standard sub-disciplines of biology. Finding answers thus requires a quantitative interdisciplinary approach, combining molecular biology, theoretical and quantitative analysis, modeling, and precision microscopy measurements. With our research team, we will develop novel molecular tools to specifically induce mtDNA damage, follow single nucleoids and count single copies (AB), image hundreds of cells to resolve their mitochondria and mtDNA at resolutions of 10-100 nm (SM), use microfluidics devices to follow 10^5 - 10^6 mutants and interpret fluctuations in copy number using stochastic theory (JP), and perturb, characterize and synthesize our observations into geometric models of cellular architecture (WM). On a fundamental level, we wonder why mitochondria form dynamic networks. Many have asked how mitochondrial dynamics or network morphologies contribute to cellular health through optimized energy production, ion buffering, or myriad other important roles. We hypothesize that the mitochondrial network, and the dynamic processes that produce it, exist largely to support the life cycle of the mitochondria as an endosymbiont, allowing its genome to be stably propagated in an intact form.
2021 -
Grant Awardees - Program

Decoding acoustic communication in mosquitoes: from distortion products to vector control

ALBERT Joerg (GERMANY)

Ear Institute - University College London - London - UK

BOZOVIC Dolores (USA)

Dept. of Physics and Astronomy - University of California Los Angeles - Los Angeles - USA

CHEN Chun-Hong (CHINA, REPUBLIC OF (TAIWAN))

Institute of infectious diseases and Vaccinology - National Health Research Institutes - Zhunan - CHINA, REPUBLIC OF (TAIWAN)

KAMIKOUCHI Azusa (JAPAN)

Graduate School of Science - Nagoya University - Nagoya - JAPAN

As mosquitoes become an increasingly common part of daily life for millions of people worldwide, so too do the diseases they transmit. The rapid global spread of mosquitoes is placing billions at risk of infection from dengue, malaria and Zika, with current control methods unable to control the increased threat. New control tools, with novel mechanisms of action, are necessary to prevent public health resources from being overwhelmed. Mosquito ears are potentially the most sensitive in the insect world; this sensitivity is necessary for males to locate the faint sound of an individual female flying through the crowd of males that compromises a mosquito swarm. Although this male attraction to the noise of a female’s wing beat has been studied for decades, tools which manipulate this attraction effectively in the wild have still not been developed. We aim to address this problem by comprehensively studying every aspect of mosquito hearing-related anatomy and behaviour. We will describe the mosquito ear itself in detail and identify the individual components which underly the hearing process. By creating new mosquito mutants, we will be able to describe exactly which components allow males to locate females within noisy environments. We will then test which sounds specifically stimulate these components, before applying these sounds to groups of caged male mosquitoes. We will model the reaction of these groups – and their ears - to different sounds using ground-breaking mathematical models, which will feed into further experiments to identify an ‘ideal song’ to attract males. A particular focus of our project will be on the role of ‘phantom tones’, which males can generate in their own ears (and which are very similar to female flight tones) to support their hearing process. In other words, we want to understand how ‘making up’ the sound of a female can help males to find a real one. Finally, we will test the identified optimized sounds in the field to assess their attractiveness in the real world. To this end, we will attach speakers to mosquito traps to test whether ‘making the right noises’ can indeed increase the number of captured males. Our project aims to provide a clearer answer as to how mosquito hearing works, and whether the use of sound is a feasible path for controlling wild mosquito populations.
2021 -
Grant Awardees - Program

Understanding how genetic and physical fluidity drive adaptive behavior in a multinucleate organism

ALIM Karen (GERMANY)

Physics Department - Technische Universität München - Garching b. Munich - GERMANY

ROPER Marcus (UK)

Department of Mathematics - University of California, Los Angeles - Los Angeles - USA

ROZEN Daniel (USA)

