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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2021
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Long-Term Fellowships - LTF
Investigating neurodevelopment in cortical organoids using voltage and neurotransmitter imaging
GANAPATHY Srividya (USA)
Department of Pediatrics, Cellular and Molecular Medicine - University of California - San Diego - USA
MUOTRI Alysson (Host supervisor)
It is estimated that 1 in 160 children are impacted by neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). In order to develop novel and more effective neurotherapeutic medication to treat ASD, we need a deeper understanding of how specific genetic mutations impact the synaptic properties of the developing brain.
In this research, I will assess the synaptic properties of cortical organoids derived from patients with a genetic predisposition for ASD using state-of-the-art genetically encoded fluorescent sensors. Cortical organoids are three-dimensional simplified model systems which recapitulate features of neurodevelopment. I will utilize voltage imaging, which is a revolutionary approach to directly read out the electrical dynamics of neurons in organoids. This method allows access to both spatial and temporal (millisecond) scales hitherto inaccessible to traditional neuroscientific methodology. I will use a fast and sensitive red-light activable voltage sensor along with a reporter for inhibitory (GABA) neurotransmission. Red-light two-photon fluorescence imaging of these voltage and GABA sensors will be used in combination with blue-light stimulation of optogenetic actuators. This method is termed all-optical-electrophysiology and will be used to investigate the impact of an ASD mutation on the intrinsic excitability of neurons and GABAergic neurotransmission. This research facilitates an exciting collaborative effort between biotechnological tool development and its application in a physiologically relevant model system.
2021
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Grant Awardees - Program
Evolution of neural circuit dynamics and brain computations in Astyanax blind cave fish
SUMBRE German (ARGENTINA)
Dept. of Biology - Ecole Normale Superieure - Paris - FRANCE
KEENE Alex (USA)
Department of Biology - Texas A&M University - College Station - USA
GJORGJIEVA Julijana (MACEDONIA)
School of Life Sciences - Technical University of Munich - Freising - GERMANY
Environmental changes often drive drastic evolutionary changes in behavior and brain function. While genetic mapping studies have provided insight into the genetic basis of behavioral evolution, much less is known about the neural circuit dynamics and brain computations that drive this behavioral change. Across phyla, cave ecosystems provide the opportunity to examine how environmental change impacts the evolution of morphology, development and behavior. The Mexican tetra, Astyanax mexicanus is a leading model for studying genetic mechanisms underlying trait evolution. A. mexicanus consists of a surface (river) and several cave populations that independently evolved in largely isolated caves, allowing for comparative approaches to identify genetic and neural variants associated with behavioral evolution.
Cave populations of A. mexicanus exhibit prominent changes in sensory systems including loss of vision and expansion of smell, taste, mechanosensation and lateral line. Despite the robust changes in behavior and morphology, the shifts in processing sensory information within the brain has been unexplored. Here, we will apply an interdisciplinary approach that leverages newly developed genetic tools and synergistic interaction between PIs with expertise in behavioral evolution, functional imaging and theoretical modeling to investigate how changes in neural dynamics underlie the evolution of sensory systems to new environments with different sensory constraints. This synergistic collaboration will shed light on general evolutionary principles underlying the repurposing of neural circuit dynamics and computations of sensory systems that could have broad implications for understanding the evolution of brain function, plasticity and intra-species differences in sensory processing.
2021
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Long-Term Fellowships - LTF
How host cell post-transcriptional regulatory adaptations impact chronic coxsackievirus B3 infection
GRIFFITHS Cameron (CANADA)
Department of Biomedical Engineering - University of Virginia - Charlottesville - USA
JANES Kevin (Host supervisor)
This project studies chronic coxsackievirus B3 (CVB3) infection from a systems biology perspective. CVB3 is a positive sense RNA virus that prefers to infect the heart. Although most CVB3 infections are cleared by the immune system, some infections shift to a long-term chronic state for enigmatic reasons. The chronic infection damages the heart, leading to a disease called dilated cardiomyopathy (DCM), which is characterized by a large weakened heart. The only treatment for DCM is heart transplant. During acute CVB3 infection, the positive sense genome is much more abundant than the antisense genome, which is a replication intermediate used as a template to create new sense genomes. However, during chronic infection the sense/antisense ratio is close to 1. My project will test the hypothesis that a shift in the host post-transcriptional regulatory system causes this altered sense/antisense ratio. I will test this hypothesis in a cell culture model of chronic CVB3 infection by interfering with regulatory proteins that can bind to and degrade the CVB3 sense genome. I will also examine how chronically infected cells respond to inflammatory stimuli and how these stimulations impact the CVB3 sense/antisense ratio. In parallel, I will use a computational model of CVB3 infection to identify cellular states that cause an altered sense/antisense ratio and are conducive chronic infection. Finally, I will examine the post-transcriptional regulation and CVB3 sense/antisense ratio in a clinical dataset of gene expression, collected from the hearts of 149 patients with DCM. This project uses an innovative systems-level approach to enhance our understanding of chronic CVB3 infection.
