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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
2022
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Grant Awardees - Early Career
How do ecological network dynamics mediate the response of organisms to novel environments?
PILOSOF Shai (ISRAEL)
Department of Life Sciences - Ben Gurion University of the Negev - Beer-Sheva - ISRAEL
DE DOMENICO Manlio (ITALY)
Dept. of Physics and Astronomy Galileo Galilei - University of Padua - Padova - ITALY
HALL James (UK)
Department of Evolution, Ecology and Behaviour - Institute of Infection, Veterinary and Ecological Sciences - Liverpool - UK
In a world fraught with human impact, predicting the response of organisms to environmental changes is a fundamental challenge. A dominant approach is to investigate how demographic and genetic factors determine the adaptability of a single taxon. However, organisms do not live in isolation. Hence, community ecologists investigate how the structure of species interaction networks affects community stability. While the interplay between species-level processes and community-level structures governs the response to environmental change, these two approaches have been disconnected. Moreover, how specific kinds of environmental heterogeneity and perturbations modulate this interplay is understudied. We propose to address these gaps by integrating theory and experiments using bacteria as a model organism. Bacteria are a dominant life form, colonizing almost every environment. In addition, genetic change in bacteria is partly driven by horizontal gene transfer (HGT)--a community-level process whose interplay with other interactions (e.g., competition) has not been studied at a community level. We will develop a theoretical framework to explore how species-level factors interact with the environment, affecting competitive ability and emerging community structures. We will use bacteria to experimentally test communities' responses to multiple kinds of environmental change, testing our theory. Our work will establish a framework for a mechanistic understanding of the interplay between species-level processes, community-level structures, and the environment. While targeted at bacteria, insights from this work will have broad implications for other organisms. This work is only achievable through a unique international collaboration that bridges ecology and evolution, microbiology, and statistical physics.
2022
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Long-Term Fellowships - LTF
Understanding the role of mtDNA mutations and electron transport chain function in thyroid cancer
DE LA CALLE ARREGUI Celia (.)
. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
MCFADDEN David (Host supervisor)
Cancer cells present altered metabolism to meet the bioenergetic and biosynthetic demands of high proliferation rates. Even though the mitochondrial genome (mtDNA) encodes key components of cellular energy homeostasis, and somatic alterations in mtDNA have been observed in many cancers, the functional significance of mtDNA mutations and alterations in the ETC remains incompletely understood. Previous research from Dr. McFadden’s lab has shown that the vast majority of the mtDNA in Hürthle cell carcinoma of the thyroid (HTC) harbored mutations in the complex I subunit of the electron transport chain (ETC). This loss of complex I function represents an early event in the progression of the disease and is maintained even during metastasis. This suggests that mtDNA mutations are a central driver in the pathogenies of this disease and opens the counterintuitive and exciting possibility that certain cancer types benefit from an impairment of mitochondrial respiration. Thus, I hypothesized that HTC represents an ideal disease outlier in which to interrogate the role of mtDNA alterations and ETC function in cancer. By using highly complementary approaches, I will first interrogate whether mtDNA mutations in humans predict impaired respiration and lead to altered metabolism. Then, I will study the mechanism by which mtDNA mutations confer a metabolic advantage in HTC in vitro, and finally, I will use novel genetically engineered mouse models to interrogate the role of complex I in thyroid tumorigenesis. To address these aims, I will use metabolomics, 13C tracer analysis, exome sequencing analysis, and in vitro and in vivo models of HTC. With this project, I will deliver a mechanistic and functional understanding of mtDNA mutations and complex I loss in HTC which will lead to insights more broadly applicable to tumors harboring mutations in mtDNA such as kidney and colorectal cancers.
2022
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Long-Term Fellowships - LTF
Light induces lymph node activation via a sympathetic eye-to-lymph node pathway
DE VIRGILIIS Francesco (.)