Institute of Biology - Leiden University - Leiden - NETHERLANDS

The giant cellular compartments of syncytial organisms can harbor millions of nuclei. In Physarum polycephalum plasmodial fusion can produce complex nuclear-level interactions, including selective killing of nuclei after somatic fusion. At the same time, the shared plasmodial cytoplasm traffics resources and information, allowing the entire organism to gain resistance to antibiotics even when only a fraction of its nuclei carries resistance genes. Working at the interface of physics, evolutionary biology, and applied mathematics, we will uncover how cooperative and competitive dynamics between nuclei interact to produce emergent organism-scale behaviors. We exploit three key features of Physarum: 1. Diverse genotypes can be integrated into a single chimeric plasmodium via cellular fusion, 2. Flows of cytoplasm and nuclei can be dynamically tracked throughout the plasmodial network, 3. A rich, and poorly understood, repertoire of organismal behaviors, including learning and distributed intelligence. The project requires the combined skills of the PIs to: 1. Generate chimeric plasmodia in which nuclei have different complementary phenotypes (e.g. antibiotic resistance and sensitivity) and mapping and modeling shifts in nuclear proportions and spatial distributions when confronted by selective conditions. 2. Mechanistic study of how cytoplasmic flows can break down nuclear-division synchrony, allowing nuclear proportions to change in response to the environment. 3. Quantification and modeling of how nuclear dispersal and proliferation feed back on morphological changes and thus behaviors of the plasmodial network. Our quantitative understanding of nuclear interactions, bridging the scale from few nuclei interacting in a single plasmodial tube to the population dynamics of nuclei across the entire syncytial organism, will provide unprecedented insight into how nuclear interactions control and are controlled by network architecture, energy and information flow across the organism. We will give new insight on the mechanisms controlling Physarum’s surprisingly complex behaviors and revolutionize our understanding of the evolution of multinucleate cells, which occur in all biospheres and across all kingdoms of life.
2021 -
Grant Awardees - Program

Memory – from material to mind

BARAK Omri (ISRAEL)

Faculty of Medicine and Network Biology Research Laboratories - Technion - Israeli Institute of Technology - Haifa - ISRAEL

DIAMOND Mathew (ITALY)

Tactile Perception and Learning Lab - International School for Advanced Studies (SISSA) - Trieste - ITALY

KEIM Nathan (USA)

Dept. of Physics - Pennsylvania State University - University Park - USA

The brain’s capacity to store and retrieve information is the target of enormous research efforts. Seemingly unrelated research in physics has begun to focus on information storage and retrieval in non-living systems. For instance, a crumpled nickel-titanium wire spontaneously reconfigures into its remembered shape – a paperclip – upon heating. Our proposal posits that the memory dynamics being discovered in non-living systems are less remote from brain memory than might be supposed. Through our experimental neuroscience expertise (DIAMOND), we will train rats in perceptual memory behaviors. To uncover fundamental rules that extend beyond a single paradigm, we will use one stimulus set as the external drive from which the brain generates multiple distinct percepts; furthermore, we will train rats to act upon these percepts in a diverse library of tasks. Through our soft matter physics expertise (KEIM), we will chart out a general framework for memory storage and retrieval aimed at replicating key rat findings, such as the interaction between short-term and longer-term memories. Materials that extract and store information, such as driven suspensions, can be arranged in a flexibly interacting network to serve as a physical model of brain networks. Our computational neural networks expertise (BARAK) will act as the bridge. In a feedback loop within the project, BARAK will characterize materials networks in a language that can be applied to experimental neuroscience. By converting materials network properties into biological mechanisms, such as persistent firing patterns, BARAK will provide DIAMOND with quantitative predictions for the neuronal population states across a network of cortical regions (analogous to the network of materials). Removal of a single module from the materials network might be analogous to optogenetic suppression of a single cortical region; the team, together, will interpret parallel experiments of this sort. While not neglecting what makes the brain qualitatively different from an inanimate material, our identification of common motifs between material and mind engenders a new approach that envisions behavior as the task-dependent configuration of a repertoire of fundamental memory properties.
2021 -
Grant Awardees - Program

The biology of left-right asymmetry - linking structural determinants to ecology and evolution

BARRETT Spencer C.H (CANADA)

Dept. of Ecology and Evolutionary Biology - University of Toronto - Toronto - CANADA

DEINUM Eva (NETHERLANDS)

Dept. of Mathematical and Statistical Methods (Biometris) - Wageningen University & Research - Wageningen - NETHERLANDS

ILLING Nicola (SOUTH AFRICA)

Dept. of Molecular and Cell Biology - University of Cape Town - Rondebosch - SOUTH AFRICA

