Awards | Human Frontier Science Program

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.
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
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.
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.
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2021 -

Grant Awardees - Early Career

How life got moving: reconstructing and re-evolving the bacterial flagellar motor, piece-by-piece

BAKER Matthew (AUSTRALIA)

School of Biotechnology and Biomolecular Science - University of New South Wales - Kensington - AUSTRALIA

MATZKE Nicholas (USA)

School of Biological Sciences - University of Auckland - Auckland - NEW ZEALAND

KACAR Betul (USA)

Dept. of Bacteriology - University of Wisconsin Madison - Madison - USA

MCNALLY Luke (IRELAND)

School of Biological Sciences - University of Edinburgh - Edinburgh - UK

Many organisms move, but the origin of the first motility is not known. We focus on the oldest propellers: flagellar motors. Remarkably, these evolved twice: the bacterial flagellar motor (BFM) and the archaeal flagellar motor (AFM). Both require dozens of cooperating proteins to function, and both are partially homologous to secretion systems. BFM function and assembly has been researched for decades, however the key question of: ‘how did such functional complexity first arise?’ has only been addressed, in outline, in a handful of publications. We hypothesize that the earliest proto-flagella evolved by coupling secretion systems to power sources (BFM: ion pumps; AFM: ATPases), providing a small, yet selectively advantageous, improvement in dispersal ability. We will test this hypothesis by reconstructing, resurrecting, and examining possible ancestor-like proteins. We will do this one-component-at-a-time, and then in combinatoric fashion using high-throughput motility screens. We will measure the biophysical characteristics of proto-motors in hosts over which we have genetic control. We will measure chemotaxis parameters to model what selective benefits are gained, at what cost, as the proto-motor adapts to optimise for efficiency in assembly and function. Our ultimate target is to recreate, in the lab, the moment where suitable machinery was co-opted to impart a selective advantage (motility) to an ancestral organism. To prepare to tackle this ambitious goal, we will comprehensively characterise the evolution and differentiation of the ion-powered stator units. Our team comprises experts in the complementary areas this project requires: Bayesian statistical phylogenetics; biophysics of the flagellar motor, ancestral sequence reconstruction and experimental evolution; and theoretical eco-evolutionary microbiology. Our project outcomes will characterise how flagellar motors adapt to improve motility in different conditions, and determine plausible pathways for how motility first emerged.

2021 -

Grant Awardees - Program

Memory – from material to mind

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

BARAK Omri (ISRAEL)

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

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

LENHARD Michael (GERMANY)

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

BARRETT Spencer C.H (CANADA)

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

ILLING Nicola (SOUTH AFRICA)

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

DEINUM Eva (NETHERLANDS)

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

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 - Early Career

Conferring carnivorous plant-like traits by single gene transfers

FUKUSHIMA Kenji (GERMANY)

Department of Botany I - University of Würzburg - Würzburg - GERMANY

RENNER Tanya (USA)

Department of Entomology - The Pennsylvania State University - University Park - USA

BAUER Ulrike (GERMANY)

School of Biological Sciences / Mechanical Ecology Lab - University of Bristol - Bristol - UK

In principle, all botanical research, regardless of the species studied, will ultimately contribute to human welfare, by, for example, providing useful knowledge and genetic materials to improve crops. A key challenge is to efficiently select genes that have a high chance of achieving predicted trait modifications. Because the same mutations led to the same evolutionary outcomes among different organisms, convergently evolved traits based on the same genetic changes may be less dependent on the genetic background, and thus more easily transferable. Here, we test this idea with carnivorous plants, which evolved multiple fascinating traits in disparate groups of flowering plants. To achieve this goal, we will combine bioinformatics, biomechanics, and experiments involving live plants, insects, and pathogens to evaluate the performance of crop plants into which carnivorous plant genes are transferred. Carnivorous plants are a source of many potentially useful traits that may enhance crop production when transferred. These plants produce highly modified leaves that serve as prey traps. Those with flypaper-type and pitcher-type trapping mechanisms are popular ornamentals. The traps themselves are armed with biochemical and biomechanical weapons to repel pathogens and insects. For example, many carnivorous species secrete hydrolytic cocktails to digest prey, which contain enzymes derived from pathogenesis-related proteins. Additionally, carnivorous plants with pitcher-type traps can have digestive fluids that are highly viscoelastic, aiding in prey retention, as well as sophisticated surface microstructures that prohibit insect attachment. When successfully transferred, these traits can help increase crop production under exposure to pathogens and herbivorous insects. Because independent lineages of carnivorous plants have been confirmed to have functionally important genes that have been modified through similar evolutionary pathways, they are ideal systems to perform a proof-of-concept study of efficient trait transfers by taking advantage of convergently evolved genes. This project will result in novel insights into how to prioritize genes for trait transfers, as well as how carnivorous traits can enhance crop health and production.

