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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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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
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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
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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
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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
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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
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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.
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.