2021
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Grant Awardees - Program
Friends with benefits? A holistic approach to diffuse mutualism in plant-pollinator interactions
SICARD Adrien (FRANCE)
Plant Biology department - Swedish University of Agricultural Sciences - Uppsala - SWEDEN
RISSE Benjamin (GERMANY)
Computer Vision and Machine Learning Systems Group - Faculty of Mathematics and Computer Science - Münster - GERMANY
GROZINGER Christina (USA)
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
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Long-Term Fellowships - LTF
Protein correlation profiling analysis of the Nipah virus-host interface
HARRISON Angela (AUSTRALIA)
Centre for Gene Regulation and Expression - University of Dundee - Dundee - UK
LAMOND Angus (Host supervisor)
Nipah virus (NIV) is a highly lethal henipavirus with pandemic potential. Outbreaks of NIV occur almost annually in Asia and there are no approved treatments or vaccines, highlighting the need for research into NIV biology. NIV proteins V and M are highly multifunctional; NIV V disables multiple arms of the type I interferon response to potently suppress antiviral immunity, while NIV M has roles in immune evasion, virus assembly/budding, and modulating cell biology, including ribosomal RNA biogenesis. These many functions are mediated through an array of protein-protein interactions. However, how these viral proteins coordinate so many interactions/functions is currently unclear, as is their impact on endogenous cellular multiprotein complexes more globally, including the translational machinery. The proposed project therefore aims to systematically analyse the molecular composition of distinct complexes formed and altered by NIV V and M proteins using state-of-the-art proteomics strategies. Specifically, the project will use highly innovative fractionation technologies, including ‘full-spectrum’ and ‘Ribo-Mega’ size exclusion chromatography, combined with protein correlation profiling and mass spectrometry, to investigate how NIV V and M proteins exploit and remodel the intracellular host environment to benefit infection. The project is expected to provide unparalleled insight into the NIV:host interface and mechanisms of infection, and be of significant value for accelerating therapeutic/vaccine development. The project will also establish these highly advanced proteomics approaches as valuable tools to study other important viruses.
2021
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Long-Term Fellowships - LTF
The role of metabolism in regulating pathological osteoclastogenesis in arthritis
HASEGAWA Tetsuo (JAPAN)
MRC Laboratory of Molecular Biology - University of Cambridge - Cambridge - UK
PEARCE Edward (Host supervisor)
CLATWORTHY Menna (Host supervisor)
Osteoclasts are macrophage lineage cells with unique bone-destroying capacity, playing key roles in steady-state bone remodelling inside the bone marrow (BM) and pathological joint destruction in patients with rheumatoid arthritis (RA), in which the hypertrophied synovium (called "pannus") invades the outer surface of the articular bone. While osteoclastogenesis is known to involve dynamic metabolic changes, little is known about the metabolic pathways involved in the pathological osteoclastogenesis in the inflammatory synovial tissue setting. I therefore aim to elucidate the extracellular energy microenvironment and metabolic regulation of pathological osteoclasts causing bone destruction in arthritis. I will perform imaging mass spectrometry of the knee joints of arthritic mice to elucidate the metabolic states of osteoclasts in the pannus microenvironment and compare it with physiological BM settings. I will also extract the pannus directly into the metabolite extraction buffer, and analyze the extract through mass spectrometry by comparing healthy and diseased joints. Based on these in situ information, I will elucidate how the energy microenvironment and metabolites enriched in the arthritic joints govern the function and metabolism of osteoclasts through analysing metabolic profiling assays, such as extracellular acidification rate, oxygen consumption rate, and carbon isotype (13C) tracing. Overall, these proposed studies will provide novel insights into the metabolic regulation of pathological osteoclastogenesis, potentially leading to the development of a new strategy for treating bone destruction in RA without interfering with physiological bone remodelling.