2021 -

Grant Awardees - Program

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

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

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

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

ENGEL Benjamin (USA)

Helmholtz Pioneer Campus - Helmholtz Zentrum Munich - Neuherberg - GERMANY

CROCE Roberta (ITALY)

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

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 -

Long-Term Fellowships - LTF

Dissecting tissue specific antibody mediated immunity to Rotavirus infection

BERNSHTEIN Biana (ISRAEL)

- Ragon Institute of MGH, MIT and Harvard - Cambridge - USA

ALTER Galit (Host supervisor)

Our immune system efficiently fights pathogens by recruiting and activating immune cells within the infected tissue to clear out the infection. Antibody mediated immune response is a critical part of this process. In my postdoctoral studies, I plan to study the role of antibodies in orchestrating the immune response through interactions with innate immune cells within the tissue. As a model system I propose Rotavirus (RV), a devastating enteropathogen causing pediatric gastroenteritis worldwide. A vaccine against RV infection prevented millions of hospitalizations worldwide, however it is insufficient to provide protection in young children in developing countries. While vaccine induced antibody levels serve as a biomarker of vaccine response, the precise immunological mechanisms of vaccine-mediated protection remain undefined, rendering improved vaccine design challenging. Here I aim to systematically probe the antiviral functions of RV vaccine-induced antibodies. Using the Alter lab’s systems serology platform, I will study the ability of antibodies to directly block RV infection, as well as to recruit the innate immune system. The protective signatures defined in the human vaccine study will be mechanistically dissected in an in-vivo RV infection model. Ultimately, I aim to define the rules by which antibodies direct mucosal immune cells to fight RV, potentially unlocking novel roles for antibody-innate immune cell interactions. These studies will expand our understanding of the role of antibodies in guiding innate immune function in the intestinal mucosa, paving the way towards developing efficacious vaccines against additional enteropathogens or diseases of the gut.

2021 -

Long-Term Fellowships - LTF

Dissecting the mechanisms underlying cytoplasmic reorganization and embryo patterning in ascidians

BOLGER-MUNRO Madison (CANADA)

- Institute of Science and Technology Austria - Klosterneuburg - AUSTRIA

HEISENBERG Carl-Philipp (Host supervisor)

The asymmetric distribution of cytoplasmic domains and RNAs is critical for asymmetric cell division and fate determination. Therefore, unraveling the mechanisms that drive the asymmetric distribution of the cytoplasm is essential for understanding animal development. Once fertilized, ascidian eggs undergo a massive cytoplasmic reorganization that precisely localizes maternal determinants to establish the anterior-posterior body axis. Following this reorganization, an invariant cleavage pattern predictably segregates maternal determinants asymmetrically into blastomeres, conferring differential cell fates. Thus, the establishment of polarity in the ascidian egg determines the body plan of the whole animal. Thus, ascidians are a powerful model for studying how cytoplasmic organization and the asymmetric distribution of maternal factors patterns animal development. Despite its vital role in establishing embryonic patterning, remarkably little is known about the mechanisms that orchestrate cytoplasmic reorganization and the distribution of maternal factors. In this project, I will use high-resolution microscopy, force and cell shape manipulations, and proximity biotinylation to address the following fundamental questions: 1) What mechanisms regulate cytoplasmic reorganization and anterior-posterior polarity in the ascidian egg? 2) How is cytoplasmic reorganization translated into the precise positioning of maternal determinants? Significance: This study will shed light on the processes that define the anterior-posterior body axis and pattern of development in ascidians and deepen our understanding of how embryogenesis is conserved and has evolved among chordates.

