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2021 -
Cross Disciplinary Fellowships - CDF

Information flow in the brain at single-neuron resolution


Department of Neuroscience - Cold Spring Harbor Laboratory - Cold Spring Harbor - USA

ZADOR Anthony (Host supervisor)

The flow of information between different regions of the brain during decision making is a largely unknown process. This is mainly because there are no tools available to disentangle the complex interaction of myriad cell types in the brain, governed by gene expression, connectivity, spatial organization, and other properties. This proposal aims to investigate the anatomical substrate of inter-regional communication at single neuron level. We hypothesize that a specific group of neurons that project directly between brain areas provide the “scaffolding” for the correlation between structural and functional connectivity. Tools developed in the proposed host group, as well as their previous work on the topic, make this question accessible for investigation. We aim to identify this privileged subpopulation of neurons by combining two-photon imaging of activity in single neurons with anatomical projections extracted using Barcoded Anatomy Resolved by Sequencing (BARseq). Successful completion of this project would generate unprecedented datasets that bridge information at all levels–anatomical, genetic, physiological and behavioural. Gaining knowledge of the flow of information in the brain would push the frontiers of what it is one of the grand challenges of our time–to understand how behaviour arises from neural circuits.

2021 -
Long-Term Fellowships - LTF

Molecular determinants of selective viral RNA recognition by MDA5


Department of Medicine - University of Cambridge - Cambridge - UK

MODIS Yorgo (Host supervisor)
Mammalian cells can recognize the presence of a viral infection by sensing the viral nucleic acids in the cytosol. Viral RNAs activate a specific set of pattern-recognition receptors called RIG-I-like receptors (RLRs). Among these, melanoma-differentiation associated gene 5 (MDA5) selectively recognizes long dsRNAs. Upon recognition of the viral genetic material, RLRs activate an inflammatory type I interferon response. This response needs to be sensitive and specific as its aberrant activation has been linked to autoimmune and autoinflammatory diseases. In the case of MDA5, single nucleotide polymorphisms in IFIH1, the gene encoding MDA5, have been associated with autoimmune diseases including Aicardi-Goutières syndrome, Singleton-Merten syndrome and other interferonopathies where interferon is chronically produced. However, how these mutations lead to the aberrant expression of interferon is still unknown. Besides, it is still poorly understood how MDA5 distinguishes between cellular and viral RNA and how naturally occurring RNA modifications affect the selectivity of MDA5. This work will focus on how MDA5 recognizes viral RNA in the normal and disease-associated contexts. Different variants of MDA5 will be assessed and their dsRNA-activated interferon signaling activities will be compared. The cryo-EM structures of MDA5 filaments will be determined with the aim of understanding at the atomic level how RNA modifications and mutations in MDA5 alter its recognition of dsRNA. This project will provide invaluable insights into viral RNA recognition in health and disease, and will suggest new immunomodulatory strategies.
2021 -
Long-Term Fellowships - LTF

The mechanics of cephalopod remarkable feeding system: how to bite without a joint


Department of Mechanical Engineering - University College London - London - UK

MOAZEN Mehran (Host supervisor)
With their multiple arms, three hearts, suckered tentacles, camera eyes, and fast colour-changing skin, cephalopods seem to come from an imaginary world. These iconic invertebrates play a major role in balancing the entire marine ecosystem, yet the 4 million metric tons caught annually have led to their global decrease. Cephalopod diet and feeding systems remain enigmatic. They have a ‘beak’ composed of two jaws with no direct contact, a radula, and specialised masticatory muscles. Unravelling the secrets of their feeding system can inform us about their diet and potentially have huge global impact by aiding their survival. In this project, I will bring together for the first-time expertise in cephalopod biology and biomechanics to quantitatively characterize the anatomy and function of the feeding system in different species representing all cephalopod families. I will use a range of techniques based on material characterization and computational modelling to test 4 hypotheses. I will investigate the (1) material content and mechanical properties of the jaws and correlate these with their bite force and diet; (2) shape and surface properties of cephalopod jaws and its potential correlation with their diet; (3) muscular jaw articulation of cephalopods and the mechanisms that control its motion considering a range of diet; (4) impact of overall jaw and muscular joint morphology on the level of mechanical strain across each component. A major part of cephalopod biology will be unravelled in this project, providing new foundations for cephalopod conservation and other areas such as bioinspired soft robotics.
2021 -
Grant Awardees - Program Grants