2021
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Grant Awardees - Program
Assembling and recombining the Arabidopsis centromeres
HENDERSON Ian (UK)
Department of Plant Sciences - University of Cambridge - Cambridge - UK
SCHATZ Michael (USA)
Departments of Computer Science and Biology - Johns Hopkins University - Baltimore - USA
KAKUTANI Tetsuji (JAPAN)
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
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Long-Term Fellowships - LTF
Molecular determinants of selective viral RNA recognition by MDA5
HERRERO DEL VALLE Alba (SPAIN)
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
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Grant Awardees - Program
Structural damage to axons resulting from repetitive mechanical motion
HESS Henry (GERMANY)
Biomedical Engineering - Columbia University - New York - USA
SHEFI Orit (ISRAEL)
Faculty of Engineering - Bar-Ilan Institute of Nanotechnology and Advanced Materials - Ramat Gan - ISRAEL
KAKUGO Akira (JAPAN)
Faculty of Science - Hokkaido University / Graduate School of Science - Sapporo - JAPAN
RAFFA Vittoria (ITALY)
Department of Biology - Università di Pisa - Pisa - ITALY
Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. Biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. For example, “tensegrity” refers to the emergence of stability as a result of a balance of tensile and compressive elements in a mechanical structure. It was inspired by the human musculoskeletal system, applied to architectural designs, and returned to biology as a framework to understand cellular mechanics.
However, progress in the engineering discipline of mechanics also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures, and its origin in processes such as materials fatigue. Some tissues, such as the spinal cord, are formed from long-lived nerve cells which maintain their function over the entire lifetime of the organism. How do these cells maintain their operation despite being constantly subjected to mechanical stresses? How do the mechanical stresses degrade intracellular structures, and what mechanisms are activated to effect repair? These are the fundamental biological questions we aim to address.
We will mimic the repetitive mechanical motion and study how it damages internal structural components in the long extensions of nerve cells and which repair mechanisms contribute to maintaining their health. Specifically, we will: (1) develop a novel experimental setup to exert thousands of cycles of stretching and bending deformations on the nerve cell extensions, (2) characterize the structural damage to them, (3) characterize the functional damage to them, (4) identify the repair mechanisms employed by the cell to mitigate and reverse the mechanical damage, and (5) integrate the obtained information into a coherent model.
The newly formed team is composed of experts in biomechanics, materials science and nanotechnology, neuroscience and regenerative medicine, and will combine experimental and modeling approaches. Overall, we take an engineering perspective and apply it to cell biology by asking not “How does it work?” but “How does it keep working for so long?”. The obtained insights will inform our understanding of the mechanical aspects of maintaining cellular health, inspire new biomimetic approaches to engineering, and yield a better appreciation of the cell as a “self-repairing machine”.
2021
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Grant Awardees - Program
Understanding the cellular mechanics of coral bleaching
HU Ke (CHINA, PEOPLE'S REPUBLIC OF)
Center for Mechanisms of Evolution - Arizona State University - Tempe - USA
INABA Kazuo (JAPAN)
Shimoda Marine Research Center - University of Tsukuba - Shizuoka - JAPAN
Mutualistic and parasitic intracellular symbionts have an enormous impact in the global ecosystem as well as on the health and behavior of their hosts. Coral bleaching, a major global ecological crisis, is caused by the massive loss of the symbiont dinoflagellate Symbiodinium from its coral hosts. Sustained coral bleaching leads to coral death, destroying an essential foundation of the marine ecosystem. While the importance of Symbiodinium spp in the marine ecosystem has long been established, the cellular mechanics of how the intracellular association with their hosts is established and dissolved is not understood. To tackle this problem, the joint team of the Hu Lab (Arizona State University, U.S.A.) and the Inaba Lab (Shimoda Marine Research Center, University of Tsukuba, Japan) will combine our expertise in cell biology, microscopy, parasitology, evolution biology and marine biology. We will use an evolution-guided strategy to test whether two seemingly incongruent processes - the exodus of Symbiodinium from cnidarians and the egress of apicomplexan parasites from mammalian cells- share a common evolutionary origin and cellular mechanics. Our work will reveal the nature of the force driving exodus of symbiont from coral, and develop molecular genetic tools that are essential for investigating the fundamental biology of the Symbiodinium-cnidarian partnership.