. - University of Geneva (Université de Genève) - Geneva - SWITZERLAND
SCHEIERMANN Christoph (Host supervisor)
Lymph nodes (LNs) are the lymphoid organs where the adaptive immune response is initiated, which makes them extremely interesting in the clinics. LNs are richly innervated and several studies reported a regulatory effect of sympathetic innervation on LN activity (1,2). Additionally, recent studies demonstrated how both the nervous and immune system, including LN and lymphocytes, possess diurnal oscillation associated with changes in environmental stimuli, such as light (3, 4). Together, these findings suggest the hypothesis that light stimulation could directly influence LN activity via a descending neuronal pathway. Specifically, I propose that light stimulates specific non-image producing receptors in the retina (ipRGCs) connected to the suprachiasmatic nucleus (SCN) in the hypothalamus, which relays this photic information to the sympathetic ganglia (SG), ultimately leading to SG activation and LN modulation. Therefore, here, using a combination of stepwise genetic, pharmacological and surgical approaches, I aim to dissect this eye-to-LN neuronal pathway and its function in regulating LN as well as to create a first cell-specific atlas of molecular signatures in the LN induced by environmental stimuli such as light stimulation. Together, these data will pave the way to unprecedented, non-invasive approaches to modulate the immune system in the clinics with light stimulation.
2022
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Grant Awardees - Program
The walking fish: Integrating biomechanics, energetics and robotics to study water-land transition
DI SANTO Valentina (ITALY)
Department of Zoology - Stockholm University - Stockholm - SWEDEN
IIDA Fumiya (JAPAN)
Department of Engineering - University of Cambridge - Cambridge - UK
SHUBIN Neil (USA)
Department of Organismal Biology and Anatomy - The University of Chicago - Chicago - USA
The transition from water to land in vertebrates occurred over 370 million years ago, however many of the fundamental morphological and physiological traits necessary to life on land arose prior to the origin of land walking. Several groups of fully aquatic fishes walk underwater, raising the question of why and which traits fishes need to take advantage of this mode of locomotion. Unfortunately, no work to date has explored the energetic benefits of this fundamental behavior across different environments, hindering the capacity to test hypotheses on the performance of transitional forms found in the fossil record and to understand the ecology of many extant species. Moving over complex and three-dimensional structures of the natural environment requires adaptive locomotor behaviors, and it is unclear how fishes during their growth might take advantage of the complexity of the substrate of the oceans and littoral zones. How do walking fishes achieve these versatile locomotor behaviors when moving over substrates of different complexity? Is there an ontogenetic shift in walking performance? What is the cost of walking and how does it compare to swimming? Here, we propose a study on the effect of environmental plasticity of walking behavior and fin anatomy of a fish, Polypterus, reared under different substrate types (flat and 3D), underwater and semi-terrestrial. We will combine anatomical measurements, developmental biology, biomechanical and physiological analyses, and robotic platforms to show how energetically efficient it is for a fish to walk and swim over different substrates and media. Experimental data will guide the design of a robotic platform capable of both walking and swimming. We will develop the bioinspired soft robotic model (the “robofish”) to understand the relationship between mechanical features and how they interact with motor patterns to form adaptive behaviors over different substrates at different body sizes. The performance of the robofish will be compared to that of real fish across treatments, and this will form the basis to create a platform to compare locomotor efficiency and plasticity of extant and extinct species of fish and their closest relatives.
2022
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Long-Term Fellowships - LTF
Circuits for perception of state of self and others
DOLENSEK Nate (.)