2021 -

Grant Awardees - Early Career

T cell microvillus as a new signaling organelle

SU Xiaolei (CHINA, PEOPLE'S REPUBLIC OF)

Department of Cell Biology - Yale School of Medicine - New haven - USA

ZHAO Wenting (HONG KONG, CHINA)

School of Chemical and Biomedical Engineering - Nanyang Technological Unviersity - Singapore - SINGAPORE

BOTTANELLI Francesca (ITALY)

Institute of Biochemistry - Freie Universität Berlin - Berlin - GERMANY

The surface of many immune cells is covered with submicron-sized membrane protrusions called microvilli. Microvilli were traditionally considered to be involved in lymphocyte migration and adhesion. Interestingly, recent studies suggest that microvilli enrich the T cell receptor (TCR) in their tips, and those are where T cells form initial contacts with the antigen-presenting cells (APCs). However, beyond those descriptive findings, it remains unknown how the unique architecture of microvilli regulates the nanoscale localization of signaling proteins and lipids, and the associated biochemical reactions that lead to transmembrane signaling and T cell activation. It remains a daunting challenge to tackle these problems because of the nanoscale size and highly dynamic nature of microvilli. To reveal the spatial organization and signaling function of T cell microvilli, we have assembled a team composed of a T cell biologist (SU), a nano-engineering scientist (ZHAO), and a super-resolution microscopy expert (BOTTANELLI). Our central hypothesis is that microvilli spatially segregate and organize proteins and lipids to effectively initiate and transduce TCR signaling. This project will be supported by our complementary technical and biological expertise in T cell signaling and biochemical reconstitution (SU), nanofabrication and membrane biophysics (ZHAO), and live-cell stimulated emission depletion (STED) super-resolution microscopy and membrane trafficking (BOTTANELLI). We aim to establish the microvillus as a new signaling organelle for immune responses. Our contributions are expected to expand the classical 2D textbook models of membrane receptor signaling into a 3D perspective.

2021 -

Cross Disciplinary Fellowships - CDF

Spatiotemporal patterning of polydisperse multispecies microbial communities

BOWAL Kimberly (CANADA)

John A. Paulson School of Engineering and Applied Sciences - Harvard University - Cambridge - USA

MAHADEVAN Lakshminarayanan (Host supervisor)

Bacteria play a significant role in human health, the environment and industrial applications. In these environments bacteria are most often found in multispecies communities in which colonies containing different cell shapes interact closely. Recently, time-lapse microscopy has shown that these multispecies interactions can be cooperative or competitive, presenting dynamic and complex behaviours hypothesised to be a consequence of the shape-dependent physical and chemical interactions. However, the role of shape polydispersity in individual and collective dynamics is poorly understood, prompting questions such as: How do different bacterial shapes influence interspecies interactions? How do polydisperse communities engage in competitive or cooperative actions that direct spatiotemporal patterning? I will address these questions using agent-based modelling grounded in experimental data to provide a predictive understanding of multispecies interactions in space and time. This biophysical model will describe physical and chemical interactions between sphere- and rod-shaped individuals and be used to probe the principles governing multispecies bacterial communities considering a variety of factors. This will allow me to map out spatiotemporal patterns related to cooperative and competitive behaviours, highlighting the role of shape polydispersity in partitioning or mixing of dynamic multispecies communities. The theoretical framework generated and interaction principles elucidated will shed light on complex multispecies bacterial systems of great importance and will also have the potential to address other active collectives that feature polydisperse interacting communities.

2021 -

Grant Awardees - Program

How a single cell shapes a shoot

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

SMITH Richard S. (UK)

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

BRADY Siobhan (CANADA)

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

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 -

Long-Term Fellowships - LTF

Identifying metabolic drivers of anti-tumor immunity

BRUNNER Julia Stefanie (AUSTRIA)

Cell Biology Program - Memorial Sloan Kettering Cancer Center - New York - USA

FINLEY Lydia (Host supervisor)