LENHARD Michael (GERMANY)

Institute for Biochemistry and Biology - University of Potsdam - Potsdam - GERMANY

Consistently telling left from right is no small feat, and how developing organisms do so to form left-right (LR) asymmetric structures is a fascinating question in biology. While the molecular mechanisms involved are known in some detail in the case of LR asymmetric internal-organ placement in vertebrates, a number of key issues remain poorly understood. These include the questions (1) how symmetry is initially broken in a consistent manner; (2) how this is translated into asymmetric organ growth; (3) what the functional importance of LR asymmetries is; and (4) how they evolved. Here, we will work towards an integrative understanding of LR asymmetries by answering the above questions for mirror-image flowers as a highly suitable model. In mirror-image flowers, the upper part of the female reproductive organ, the style, is bent away from the midline that runs from the top to the bottom of the flower, either to the left or to the right. Conversely, one of the male organs, the anthers, is bent in the opposite direction. While in some species individuals carry both left- and right-styled flowers, in others each individual has either only left- or only right-styled flowers, and this difference in orientation between the individuals is controlled by a single gene. This arrangement means that pollen from a left-styled individual (with its anthers on the right) should be deposited on a pollinating insect in such a way that it can be efficiently transferred to the female organs on a right-styled individual, and vice versa. As such, mirror-image flowers are thought to promote outcrossing. In this project, we will use the genetic control of left/right orientation in mirror-image flowers to identify the responsible genes and study how the encoded proteins break the left-right symmetry and cause the style to bend. Experimental studies will be complemented by computational modelling to understand the minimum requirements for consistent organ deflection. Using field experiments we will test the prediction that mirror-image flowers promote efficient outcrossing. We will also study the evolution of mirror-image flowers and compare the results about the orientation-determining genes between the three independently evolved cases of genetically controlled mirror-image flowers. This will indicate whether each of them found a unique solution to the problem of telling left from right, or whether the same mechanism is used repeatedly. As a result, this project will provide an integrated understanding of left-right asymmetry.
2021 -
Grant Awardees - Program

Darwin rwinDa: rewinding and rerunning evolution to study innovation in action

BEEBY Morgan (UK)

Department of Life Sciences - Imperial College London - London - UK

CARY Craig (NEW ZEALAND)

Thermophile Research Laboratory - University of Waikato - Hamilton - NEW ZEALAND

HOCHBERG Georg Karl Albert (GERMANY)

Evolutionary Biochemistry group - Max Planck Institute for Terrestrial Microbiology - Marburg - GERMANY

PEDACI Francesco (ITALY)

Dept. of Biophysics and Bioengineering/Centre de Biochimie Structurale - CNRS UMR 5048 - UM - INSERM U 1054 - Montpellier - FRANCE

How does evolution create novelty? The underpinning of evolution is molecular; cells are filled with molecular machines whose origins involved evolution of many new components. Understanding how evolution created such novelty is a substantial gap in evolutionary theory. Current understanding, however, is limited by the absence of a molecular fossil record and challenges in determining the structures and functions of molecular machines from diverse species. We propose a study to overcome these limitations by combining breakthroughs in metagenomics, evolutionary biology, structural biology, and single molecule biophysics to provide a description of the evolutionary path of a molecular machine. We will experimentally rewind evolution of the high-torque flagellum from epsilon-proteobacteria (ePB), an ideal model system which incorporated several new proteins as it evolved higher torque. We will determine when new proteins were added from protein phylogenies (HOCHBERG) aided by metagenomics-informed environmental sampling of uncultured diversity in sparse parts of the tree (CARY). We will infer the structure of motors along this trajectory by imaging motors in situ at crucial branches with cryoelectron tomography and microscopy (BEEBY) and infer their selective benefits by biophysically measuring motor output (PEDACI). Our work will reveal whether the evolution of molecular machines follows traditional gradualist theories of evolution, or whether their construction from discrete proteins necessitates discontinuous evolutionary leaps. We will address how initially merely useful accessory proteins became completely essential using ancestral sequence reconstruction (HOCHBERG), genetic manipulation of newly isolated bacteria (BEEBY and CARY), and experimental evolution (BEEBY). Lastly, we will use resurrected ancestral flagellar proteins (HOCHBERG) together with experimental evolution (BEEBY) to test whether receptivity of the motor or the availability of suitable proteins limits protein recruitment. Our work will reveal whether nature’s nanomachines come from efficient evolutionary optimization or whether historical accidents have introduced gratuitous complexity. More generally, we will extend the reach of comparative evolutionary biology to the nanomachines that drive cells and make a first step in uncovering the rich molecular natural history of the cell.
2021 -
Grant Awardees - Program