2021
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Long-Term Fellowships - LTF
Molecular dynamics of size sensing at the single cell level
KAPADIA Nitin (CANADA)
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
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Long-Term Fellowships - LTF
Elucidating key neuroinflammation pathway(s) involved in the brain of Drosophila
KHAN Anzer (INDIA)
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
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Long-Term Fellowships - LTF
The role of cancer-induced hematopoietic stem cell activation in the development of atherosclerosis
KISS Máté (HUNGARY)
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
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Grant Awardees - Program
Revealing the interplay of genetics and biomechanics underlying butterfly scale morphogenesis
KOLLE Mathias (GERMANY)
Department of Mechanical Engineering - Massachusetts Institute of Technology - Cambridge - USA
WILTS Bodo (GERMANY)
Department of Chemistry and Physics of Materials - University of Salzburg - Salzburg - AUSTRIA
NADEAU Nicola (UK)
Dept. of Animal and Plant Sciences - The University of Sheffield - Sheffield - UK
During the final stage of metamorphosis, butterfly wings sprout with hundreds of thousands of scales, each formed by a single cell and carrying precise nanostructural motifs. Delicate control of scale structure on the single-scale level determines multiple functions of the wing, including brilliant colors, water repellency, thermoregulation, and lift generation. Despite these functions being of great interest to biologists and engineers alike, we only have limited knowledge of the mechanisms underlying scale formation. This project aims to decipher the processes underlying butterfly scale morphogenesis using newly developed methods for observing the scales while they are forming in the chrysalis, combined with biomechanical modeling, molecular analysis, genetic manipulation of scale formation, and nano-scale electron-microscopic analysis of formed scale morphologies. To understand the coordination across different morphological features, the characterization of the temporal changes during stages of development is critical. By integrating these different approaches, we will shed light on the mechanical effects, biomolecular constituents, and genetic factors that drive the temporal and spatial coordination during wing scale development.
The result of this collaborative interdisciplinary effort between biologists, materials scientists, and engineers will be a complete time-resolved picture of scale structure formation, paired with information about the landscape of molecular constituents in critical developmental phases, a deeper understanding of the biomechanical phenomena, and a clearer view on the interplay between specific genetic components, their effect on the scales’ biochemistry and its influence on critical biomechanical interactions. We will test our understanding through genetic manipulation and through time-sensitive inhibition of structural components. The deeper understanding of biological formation of functional material architectures gained through this effort will form the basis for future targeted initiatives aimed at translating structure formation principles from biological systems into synthetic functional materials for applications in optics, sensing, biomedical devices and textile technology, sustainable paints and coatings, and augmented reality infrastructure.
2021
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Long-Term Fellowships - LTF
How transcriptional and epigenetic networks shape lung-resident memory T cells and tissue immunity
LERCHER Alexander (AUSTRIA)
Laboratory of Virology and Infectious Disease - Rockefeller University - New York - USA
RICE Charles M. (Host supervisor)
Immunological memory is a cardinal feature of adaptive immunity and forms the molecular basis of vaccines. Memory T cells provide long-term antigen-specific protection against intracellular pathogens. Circulating memory T cells provide de-centralized immune surveillance, whereas tissue-resident memory T cells (Trm) provide highly potent immune responses on-site that are tailored to the tissues in which they reside. Trm cells are highly abundant in barrier sites and enable rapid immune responses upon antigen re-encounter and are thus an integral part of the first line of defense against pathogens. In the lung, Trm cells are important to fend off recurring respiratory pathogens, but they are hampered by poor longevity. Here, I propose to combine disease-relevant infection model systems with cutting-edge single cell technologies to chart a map of transcriptional and epigenetic networks that govern Trm cell ontogeny and function in the lung. Genetic perturbation and molecular dissection of putative regulators of Trm cell identity in vivo will help to unravel novel therapeutic targets to boost Trm cell formation and/or functionality. Employing superinfection models with heterologous pathogens will help to expand those findings beyond antigen-specific immune responses. Together, the insights gained in this interdisciplinary project will broaden our understanding of adaptive tissue immunity towards respiratory pathogens and advance our portfolio of therapeutic prevention or intervention strategies.