Cytotoxic T lymphocytes (CTLs) are major effectors of the adaptive immune defense against cancer. Local microenvironmental cues induce CTLs to undergo specialization into effector, memory or exhausted programs. CTL fate decisions have dramatic effects on successful cancer clearance, but how these programs are controlled remains ill-defined. Recently, metabolites have emerged as potential regulators of gene expression programs, raising the possibility that local metabolite levels may control cell fate programs. In particular, the universal methyl donor, S-adenosylmethionine (SAM), has been suggested to control chromatin methylation and cell fate decisions, but the degree to which SAM levels fluctuate in physiological contexts and the pathways that respond to changes in SAM levels remain unknown. To date, the lack of tools to probe metabolite levels in defined cell populations has hampered the study of the role of metabolites in cell fate decisions in vivo. Here, using cutting-edge, RNA based SAM biosensors, I will overcome current technical limitations by imaging SAM abundance in real-time on a single cell level. These novel tools will allow me to determine how physiological fluctuations in SAM influence CTL asymmetric divisions, effector functions and tumor cell killing. Leveraging SAM biosensors in the context of tumor cell models will show the impact of metabolite availability on CTLs in the tumor niche. These studies will reveal fundamental principles of immune cell fate commitment and provide a paradigm-shifting approach to study the contribution of intracellular metabolic fluxes to the regulation of cell fate decisions in physiologically relevant microenvironments.

2021 -

Long-Term Fellowships - LTF

Visualizing the cohesin-RNA Polymerase II interaction at nanometer resolution

CACCIANINI Laura (ITALY)

Department of Biology - Massachusetts Institute of Technology - Boston - USA

VOS Seychelle (Host supervisor)

Throughout a cell’s life, DNA must be accessed to express genes, copied and equally partitioned when the cell divides, and simultaneously this 2 meter long fiber is compacted in a micron-scale space. Chromatin architecture is highly regulated and is linked to gene expression. DNA looping is a preferential mechanism of DNA-related compaction in mammals. These loops are generated by cohesin, a complex known to keep sister chromatids together and that extrudes DNA loops in a ATP-dependent manner. Disruption of loop-based structures or perturbations of cohesin pathway can have dramatic effects on transcription. Despite the growing evidence of a cohesin-RNA Polymerase (Pol) II interaction, little is known about its structural details. My goal is to establish how these two complexes contact each other by means of correlative light electron microscopy (CLEM). Recent evidence indicates that cohesin is necessary to retain Pol II at centromeres and to ensure proper silencing of chromosome arms. Mitotic transcription offers the advantage of being localized in space and time. To understand how cohesin can maintain Pol II at centromeres in mitosis I will perform: (i) two-color STORM to assess cohesin-Pol II spatial distribution; (ii) in-situ cryo electron tomography (cryo-ET) on Xenopus laevis egg extracts; (iii) in-situ cryo-ET in FIB-milled mitotic cells, exploiting the physical alignment of metaphase plate and fluorescently labelled centromeres to identify the plane of interest. The latter two steps are related but independent. This study will provide the structural information needed to understand the interplay between genome folding and transcription.

2021 -

Grant Awardees - Program

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

GRANDFIELD Kathryn (CANADA)

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

GOURRIER Aurélien (FRANCE)

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

CARRIERO Alessandra (ITALY)

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

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 -

Cross Disciplinary Fellowships - CDF

Birth, life and death of marine snow: real-time observations and biophysics of a sinking eco-system

CHAJWA Rahul (INDIA)

Department of Bioengineering - Stanford University - Stanford - USA

PRAKASH Manu (Host supervisor)

Ecosystems on our planet are driven out of equilibrium with energy input from the sun resulting in a flux of matter across food chains, joining the carbon cycle. This flux is remarkably vivid in the biological pump of our oceans, with gravity driving the downward flux of carbon in the form of marine snow, and the microbes inhabiting and decaying it, thus regulating global climate. The hydrodynamic, biotic and non-equilibrium character of this sinking microbial ecosystem, warrants an active matter physics framework, in an atypical setting. We propose a unique approach to understanding marine snow as a novel class of sedimenting active matter, using a newly invented “hydrodynamic treadmill” capable of direct micro-scale observations of particles sedimenting virtually forever. This would allow us to observe both short and long term dynamics of marine snow sinking in an ambient microbiome, thus achieving an ecologically relevant setting on a tabletop. Through a controlled physical simulation of oceanic conditions we would offer novel insights into birth, life and decay of marine snow aggregates with the following aims- Aim 1: study the formation and dynamics of marine snow aggregate from microscopic density fluctuations of sinking phytoplankton cells, which can now be observed for the first time. Aim 2: make quantitative the efficiency at which ambient microbes can find and populate sinking particles via hydrodynamic and chemical cues, highlighting the role of marine microbes on the global climate. Aim 3: study the long-time dynamics and decomposition of this self-organized active matter as an open microbial ecosystem made of microbes sinking with “islands” of marine snow.