Adaptation of photosynthetic membranes to environmental change


Department of Chemistry - Southern Methodist University - Dallas - USA

ENGEL Benjamin (USA)

Helmholtz Pioneer Campus - Helmholtz Zentrum Munich - Neuherberg - GERMANY


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 -
Grant Awardees - Program Grants

Friends with benefits? A holistic approach to diffuse mutualism in plant-pollinator interactions


Plant Biology department - Swedish University of Agricultural Sciences - Uppsala - SWEDEN


Computer Vision and Machine Learning Systems Group - Faculty of Mathematics and Computer Science - Münster - GERMANY


Department of Entomology - Center for Pollinator Research - University Park - USA

Most flowering plant species benefit from the pollination services of animals, where the animal helps transport pollen between flowers and individual plants, thereby supporting seed and fruit production. In turn, plants provide nutritional resources to pollinators, include nectar (which serves as a source of carbohydrates) and pollen (which serves as a source of protein and fat). This plant-pollinator mutualism is essential to supporting terrestrial ecosystems and is also vital for human agricultural production. Declines in pollinator populations due to anthropogenic change (including habitat loss) endangers these ecosystems and threatens food security. Generalist pollination systems in which flowering plant species uses a broad spectrum of pollinators for pollination services, and pollinator species visit diverse plant species to meet their nutritional needs, can create robust and resilient plant-pollinator communities. Designing and restoring habitats with these generalist systems can serve to reduce or reverse pollinator decline, since multiple pollinator species will be supported. Yet, how such generalist and diffuse mutualisms are formed in an ecological community remains a mystery - primarily due to the lack of tools supporting high throughput monitoring of pollinator visitation patterns and the lack of plant systems where pollinator-attractive traits can be precisely genetically controlled. This interdisciplinary project combines computer vision with plant genetics and pollinator behavioral ecology to identify the mechanisms mediating plant-pollinator interaction networks in generalist pollination systems. In addition to generating novel, broadly accessible monitoring tools and experimental plant systems, this study will provide the first comprehensive characterisation of the plant traits that attract and reward different pollinator species and the pollinator behavioral strategies which optimise pollinator nutrient acquisition in ecological communities. By linking plant genetics, pollinator health and quantitative behavioral data, this project will generate novel concepts and approaches to mitigate pollinator decline in agricultural, urban and natural ecosystems.
2021 -
Cross Disciplinary Fellowships - CDF

Molecular insights into RNA-directed integration by transposon-encoded CRISPR–Cas systems


Department of Biochemistry and Molecular Biophysics - Columbia University - New York - USA

GONZALEZ Ruben Jr (Host supervisor)

Over the past decade, programmable gene editing has been transformed by the discovery and development of prokaryotic adaptive immune systems known as CRISPR-Cas. These systems, which evolved to eliminate foreign genetic elements such as plasmid and phage via RNA-guided nucleic acid degradation, have been powerfully redeployed for many gene editing applications. Recently, these systems have been expanded with the discovery of nuclease-deficient CRISPR-Cas systems that direct RNA-guided transposition. Transposon-encoded CRISPR–Cas systems can insert large genetic payloads into bacterial genomes without relying on DNA double-strand breaks or host repair factors, eliminating the major limitations of current integration approaches that rely on CRISPR-Cas9. Nonetheless, the molecular mechanisms of key steps in this newly discovered RNA-guided transposition pathway remain uncharacterized, restricting the applications of this potentially powerful technology. Specifically, the mechanisms through which the transposase machinery is recruited following DNA targeting, the integration orientation of donor DNA is selected, and the megadalton protein-DNA transpososome complex is disassembled, are yet to be elucidated. To determine these mechanisms, I propose to employ a powerful combination of genetic, biochemical, and single-molecule biophysical approaches that is made uniquely possible by integrating the expertise in the Sternberg and Gonzalez laboratories. The results of my studies will transform RNA-guided transposition into a highly tractable, precise, and efficient RNA-guided DNA integration tool for next-generation genome engineering.