2021
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Grant Awardees - Program
Teratology in microfossils as a proxy for understanding mass-extinctions through time
VANDENBROUCKE Thijs (BELGIUM)
Department of Geology - Ghent University - Ghent - BELGIUM
VAN DE SCHOOTBRUGGE Bas (NETHERLANDS)
Dept. of Earth Sciences - Utrecht University - Utrecht - NETHERLANDS
LOMAX Barry (UK)
Dept. of Agriculture & Environmental Science - University of Nottingham - Nottingham - UK
LOOY Cindy (NETHERLANDS)
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.
2021
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Cross Disciplinary Fellowships - CDF
Dynamics of active matter in complex and heterogeneous habitats
MARTÍNEZ CALVO Alejandro (SPAIN)
Department of Chemical and Biological Engineering - Princeton University - Princeton - USA
DATTA Sujit (Host supervisor)
Bacteria can self-organize into a myriad of morphologies and thrive in diverse ecosystems by developing survival strategies that protect the community from external threats. It has been recently proposed that understanding the collective mechanisms of prokaryotic cells could pave the way to fathoming the strategies developed by eukaryotic communities, yet this connection remains unclear. Both systems grow in heterogeneous habitats, namely organs or tissues. In this project, through experiments and mathematical modeling I aim to unravel the collective behavior and cooperativeness that bacteria and eukaryotic cells have in common in complex environments. To this end, several bacterial species, as Escherichia coli and Pseudomonas aeruginosa, and MDCK eukaryotic cells, will be cultivated in different 2D and 3D media mimicking realistic conditions, exposing them also to different external stimuli and heterogeneities, namely chemical and thermal gradients, shear flows, or mechanical forcing. From the theory side, I will employ and derive continuum nematic models, and active vertex models in the case of eukaryotic systems. The interplay between experiments, theory and simulations will be essential to understand the underlying cooperative mechanisms and the collective response of active matter in competitive and heterogeneous habitats, a research direction that remains almost virgin to date. Natural outcomes stemming from this proposal are a better understanding of cancer pathogenesis and antibiotic resistance, or the production of living and synthetic meta-materials at our whim by controlling the morphogenic response of active systems.
2021
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Long-Term Fellowships - LTF
Understanding adaptability of egg-laying behavior in Aedes aegypti
MOHAMMED GARBA Yunusa (NIGERIA)
Department of Zoology - University of British Columbia - Vancouver - CANADA
MATTHEWS Benjamin (Host supervisor)
Aedes aegypti mosquitoes are endemic to many regions throughout the world and are vectors of arboviral pathogens that cause Dengue fever, yellow fever, Chikungunya, and Zika. Ae. aegypti are supremely adaptable and can be found breeding in a wide variety of urban and rural aquatic sites associated with human habitation, likely requiring physiological and behavioral adaptability to thrive in these diverse environments.
Ae. aegypti decide where to lay eggs based on sensory cues in liquid water to maximize survival of their offspring. The aims of my proposal are to 1) Establish colonies of Ae. aegypti derived from wild strains that exhibit differential preference for egg-laying water mixtures. 2) Perform neuronal imaging to quantify differences in sensory neuron tuning to different egg-laying water mixtures. 3) Use RNA-seq to quantify any changes in expression or sequence of chemoreceptor gene function across tissues involved in egg-laying in strains with divergent preference.
This work will build on previous work by my host supervisor and my PhD training in neuroscience and chemical ecology to understand egg-laying preference in Ae. aegypti at multiple biological levels and also to determine why Ae. aegypti (and not other species of mosquitoes) have become so intertwined with human settlement. I will also build genetic tools that will allow researchers to probe many aspects of mosquito biology to support critically important mosquito control efforts around the world.