. - The Regents of the University of California, Berkeley - Berkeley - United States
TSAO Doris (Host supervisor)
Our faces and the information they exhibit are crucial for the formation and continued functioning of human relationships and communities. Facial features enable us to accurately determine a person’s identity, and facial expressions enable us to judge their internal state and attempt to predict their intentions. Interestingly, this reliance on facial information is not unique to humans. Highly social primate species such as rhesus macaques also exhibit facial expressions in social contexts and possess sophisticated neural machinery for face processing. However, while much is known about how areas in the superior temporal sulcus (STS) process face identity, we know less about processing of expression, except that it is separate from the former. We further know that people interacting aren’t passively waiting for their turn, but synchronize their gaze, pupil size and mimic each other’s facial expression, with an inability to do so possibly underlying social dysfunction in autism. I aim to study how the brain assigns internal state to self and others by combining visual and interoceptive information, enabling dynamic social contact. I will first create a novel machine vision-based quantitative description of macaque orofacial movement. Next, I will employ NexGen fMRI whole-brain imaging combined with Neuropixels probes to investigate the circuits involved in facial expression detection of self and others, centering on the motion sensitive parts of STS and connected regions (insula, anterior cingulate). Finally, I will perturb neural activity of each component of the identified circuit and quantitatively assess its impact on facial expression, gaze, and other behavior.
2022
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Long-Term Fellowships - LTF
Glucose regulation in nectarivorous birds
DOMER Adi (.)
. - The Regents of the University of California, Berkeley - Berkeley - United States
DUDLEY Robert (Host supervisor)
Birds, naturally hyperglycemic, can maintain approximately twice the blood-glucose concentration of mammals at equivalent size. Furthermore, they do so with only 10% of mammalian insulin levels, as they lack the primary insulin-regulating glucose transporter. It has been known for decades that glucose regulation in birds must accordingly differ from that of mammals. Birds have been previously proposed as a model system for the study of type II diabetes. However, avian regulation of glucose levels is understudied. As part of my Ph.D. on stopover ecology, I discovered correlations between glucose levels and myo-inositol (MI). MI is known to have important functions in metabolism, particularly relative to insulin mimetic activity and plasma-glucose utilization, but also in other core biochemical pathways potentially of high relevance to birds. During my postdoctoral studies I propose to further examine the role that MI, along with other key metabolites, play in avian blood glucose regulation. Moreover, I intend to quantify behavioral responses, metabolic consequences, and patterns of gene regulation which track sugar ingestion, and which underlie these hypothesized regulatory mechanisms. The hypotheses of this study will be assessed using different avian models, according to logistical limitations associated with each species. This work will assess the major metabolites which play a key role in glucose regulation in birds, their molecular and physiological mechanisms of action and associated whole-animal behavioral responses and will thus address a long-standing conundrum in avian metabolism and provide new insights into the physiology of metabolic syndromes in humans.
2022
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Long-Term Fellowships - LTF
Symmetry breaking in multicellular self-organization: a quantitative imaging approach
DUNSING Valentin (.)
. - DELEGATION CNRS PROVENCE ET CORSE - MARSEILLE - FRANCE
LENNE Pierre-Francois (Host supervisor)
Understanding the establishment of a body plan is an important challenge in biology. Progress in the field has been limited by a lack of approaches to understand multicellular tissue organization from first principles. I plan to study the first steps in mammalian development, when cell differentiation and multicellular organization establish the body axes during gastrulation. My goal is to elucidate how long range signaling cues such as morphogens and local cell-cell interactions generate tissue scale organization. As a model for primary axis formation, I will employ gastruloids, aggregates of mouse embryonic stem cells mimicking early mammalian embryos, and focus on the process of symmetry breaking, i.e. polarization of an initially homogeneous aggregate of equivalent cells. I will develop an original multiview light-sheet microscope to image multiple gastruloids live in 3D over several days with cellular resolution. I will track cells in 3D to explore 1) how signaling and differentiation propagate between individual cells; 2) how fate impacts on cell mechanics, motility and cell-cell contact dynamics. I will then apply chemical and mechanical perturbations to determine how these processes induce symmetry breaking. Finally, I will explore how robustness is achieved by monitoring symmetry breaking in aggregates of different sizes generated by global or local induction of cell differentiation. I will integrate the generated data into a mechanistic model to predict how biochemical and mechanical interactions generate tissue-scale patterning. This will provide unprecedented insights into multicellular self-organization relevant for development and regenerative medicine.