2021 -
Long-Term Fellowships - LTF

Molecular dynamics of size sensing at the single cell level


Cell Cycle Laboratory - The Francis Crick Institute - London - UK

NURSE Paul (Host supervisor)
Cells have strict control over their size to ensure proper cell physiology. They also have ways to correct for deviations, referred to as cell-size homeostasis, leading to a very narrow distribution in cell size at division. Although some of the genes involved in this process have been identified, the underlying molecular mechanism has remained elusive. One possibility is that the cell can “sense” its size through a protein whose concentrations are related to cell-size - known as the sizer model. However, this would not completely explain the fact that diploid cells are approximately twice the size of haploids, suggesting that ploidy also plays a role - something that has not garnered a lot of attention in the field. Live-cell fluorescence microscopy is well-suited to address these issues because we can directly visualize the dynamics and localization patterns of sizers, along with cell-size, and quantify these characteristics. I propose to develop a live single-cell fluorescence microscopy approach using a microfluidics device that allows mother cell lineages to be tracked across multiple generations, for use with haploid and diploid strains of the unicellular eukaryotic organism, Schizosaccharomyces pombe. This will allow me to measure protein levels of sizer candidates and their localization, along with cell length, across single lineages. This information could reveal long-term dynamics and correlations between sizer candidates and cell-size, and provide insight into the molecular mechanisms governing cell-size homeostasis and the role that ploidy plays in governing cell-size control within eukaryotes.
2021 -
Long-Term Fellowships - LTF

The mechanistic role of metabolism during germ layer specification and symmetry breaking


Tissue Biology and Disease Modelling - European Molecular Biology Laboratory - Barcelona - SPAIN

TRIVEDI Vikas (Host supervisor)
The role of metabolism during developmental processes remains largely unexplored due to challenges in measuring spatiotemporal dynamics of metabolic activities. In the mammalian post-implantation embryo, pluripotent cells differentiate into three germ layers, the ectoderm, mesoderm and endoderm that undergo specific morphogenetic movements during a process known as gastrulation. While it is known that metabolites influence cell fate by modifying the epigenetic and transcriptional states, the question, whether metabolism plays a functional role in germ layer specification, has not been addressed in an in vivo context. The two main aims of the proposed project are to characterize the metabolic profiles that accompany the emergence of germ layers and their possible function during germ layer segregation i.e. symmetry breaking that establishes the primary body axis. To accomplish both aims, I will use gastruloids, aggregates of embryonic stem cells that recapitulate hallmarks of gastrulation, as a model system. The gastruloid system will allow me to combine metabolic measurements, live imaging of biosensors and metabolic state reconstruction, to uncover emerging differences in metabolism among cells of the different germ layers. Further specific manipulations with inhibitors and optogenetic tools will test if the activity of certain metabolic pathways regulates cell fate decisions and coordinates tissue scale cell movements and thus probe possible molecular mechanisms. The findings of this project will reveal fundamental mechanisms underlying the interplay between metabolism and cell fate determination and thereby change our view of how gastrulation is robustly regulated.
2021 -
Grant Awardees - Program Grants

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


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 Grants

How a single cell shapes a shoot


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


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


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 -
Cross Disciplinary Fellowships - CDF

Recording neural activity over long time periods using a novel chemi-genetic integrator


Department of Chemistry - The University of Tokyo - Tokyo - JAPAN

CAMPBELL Robert E. (Host supervisor)