2021
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Grant Awardees - Program
The aphrodisiac gut: defining the factors promoting yeast mating within insect intestines
STEFANINI Irene (ITALY)
Department of Life Sciences and Systems Biology - University of Turin - Turin - ITALY
POLIN Marco (ITALY)
Mediterranean Institute For Advanced Studies (IMEDEA) - CSIC-University of Balearic Islands - Esporles - SPAIN
NEW Elizabeth (AUSTRALIA)
School of Chemistry - University of Sydney - University of Sydney - AUSTRALIA
SEGRE' Daniel (ITALY)
Graduate Program in Bioinformatics - Boston University - Boston - USA
Saccharomyces cerevisiae (Sce) has seen widespread use by humans throughout history for winemaking, brewing, and bakery. However, a process fundamental for this yeast’s evolution still remains only partially understood: interstrain mating (outbreeding), which potentially results in strains bearing new genomic settings and fitness. While outbreeding is easily achievable in laboratory settings, it is extremely rare in nature. In fact, we have only recently discovered the first environment where it can occur: within wasp guts. Comprehending what makes the insect gut an environment suitable for Sce mating would provide us with a better understanding of Sce evolution and expand our knowledge beyond the unnatural lab settings. Outbreeding is achieved through a multi-step process encompassing sporulation, germination, ascus break, and mates encounter. These steps may be promoted within wasp guts thanks to the sequence of drastically different chemical and mechanical stresses peculiar to this environment. We have set up a team of experts in all the fields necessary to tackle this hypothesis: microbiology, genetics, chemistry, physics, and computational biology. We will carry out in vivo experiments to assess the wasp gut environment by using dedicated sensors and Sce genes fundamental for germination and sporulation in this environment. These data will be instrumental to develop a genome-scale mathematical model exploring yeast genetics, metabolic and environmental features favoring germination and sporulation. In vitro high-throughput assays assessing both the yeast response and metabolites measured by dedicated intra- and extra-cellular sensors will provide further data to calibrate the model. Physical forces required for Sce ascus break or mate encounter will be measured through up-to-date biophysical techniques: cylindrical Couette chambers, micropipette force sensors, and microfluidic droplets. We will bring together the information that we gather about each stage to develop microfluidic devices emulating the structure and physiology of wasp guts and investigate there the entire process leading to outbreeding. This project will unveil the key factors of Sce evolution by providing fundamental insights on the biological mechanisms leading to outbreeding in natural settings, thus potentially revolutionizing our current understanding of the process.
2021
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Long-Term Fellowships - LTF
Understanding the regulation of neuropathology-associated protein and RNA repeats in Dictyostelium
NGUYEN Tu Anh (VIETNAM)
Department of Biology - Whitehead Institute for Biomedical Research - Cambridge - USA
JAIN Ankur (Host supervisor)
Expansion of short nucleotide repeats is the cause of over 30 inherited neurological diseases. These expansions could result in neurotoxicity through a loss of protein function or accumulation of misfolded repeat-containing proteins. Repeating-containing RNA, which accumulates in aberrant nuclear foci, can also be a driver of pathogenesis by sequestering RNA processing proteins and producing toxic peptides through non-canonical translation. Recently, RNA containing these disease-associated repeats (DARs) has been demonstrated to intrinsically undergo phase transition to form an aggregated state through multivalent base-pairing, providing a model for the mechanism of RNA foci formation in repeat expansion diseases. The genome of the social amoeba Dictyostelium discoideum contains an exceptionally high number of short nucleotide repeats, many of which occur in coding regions and resemble human DARs. My work will develop Dictyostelium as a model for studying evolutionarily derived mechanisms which keep DAR-containing proteins and RNA from becoming pathogenic. Specifically, this proposal presents experimental strategies for identifying factors which prevent the aggregation of DAR-containing proteins and RNA, and non-canonical translation of DAR-containing RNA. The efficacy of these factors in suppressing DAR toxicity will be investigated in mammalian cells and animal disease models. Besides their relevance to disease pathogenesis and therapeutic potential, insights derived from the proposed study will also shed light on basic principles regulating RNA and protein homeostasis.