2022
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Long-Term Fellowships - LTF
Functional proteome landscape of malaria parasite during the life cycle in host and vector
DZIEKAN Jerzy (.)
. - Walter and Eliza Hall Institute of Medical Research - Parkville, Victoria - AUSTRALIA
COWMAN Alan (Host supervisor)
To achieve the ultimate goal of malaria elimination, a new generation of antimalarial therapeutics is required that have both transmission-blocking and chemoprotective properties. However, to facilitate the rational design of multi-stage targeting antimalarial drugs, we first need to bridge knowledge gaps in our understanding of malaria parasite transmission to mosquitoes and its development at the host-vector interface. Here, we will leverage two recently developed, powerful proteomic approaches, Thermal Proteome Profiling (TPP) and Limited Proteolysis Mass Spectrometry (Lip-MS), to characterise functional proteome states during malaria parasite sexual development in the host and the vector. TPP and Lip-MS allow proteome-wide readout of protein stability, which is influenced by protein interactions with diverse physiological ligands, metabolites, cofactors, DNA/RNA, posttranslational modifications and protein complex formation. Consequently, protein stability serves as a proxy for its functional state in a living cell. Monitoring stability dynamics can inform on the functional states of transcription factors, protein-protein interactions and enzyme activity. Datasets generated by this study will answer fundamental biological questions on proteome regulation during parasite development and the molecular events governing transmission. To characterise essential molecular processes, we will monitor the effect transmission-blocking agents on proteome stability, identifying their targets and pathways they disrupt. This project will not only develop a new understanding of malaria biology but will also identify novel avenues for the rational design of antimalarial interventions.
2022
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Long-Term Fellowships - LTF
Monitoring and manipulating inter-organellar contact-sites during mycobacterial infection
EISENBERG-BORD Michal (.)
. - University of Cambridge - Cambridge - United Kingdom
RAMAKRISHNAN Lalita (Host supervisor)
Tuberculosis (TB), humanity’s greatest infectious killer, kills nearly 2 million people a year with antibiotic resistance burgeoning. Understanding its fundamental pathogenesis could yield new treatments that overcome drug resistance by targeting host determinants and pathways that Mycobacterium tuberculosis (Mtb) exploits. Mtb first resides in macrophage phagosomes and phagolysosomes, then promotes macrophage necrosis, a critical pathogenic event that increases morbidity and transmission. Work in the zebrafish larval model of TB identified a macrophage necrosis pathway that requires transfer of molecules between mitochondria and lysosomes, and ER and mitochondria. I hypothesize Mtb manipulates interorganellar contact-sites to mediate pathogenesis—first intramacrophage growth and then macrophage necrosis through the newly-identified pathway. The transparent zebrafish larva is ideal to test this. I will determine which contact-sites are altered in infection using fluorescence-labeling tools and test their roles using CRISPR-Cas9 technologies. My work could lead to fundamental discoveries about both TB pathogenesis and contact-site biology while identifying potential new therapeutics. Later, I will expand to decipher the role of interorganellar contacts in other serious intracellular bacterial pathogens. My research will bring new ideas and approaches to infectious diseases pathogenesis. While acquiring training in this new area, I will bring my expertise in cell biology and interorganellar contact-sites to my mentor lab and my new field. Expertise that I acquire in the zebrafish model will provide me new toolkits to approach cell biological questions broadly in the future.
2022
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Long-Term Fellowships - LTF
Dissecting the structure-function consequences of mechanical stress on intact neural circuits
EL-QUESSNY Malak (.)