Neurons can be studied by monitoring intracellular calcium ion levels using fluorogenic calcium ion sensors. However, current sensors produce transient signals, potentially missing integral neuron activity and making it challenging to measure accumulated neuron activity over time. Alternatively, genetically encoded calcium ion signal integrators accumulate and integrate neuron activity over a defined time. However, these signal integrators are dependent on a light-assisted photoconversion process and only integrate neuron activity over a short time period. Furthermore, imaging cannot take place during irradiation and even irradiation must be ensured. We propose a calcium ion signal integrator that functions independently of photoconversion for monitoring neuron activity that has accumulated over extended time periods to address these issues. This novel tool consists of a genetically encoded protein sensor (GEPS) that undergoes a conformational change from an opened state to a closed state upon binding to calcium ions. After binding to calcium ions and adopting its closed conformation, the GEPS brings together two cysteines, which both react with a complementary and fluorogenic di-acrylamide probe. Labelling the closed GEPS with this fluorogenic probe slowly produces an irreversible and accumulating fluorescent signal independent of photoconversion but depends on calcium ion concentration. The integrated signal can be later imaged by fluorescence microscopy to identify activated neurons and their relative activity. This novel calcium ion signal integrator will greatly contribute to the future understanding of neuron development and diseases such as stroke.

2021 -
Long-Term Fellowships - LTF

Elucidating key neuroinflammation pathway(s) involved in the brain of Drosophila


Global Health Institute - École Polytechnique Fédérale de Lausanne - Lausanne - SWITZERLAND

LEMAITRE Bruno (Host supervisor)
Neurodegenerative disorders are primarily defined by neuronal loss within the central nervous system. Traditionally, research on neurodegeneration has focused on neurons, but recently a prominent role for the innate immune system has been proposed. Chronic inflammation, a feature observed in many neurodegenerative contexts, is now suspected to drive disease progression. The study of neurodegenerative disease is made complex by the late onset of neurodegenerative symptoms and difficulties in accessing the brain, amongst other challenges. In recent years, Drosophila has emerged as a powerful model to study neurodegeneration, and several models mimicking human diseases including Alzheimer’s and Parkinson’s have been developed. Here, I intend to elucidate how the innate immune system contributes to neurodegeneration in Drosophila. My first objective will be to provide a broad description of the head immune responses and decipher whether the Drosophila brain possesses a dedicated immune system with its own peculiarities. My second objective will be to characterize the immune response in the brain during neurodegeneration. Antimicrobial peptides (AMPs) have recently been implicated in neurodegeneration in flies. My third objective will be to decipher the contribution of of AMPs to disease progression, using newly generated AMP mutants Collectively, my study will provide a foundation for how neuroimflammatory pathways regulate the health of neurons and their role in neurodegenerative diseases, and it will also help us to understand whether inflammation is a driver of or a response to neurodegeneration.
2021 -
Long-Term Fellowships - LTF

Saving the reef: identifying molecular and environmental factors underlying spawning in A.millepora


Arc Centre of Excellence for Coral Reef Studies - James Cook University - Townsville - AUSTRALIA

MILLER David J. (Host supervisor)
Broadcast spawning is a method of reproduction used by many species of coral, where the corals release their gametes in a perfectly timed, synchronous manner to maximise fertilisation. The timing and molecular mechanism behind this extraordinary event are not understood. Coral bleaching and the death of reefs is something that is now firmly anchored in the public consciousness. However, another threat is looming for coral, the asynchrony of spawning. This marginalised ecosystem now faces an even bigger threat, the possibility of not being able to reproduce, spelling disaster not just for marine life, but also for the communities that depend on them. An understanding of this asynchrony is key and I have therefore designed a research plan which examines the molecular mechanisms behind the spawning event. In particular, I aim to study the light biology of coral, as they use multiple light stimuli, including moonlight, to regulate reproduction. To this day, we do not know what photopigments corals employ, where these are located and whether the algal symbiont is key in initiating different spawning steps. Moonlight is the critical signal, however, the full moon is present every 29 days, so another gating mechanism must exist. I aim to find out exactly what this is by varying different parameters in a lab setting. Using temporal differential gene expression analysis around this critical moonlight signal will provide a basis for understanding the key cellular responses driving spawning. Pioneering a deep understanding of reproductive asynchrony will allow the implementation of improved conservation measures and help save the world’s reefs from destruction.
2021 -
Grant Awardees - Program Grants