Adaptation of photosynthetic membranes to environmental change

BENNETT Doran (USA)

Department of Chemistry - Southern Methodist University - Dallas - USA

CROCE Roberta (ITALY)

Dept. of Physics and Astronomy/Biophysics of Photosynthesis - Vrije Universiteit Amsterdam - Amsterdam - NETHERLANDS

ENGEL Benjamin (USA)

Helmholtz Pioneer Campus - Helmholtz Zentrum Munich - Neuherberg - GERMANY

Photosynthetic organisms convert sunlight into biochemical energy, thereby sustaining most of the life on Earth. Changing light conditions present a fundamental challenge for these organisms, which must find a balance between increasing productivity and avoiding damage caused by overexciting the photosystem protein complexes embedded within their thylakoid membranes. Regulatory mechanisms such as state transitions and non-photochemical quenching are proposed to involve major remodeling of the thylakoid membranes and their embedded light-harvesting protein complexes. However, despite decades of intense research activity providing indirect supporting evidence, the molecular adaptation of thylakoids has never been directly observed, and there remains a disconnect between the relatively slow membrane remodeling steps and the ultrafast process of light harvesting. In our newly-formed team, we have assembled a novel combination of multidisciplinary expertise and innovative technology aimed at breaking through this longstanding barrier in the field.
2021 -
Grant Awardees - Program

How a single cell shapes a shoot

BRADY Siobhan (CANADA)

Department of Plant Biology and Genome Center - University of California, Davis - Davis - USA

SMITH Richard S. (UK)

Dept. of Computational and Systems Biology - John Innes Centre - Norwich - UK

VERNOUX Teva (FRANCE)

Laboratoire Reproduction et Developpement des Plantes - Ecole Normale Supérieure de Lyon - Lyon - FRANCE

ZURBRIGGEN Matias (GERMANY)

Institute of Synthetic Biology - CEPLAS - University of Duesseldorf - Duesseldorf - GERMANY

Phyllotaxis, the regular arrangement of leaves around stems, is one of the most striking natural patterns; it has puzzled biologists, physicists and mathematicians for centuries. Phyllotaxis first evolved in simple plants, like the moss Physcomitrium Patens, but has mostly been studied in plants of recent evolutionary origin, like Arabidopsis. In contrast with the multicellular Arabidopsis shoot apex, successive rotating division planes of a single apical cell directly determine moss phyllotaxis, with each apical cell derivative generating directly a leaf. This provides a system to understand how the geometry of a single apical cell and its daughter cells, their resultant physical forces and biochemical cues self-organize 4D patterns of division orientation and ultimately shape a shoot. To explore the fundamental question of how phyllotaxis emerged, at single cell-resolution, we will use our unique inter-disciplinary expertise to combine developmental genetics, optical and physical imaging, single cell genomics, optogenetics and computational modeling in moss. This will generate key insights into the contribution of cell division orientation to the evolution of phyllotaxis.
2021 -
Grant Awardees - Program

The role of bone cellular and sub-cellular porosity network connectomics on calcium homeostasis

CARRIERO Alessandra (ITALY)

Dept. of Biomedical Engineering - The City College of New York - New York - USA

GOURRIER Aurélien (FRANCE)

Lab. for Interdisciplinary Physics - LIPHY - CNRS - St Martin d'Heres - FRANCE

GRANDFIELD Kathryn (CANADA)

Dept. of Materials Science and Engineering - McMaster University - Hamilton - CANADA