2021 -

Grant Awardees - Early Career

Coupling movement and metabolism in plant stomatal cells: a multiscale and multiphysics approach

CHEUNG Lily (USA)

Dept. of Chemical and Biomolecular Engineering - Georgia Institute of Technology - Atlanta - USA

RAISSIG Michael (SWITZERLAND)

Centre for Organismal Studies - Heidelberg University - Heidelberg - GERMANY

ROUTIER-KIERZKOWSKA Anne-Lise (FRANCE)

IRBV, Departement of Biological Sciences - University of Montreal - Montreal - CANADA

Grasses like rice, maize, and wheat are vital for human nutrition and provide half of all calories consumed by humans. The agricultural success of grasses is partially credited to the superior dynamics of their leaf “breathing” valves called stomata, which open to facilitate carbon dioxide absorption for photosynthesis and close to minimize water loss via transpiration. Unlike most plants, grass stomata consist of two dumbbell-shaped guard cells (GCs) surrounding the aperture; each flanked laterally by a subsidiary cell (SC). This four-celled complex allows for faster response to fluctuating light and humidity. Yet, the exact function of SCs in stomatal dynamics was unclear until recently, when the first SC-specific gene involved in coordinating the movement of GCs and SCs was identified in maize. This gene is a sugar transporter of the SWEET family, suggesting that SCs function through a complex mechanism involving the interplay between cell deformation and metabolism. In this project, we will develop a mechano-metabolic modeling framework to integrate the role of sugars with cell morphology and mechanics in stomatal dynamics—a goal impossible to reach with genetics, biochemistry or physics alone. Our model will be informed by mutant analysis in the newly adopted model grass Brachypodium distachyon, 3D cell shape reconstructions, and in vivo measurements of transporter activity, sugar concentration, cell wall elasticity, and turgor pressure. We will use this model to test a proposed feedback mechanism involving cell deformation, water flow, osmotic pressure, and energy metabolism to predict stomatal dynamics. By elucidating the relevance of sugar transport in a cell-type-specific manner, as well as the role of mechanical anisotropy and cell geometry, our modeling framework will explain why grass stomata present very fast opening and closing dynamics. It could also help predict physiological and cellular characteristics that can be targeted by bioengineering to make faster stomata and, ultimately, increase water-use efficiency in crops to help them withstand the drought and heatwaves associated with climate change.

2021 -

Grant Awardees - Early Career

Unraveling the fundamental mechanisms of neuromodulation by focused ultrasound

HARTEL Andreas (GERMANY)

Bioelectronic Systesm Lab - Columbia University - New York - USA

COSTA Tiago (PORTUGAL)

Dept. of Microelectronics/Bioelectronics - Delft University of Technology - Delft - NETHERLANDS

KOPEC Wojciech (POLAND)

Dept. of Theoretical and Computational Biophysics - Max Planck Institute for Biophysical Chemistry - Goettingen - GERMANY

Cellular communication is mediated by voltage-gated, ligand-gated and mechanosensitive ion channels. Tools for modulating neuronal communication based on focused ultrasound (FUS) were developed to overcome fundamental limitations in optogenetics, combining non-invasive approaches and high spatial resolution without the need for genetic modification of neurons. Yet, little is known about the fundamental mechanisms of how focused ultrasound waves influence the finely tuned interplay of ion channels and lipid bilayers. How does the frequency and intensity of the ultrasound wave affects the lipid bilayer and different types of ion channels? What is the physical mechanism that governs the triggering of ion channel activity? These questions remain unanswered, with existing hypothesis limited by the spatio-temporal resolution of traditional optical, electrophysiology and ultrasound tools, which prohibit observations at the single ion channel level. To answer these questions we hypothesize that, if there would be a way to monitor effects of the FUS on the lipid bilayer and single ion channels with high temporal resolution, one should be able to monitor ultrasound-evoked oscillating current responses informing on ultrasound neuromodulation mechanisms. Hence, the aim of this proposal is to develop a concurrent experimental and computational approach, where state-of-the-art ultrasound and current read-out devices enabling high-bandwidth electrophysiology are matched with computational electrophysiology simulations. This will allow us for the first time to match the frequency of the focused ultrasound with the bandwidth of single ion channel recordings and the length of the computer-based simulations. We will focus our efforts in three aims, where Aim1 will establish the recording systems and simulations using model membranes alone and a mechanosensitive model channel. In Aim2 we will develop a recording platform integrating US stimulation and high bandwidth recordings in complementary metal-oxide semiconductor (CMOS) technology, extending our efforts on non-mechanosensitive channels. In Aim3, we will combine the gained knowledge from Aims 1 and 2 to focus on mechanosensitive channel that are hypothesized to be involved in neuromodulation.