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


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


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


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 -
Grant Awardees - Program Grants

Feathers as structures and sensors: understanding mechanosensing in bird flight


Dept. of Aerospace Engineering - University of Bristol - Bristol - UK


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


Dept. of Biology - McGill University - Montreal - CANADA

Birds are extremely agile and robust flyers, able to cope with challenging gusty wind conditions and perform remarkable aerial manoeuvres. To do so, birds take advantage of the flexibility of their feathers, which vibrate as a function of airflow, stimulating the mechanosensory neurons in the skin, to provide information about the airflow over the wings. We aim to explore this complex sensorimotor loop, first to identify what aerodynamic information is available to birds to help control their flight and understand how birds’ wings can act both as aerodynamic surfaces and as a distributed airflow sensing array and then to understand how this aerodynamic information is encoded in the nervous system. Although airflow sensing is thought to be critical for efficient and agile flight, almost nothing is known about how changes in airflow translate to feather movement and subsequent neural signaling. Thus, this work addresses a broad biological question about sensory encoding of aerodynamic information. This proposal represents an integrated, international collaboration to explore this question across multiple levels of organization, from the movements of feathers to neural activity during perturbed flight manoeuvres. Dr Windsor (University of Bristol, UK) is an expert in using computational image analysis to study animal dynamics and his team will use techniques from aerospace engineering to look at the aerodynamic and vibrational properties of feathered wings, including measurements of the wing motions of behaving birds. Dr Perkel (University of Washington, Seattle, USA), an expert in songbird neuroscience, will investigate the physiological mechanisms underlying the encoding of this mechanosensory information by the nervous system. His lab will record electrical signals from single neurons in the wing nerve and spinal cord of zebra finches and trace their neural pathways. Dr Woolley (McGill University, Montreal, Canada) is an expert in behaviour and neurophysiology. Her lab will map the regions of the brain responding to airflow stimuli based on insights gained from Dr Windsor’s and Dr Perkel’s groups and then measure neural responses in flying birds. By combining approaches from aerospace engineering and neuroscience we aim to understand the functional properties of wing mechanosensing that allow birds to “feel” their way through the air.
2021 -
Long-Term Fellowships - LTF

Pex ex machina: the cell biological mechanics of locally-controlled peroxisome biogenesis


Global Health Institute - EPFL - Lausanne - SWITZERLAND

VAN DER GOOT Françoise Gisou (Host supervisor)
D'ANGELO Giovanni (Host supervisor)
The peroxisome is a widely underappreciated regulator of cellular metabolism. It is often credited solely with being a metabolic detoxifier of reactive oxygen species. Peroxisomes, however, are much more than antioxidant filters. Among their multiple capabilities, peroxisomes provide intermediates for gluconeogenesis and amino acid synthesis, enable cells to synthesize complex molecules like penicillin, degrade fatty acids, and synthesize lipids essential for brain development. Peroxisomes are unique organelles in that their many functions are governed primarily by ad hoc local biogenesis. Within the accepted model peroxisomes form by fission of pre-existing organelles or de novo, from the cellular endo-membranes. However, although de novo peroxisome biogenesis explains the formation of peroxisomal membranes, we do not know how peroxisomes expand their membranes during division. Additionally, little is known about the different molecular factors that trigger peroxisome biogenesis. This proposal will examine the molecular mechanisms of peroxisome biogenesis. My goal is to gain mechanistic understanding of the early events of peroxisome formation driven by diverse conditions and identify the autonomous regulation of the partitioning of the peroxisomal membranes. That will allow us to design targeted therapies for a range of peroxisome biogenesis disorders.
2021 -
Long-Term Fellowships - LTF