Bones serve as a mineral reservoir in vertebrates to achieve calcium and phosphate homeostasis. However, the precise cellular regulation of this process is not fully understood. Osteocytes (Oy), the most abundant bone cells, form an interconnected dendritic network embedded in the bone tissue through a pore system called the lacuna-canalicular network (LCN). Oy are believed to orchestrate mineral release and uptake either indirectly, by triggering remodeling via bone resorbing/forming cells, or directly, through a localized process, known as osteocytic osteolysis (OO). Although postulated in the 1960-70s, the relative importance of OO for mineral homeostasis is unclear and its mechanisms still poorly described. Most studies on calcium transport focus on the LCN, although there is growing evidence that a complex sub-cellular mineralization pathway exists. In this proposal, we challenge the classical view that the LCN alone determines calcium transport and hypothesize the existence of an intermediate level of mesoscale porosity that plays a central role in calcium exchange. Our scientific approach uses interdisciplinary expertise in materials science, physics and biomedical engineering, and integrates a series of multiscale and multimodal imaging platforms connected through deep-learning and the application of connectomics. Here, we will: i) decipher the mesoscale porosity and mineral heterogeneity at the LCN, ii) determine the spatial distribution of OO, and iii) produce a connectomics analysis of fluid transport and calcium exchange in bone. We will use lactating and weaning C57BL6 mice that exhibit large reversible mineral depletion/remineralization. We will acquire bone ultrastructure visualization in 3D using an emerging plasma focused ion beam scanning electron microscope. This will be combined with confocal and two-photon excitation fluorescence microscopy using an original deep-learning super-resolution correlative imaging approach. Finally, multiscale network connectivity will be analyzed using connectomic approaches based on graph theory and experimental data will be used to perform numerical simulations of fluid transport. This research will reveal the structural mechanisms and extent of OO demineralization/remineralization at the cellular and sub-cellular scale and identify key parameters affecting fluid transport during OO.
2021 -
Grant Awardees - Program

Transcriptional program of Golgi biogenesis

DE BOER Jan (NETHERLANDS)

Dept. of Biomedical Engineering - Eindhoven University of Technology - Eindhoven - NETHERLANDS

KHODJAKOV Alexey (USA)

Lab. of Cellular and Molecular Basis of Diseases - Wadsworth Center - Albany - USA

POLISHCHUK Roman (RUSSIA)

Cell Biology and Disease Mechanism Program - Telethon Institute of Genetics and Medicine (TIGEM) - Pozzuoli - ITALY

The main objective of our proposal is to reveal the transcriptional program that governs Golgi biogenesis. Synthesis of new Golgi components is required in a large cohort of physiological processes ranging from cell growth to tissue biogenesis. However, how transcription contributes to Golgi biogenesis has yet to be sufficiently understood. Although several mechanisms regulating expression of Golgi genes have been described, their specificity for Golgi biogenesis remains controversial because they emerged from studying pleotropic responses to drugs, toxins, and ER stress that occur in the presence of resident Golgi (or at least its main constituents). HERE WE PROPOSE TO ANALYZE HOW THE CELL REGULATES TRANSCRIPTION TO BUILD THE GOLGI FROM SCRATCH AFTER PHYSICAL REMOVAL OF THIS ORGANELLE. To achieve this challenging objective, the Golgi-containing portion of the cytoplasm will be severed by a laser from the rest of the cell, shaped by microfabricated patterns to be amenable for such Golgi nanosurgery. This procedure triggers a massive de novo assembly of the Golgi in the remaining part of the cell (karyoplast) that contains the nucleus. Golgi biogenesis in the karyoplast occurs in the absence of a preexisting Golgi organelle enabling a straightforward analysis of the transcriptional mechanisms required to build a new Golgi. This analysis will be done by collecting karyoplasts at different stages of Golgi recovery for single cell RNA-seq. A key to the success of our strategy is the international team of investigators with interdisciplinary expertise in laser nanosurgery, transcriptomics, microfabrication and high content screening of bioengineered materials. Analysis of the transcriptome during the de novo assembly of the Golgi will unveil (i) how transcription of various genes correlates with various stages of Golgi regeneration, (ii) which signaling mechanisms are involved in this process, and (iii) which transcription factors drive Golgi biogenesis. We will establish how this transcriptional program operates in processes that require active Golgi biogenesis, specifically cell growth during preparation for division, accelerated secretion, and cell differentiation. Finally, using microfabricated scaffolds and growth patterns we will explore how this Golgi-specific transcriptional program could be controlled to promote engineering of bone and muscle tissue.