2021 -

Grant Awardees - Program

Transcriptional program of Golgi biogenesis

POLISHCHUK Roman (RUSSIA)

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

KHODJAKOV Alexey (USA)

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

DE BOER Jan (NETHERLANDS)

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

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.

2021 -

Grant Awardees - Program

How do malaria mosquitoes swarm and mate? The functional biology of mating swarms

MUIJRES Florian (NETHERLANDS)

Experimental Zoology Group - Wageningen University - Wageningen - NETHERLANDS

RIFFELL Jeffrey (USA)

Dept. of Biology - University of Washington - Seattle - USA

MUELLER Ruth (GERMANY)

Unit Entomology - Institute of Tropical Medicine Antwerp - Antwerp - BELGIUM

DIABATE Abdoulaye (BURKINA FASO)

Laboratoire de Parasitologie Entomologie - Institut de Recherche en Sciences de la Santé DRO - Bobo Dioulasso - BURKINA FASO

Malaria mosquitoes are world’s deadliest creatures. Despite our intensive vector-control efforts they still cause >400,000 human deaths each year. However, we know surprisingly little about the mechanisms that underlie their fecundity. Mosquitoes mate in-flight in complex 3D swarms of up to thousands of individuals of multiple sympatric species. It is thought that to avoid hybridization in such swarms, male and female conspecifics perform a mating dance by synchronizing their wingbeats. But interactions between freely-flying mosquitoes within a swarm have never been quantified. Here, we propose to study the complex dynamics of mating swarms using an interdisciplinary approach by combining expertise from neuroscience, bio(fluid)mechanics, machine vision, behavioral ecology and medical entomology, from laboratories across three continents (Africa, Europe and N. America). Together, we aim to collaboratively study swarming behavior in lab, semi-field and field conditions. For this, we will develop two main research methodologies: A. Dedicated machine-vision-based videography systems for tracking up to 300 mosquitoes flying in a swarm. These systems will be used to study the biomechanics and behavior of multi-species swarms in lab, semi-field and field conditions. B. Novel tethered-flight electrophysiological assays to record the neural responses to approaching conspecifics and allospecifics. By placing this system within a swarm, we will study the neural bases of mate-swarming behavior. By using these systems with a collaborative, multidisciplinary research approach, we aim to jointly answer our four main research questions: Q1. How do mating-swarms form and keep their integrity? Q2. How do individual swarming mosquitoes recognize potential mates? Q3. How do swarming mosquitoes mate in-flight? Q4. How does mosquito swarm dynamics affect mating success and hybridization? This study will generate a new understanding of the functional neuro-mechanics of mating swarms, and provide crucial knowledge about the mechanisms that underlie the fecundity of malaria-vectors. We use the malaria mosquito as our model organism because its fecundity is particularly depending on swarming dynamics, and malaria is the deadliest mosquito-borne disease. Therefore, the project outcomes will directly support the development of malaria-vector control strategies/methods, such as gene-drive, acoustic lures, and monitoring. Swarming is currently an important topic in aerial robotics research; our study will provide novel bio-inspiration for flight control strategies, systems and algorithms of such swarming robots.