The role of cancer-induced hematopoietic stem cell activation in the development of atherosclerosis


Department of Pathology and Immunology - University of Geneva - Agora Cancer Center Lausanne - Lausanne - SWITZERLAND

PITTET Mikael (Host supervisor)
The increasing number of long-term cancer survivors necessitates a better understanding of the late-onset health effects of cancer. Epidemiological studies show that survivors of cancer have an increased risk of cardiovascular disease compared to the general population; however, the underlying mechanisms remain unclear. Activation of hematopoietic stem cells (HSCs) for enhanced production of disease-promoting myeloid cells is a key driver of both tumor and atherosclerosis progression. Therefore, cancer-induced alterations in hematopoiesis may also affect coexisting atherosclerosis. In addition, tumors may induce long-term epigenetic reprogramming in HSCs, sensitizing them for systemic inflammatory signals during atherosclerosis after curative treatment of cancer. In the proposed project, I will determine whether cancer can induce persisting changes in HSCs, leading to increased myelopoiesis and exacerbated cardiovascular disease. To this end, I will combine transcriptomic and epigenomic analyses to characterize tumor-induced changes in HSCs that may influence the hematopoietic response to secondary stimuli. By inducing atherosclerosis in tumor-bearing mice or mice transplanted with cancer-primed HSCs, I will determine the role of tumor-induced HSC activation in vascular inflammation. Finally, by testing deletion of candidate receptors in the hematopoietic compartment, I aim to identify tumor-induced systemic factors driving HSC activation. This work will provide fundamental insights into the long-term impact of cancer on the immune system and its consequences on atherosclerosis development with implications for the clinical care of the growing cancer survivor population.
2021 -
Long-Term Fellowships - LTF

Neuronal mechanisms underlying group social interactions in bats


Department of Bioengineering - University of California - Berkeley - USA

YARTSEV Michael (Host supervisor)
The group setting forms the basis for most social interactions. However, despite the importance of group social behavior in almost every aspect of animal’s lives, very little is known about its neuronal substrates. This can be attributed to challenges associated with reductionist approaches to capture the complexity of group social interactions. Thus, a paradigm shift is necessary. Specifically, we identify these major gaps where most studies have: (1)focused on one brain at a time, (2)often did not consider individual differences and (3)neglected the long-term dynamics of group social behavior, especially in the natural context. To overcome these gaps, I propose an approach that leverages the rich social interactions in groups of bats, a new animal model for group social interactions in neuroscience. Utilizing cutting-edge methodologies that enable simultaneous wireless recording and manipulating of neural activity across the brains of group members, I will study the neural mechanisms of group social interactions as these naturally unfold. I will begin by focusing on two core aspects of group social interaction and their manifestation in the frontal cortex of socializing bats: (1)neuronal representations of individual’s identity as related to social vocal communication, (2)interbrain coupling across group members. Thus, I will study the relationship between group social and neural dynamics extending from the single neuron level in the individual brain to the relationship in neural dynamics across the brains of group members. Combined, this project will allow, for the first time, a unique mapping of the group social network onto the neuronal network of its members.
2021 -
Grant Awardees - Program Grants

Assembling and recombining the Arabidopsis centromeres


Department of Plant Sciences - University of Cambridge - Cambridge - UK

SCHATZ Michael (USA)

Departments of Computer Science and Biology - Johns Hopkins University - Baltimore - USA