2021 -

Long-Term Fellowships - LTF

Predicting enhancer function from sequence through in silico evolution and high-throughput screening

FALO SANJUAN Julia (SPAIN)

Department of Molecular and Cell Biology - University of California - Berkeley - USA

EISEN Michael B. (Host supervisor)

Understanding the DNA sequence rules that govern gene expression remains a major unsolved challenge in biology. Regulatory sequences, termed enhancers, are composed of binding sites for transcription factors, whose number, affinity, spacing and orientation dictate gene expression. Although the roles of some of these parameters are well established, the rules by which binding site arrangement dictate gene expression programs remain poorly understood. We could predict enhancer function if we could test all functional and non-functional enhancer sequences (the ‘enhancer space’). A viable approximation to this approach would be to investigate naturally occurring enhancers. However, not all functional combinations exist in nature, and evolution has mainly maintained functional ones. I propose to cover as much of the enhancer space as possible by: (1) Generating in silico a library of enhancers that could have appeared during evolution, starting from functional but highly divergent enhancers. (2) Testing the activity of this library in a high-throughput manner in cell culture and Drosophila embryos to discover sequence features conferring enhancer functionality, and (3) learn rules of input integration from enhancers' expression patterns. Overall, this proposal aims to discover rules of enhancer function and obtain predictive understanding of function from sequence, providing a landmark step toward decoding gene regulation in development, homeostasis and disease.

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Awardees

How life got moving: reconstructing and re-evolving the bacterial flagellar motor, piece-by-piece

BAKER Matthew (AUSTRALIA)

MATZKE Nicholas (USA)

KACAR Betul (USA)

MCNALLY Luke (IRELAND)

Abstract

Memory – from material to mind

DIAMOND Mathew (ITALY)

KEIM Nathan (USA)

BARAK Omri (ISRAEL)

Abstract

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

LENHARD Michael (GERMANY)

BARRETT Spencer C.H (CANADA)

ILLING Nicola (SOUTH AFRICA)

DEINUM Eva (NETHERLANDS)

Abstract

Conferring carnivorous plant-like traits by single gene transfers

FUKUSHIMA Kenji (GERMANY)

RENNER Tanya (USA)

BAUER Ulrike (GERMANY)

Abstract

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

HOCHBERG Georg Karl Albert (GERMANY)

PEDACI Francesco (ITALY)

BEEBY Morgan (UK)

CARY Craig (NEW ZEALAND)

Abstract

Adaptation of photosynthetic membranes to environmental change

BENNETT Doran (USA)

ENGEL Benjamin (USA)

CROCE Roberta (ITALY)

Abstract

Dissecting tissue specific antibody mediated immunity to Rotavirus infection

BERNSHTEIN Biana (ISRAEL)

ALTER Galit (Host supervisor)

Abstract

Dissecting the mechanisms underlying cytoplasmic reorganization and embryo patterning in ascidians

BOLGER-MUNRO Madison (CANADA)

HEISENBERG Carl-Philipp (Host supervisor)

Abstract

T cell microvillus as a new signaling organelle

SU Xiaolei (CHINA, PEOPLE'S REPUBLIC OF)

ZHAO Wenting (HONG KONG, CHINA)

BOTTANELLI Francesca (ITALY)

Abstract

Spatiotemporal patterning of polydisperse multispecies microbial communities

BOWAL Kimberly (CANADA)

MAHADEVAN Lakshminarayanan (Host supervisor)

Abstract

How a single cell shapes a shoot

VERNOUX Teva (FRANCE)

ZURBRIGGEN Matias (GERMANY)

SMITH Richard S. (UK)

BRADY Siobhan (CANADA)

Abstract

Identifying metabolic drivers of anti-tumor immunity

BRUNNER Julia Stefanie (AUSTRIA)

FINLEY Lydia (Host supervisor)

Abstract

Visualizing the cohesin-RNA Polymerase II interaction at nanometer resolution

CACCIANINI Laura (ITALY)

VOS Seychelle (Host supervisor)

Abstract

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

GRANDFIELD Kathryn (CANADA)

GOURRIER Aurélien (FRANCE)

CARRIERO Alessandra (ITALY)

Abstract

Birth, life and death of marine snow: real-time observations and biophysics of a sinking eco-system

CHAJWA Rahul (INDIA)

PRAKASH Manu (Host supervisor)

Abstract

Coupling movement and metabolism in plant stomatal cells: a multiscale and multiphysics approach

CHEUNG Lily (USA)

RAISSIG Michael (SWITZERLAND)

ROUTIER-KIERZKOWSKA Anne-Lise (FRANCE)

Abstract

Unraveling the fundamental mechanisms of neuromodulation by focused ultrasound