Dept. of Biological Sciences - The University of Tokyo - Tokyo - JAPAN

Centromeres are essential to attach chromosomes to spindle microtubules during cell division. Despite this deeply conserved role, the DNA sequences underlying centromeres are extremely fast evolving, which is termed the ‘centromere paradox’. Many centromeres consist of highly repetitive satellite repeats, where individual repeats are often ~170-200 bp in length and occur in massive tandem arrays. Intriguingly, satellites show concerted evolution within and between chromosomes, indicating mechanisms of sequence exchange between the repeats. However, the recombination pathways that change satellite arrays, and their influence on centromere function, remain poorly understood. In this project, we will investigate genetic and epigenetic factors that control satellite dynamics and centromere function, using Arabidopsis thaliana. Accurate analysis of the Arabidopsis centromeres via short-read sequencing has been impossible, due to the high degree of satellite repetition. Long-read technology has created new opportunities to sequence and assemble the centromeres for the first time. We aim to harness nanopore technology to assemble the Arabidopsis centromeres and dissect the roles of meiotic recombination and epigenetic information. Our success requires interdisciplinary innovation via a combination of genetics, epigenetics and computer science. The Henderson and Kakutani groups will generate Arabidopsis nanopore data. Analysis of long-read sequencing data and repeat regions requires significant computational expertise, which is provided by the Schatz laboratory. They will perform new computer science research into the fundamental algorithms and data structures for the assembly, alignment and analysis of highly repetitive texts, including centromere sequences. The Henderson group will test the role of meiotic recombination on centromere stability, while the Kakutani group will test the role of epigenetic information. The Schatz group are using cutting-edge computational methods to map DNA methylation in nanopore data, which will synergize with our experiments testing the role of this epigenetic mark within the centromeres. The team’s combined computational and biological expertise is strongly complementary and synergistic. Our strategic aim is to provide fundamental insights into the genetic and epigenetic mechanisms that control centromere dynamics in eukaryotes.
2021 -
Grant Awardees - Program Grants

Teratology in microfossils as a proxy for understanding mass-extinctions through time


Department of Geology - Ghent University - Ghent - BELGIUM


Dept. of Earth Sciences - Utrecht University - Utrecht - NETHERLANDS

LOMAX Barry (UK)

Dept. of Agriculture & Environmental Science - University of Nottingham - Nottingham - UK


Dept. of Integrative Biology - University of California, Berkeley - Museum of Paleontology - Berkeley - USA

Mass-extinction events in Earth history can provide us with crucial baselines by which ongoing biodiversity loss can be compared and its selectivity calibrated. All mass-extinction events are connected to extreme perturbations of the carbon cycle, including changes in greenhouse gas concentrations and associated global warming/cooling. These major changes in the carbon cycle are thought to be driven by interconnected episodes of widespread volcanism, rapid increase or burning of biomass, burial, erosion or oxidation of carbon, destabilization of methane from the seafloor and permafrost, and marine anoxia. A recently discovered phenomenon associated with mass-extinction events is an increase of teratological microfossils (pollen, spores, organic-walled phyto- and zooplankton) with aberrations in morphology and texture. These malformed fossils allow us to make direct inferences about the proximate mechanisms behind these biotic crises. Unique in the fossil record, these tell-tale signatures co-occur in, and can be recovered from both the marine and terrestrial realms, allowing for the integration of these records and a search for commonality. With this interdisciplinary project we aim to test a set of interrelated hypotheses that link malformation to either metal toxicity (Hg, Cd, Ni, Pb), or increased UV-B radiation due to ozone loss, or to environmental stress related to climate change. Here, we propose to use these microfossils and their modern analogues in experimental and field settings to explore the true potential of teratology as a proxy to test, integrate and refine the many existing models for biotic crises across time and space. The deep time perspective is provided by work packages led by Ghent University and Utrecht University working on Paleozoic and Mesozoic events characterized by the presence of abundant malformed microfossils reflecting both marine and terrestrial ecosystems. Planned work will tease out the relative influence of metal toxicity related to marine anoxia and volcanic activity from geochemical and micropaleontological analyses of core and outcrop material complemented by studies of modern analogs. Work at UC Berkeley and University of Nottingham, focusing on the role of UV-B radiation, metals and temperature, will ground-truth observations from deep time via growth experiments using nearest living relatives.