. - ICFO – The Institute of Photonic Sciences - Castelldefels - SPAIN
KRIEG Michael (Host supervisor)
Traumatic brain injuries (TBI), induced by strain or mechanical compression, compromise gross brain vasculature and signaling. On a cellular level, TBI has been shown to disrupt excitatory signaling as well as altering cellular morphology and the axonal cytoskeleton, which are now used as early indicators of progressive neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Although the clinical importance of neuronal injury is widely recognized, a complete understanding of how mechanical forces influence the changes in neural structure and signaling remains unknown.
In this proposal, I develop a novel method for understanding the structure-function consequences of mechanical stresses, on intact mouse cerebral organoids, to study how neural circuits respond to injury. To do this, I will utilize a mouse line that stochastically expresses different fluorescent reporters, one of which is a genetically encoded calcium indicator (GCaMP), and culture their embryonic stem cells to form three-dimensional cerebral organoids (Lancaster et al 2013), yielding a “brainbow” inspired multicolor toolbox (Cai et al. 2013). Next, I will use a light sheet microscope (Huiskin et al. 2004) fitted with a microfluidic and mechanical confiner (Venturini et al. 2020) to probe the three-dimensional morphology of fluorescently labeled single neurons, their calcium responses to mechanical stresses, as well as the functional dynamics across organoid networks. With these tools, I can uncover the mechanism by which biomechanical stimuli influence the structure and function of mammalian circuits following injury and the cellular underpinnings of their subsequent degeneration.
2022
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Grant Awardees - Program
Bridging biophysics and evolution: impact of intermediate filament evolution on tissue mechanics
TOMANCAK Pavel (CZECH REPUBLIC)
Max Planck Institute of Molecular Cell Biology and Genetics - Max Planck Society - Dresden - GERMANY
HEISENBERG Carl-Philipp (GERMANY)
Heisenberg Lab - IST Austria - Klosterneuburg - AUSTRIA
HEJNOL Andreas (GERMANY)
Department of Biologial Sciences/Comparative Developmental Biology - Friedrich Schiller University Jena - Jena - GERMANY
EXTAVOUR Cassandra (CANADA)
Dept. of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA
Interactions between mechanical and biochemical processes determine the shape of living matter. However, we do not understand how this interaction evolves to give rise to the large diversity of shapes of life. Our team will take a comparative approach at the interface between evolutionary developmental biology and biophysics to identify conserved and divergent mechanochemical interaction principles determining animal shape. Specifically, we will elucidate how the biochemical evolution of intermediate filaments (IFs) impacts the mechanical and morphogenetic properties of epithelial tissues undergoing spreading in different model and non-model organisms across the tree of life. Epithelial spreading, whereby a sheet of connected cells stretches to increase its surface area, is a common phenomenon in various developmental and disease-related processes, such as gastrulation, oogenesis and wound healing. IFs are generally thought to function in this process by providing epithelia with mechanical support, and to protect them from damage by external and internal forces. Our preliminary observations suggest that different mechanical properties of spreading epithelia in arthropods and vertebrates are associated to the presence of IFs in vertebrates, and their loss in arthropods. We thus hypothesize that the diversification of IFs is responsible for the evolution of species-specific mechanical properties of epithelial tissues determining their spreading behavior. We will test this hypothesis by strategically sampling species across animal phylogeny and determine how changes in IF biochemistry cause changes in epithelial mechanics and spreading. Finally, we will challenge this hypothesis by ambitious experiments where entire IF molecular machineries will be added to the genomes that do not have it, and examine the impact on epithelial tissue mechanics and morphogenesis. Our major innovation is bridging evolutionary biology and tissue biomechanics. This transdisciplinary approach will elucidate the physical basis for the genotype-phenotype relationship, revealing how mechanochemical processes evolve to yield diverse animal shapes. Our proposal combines the strengths of traditionally separate disciplines to investigate the morphogenetic role of IFs, central yet understudied cytoskeletal elements, across phylogeny.
2022
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Grant Awardees - Early Career
How fishes use historical hydrodynamic motion cues in search and navigation tasks
HERBERT-READ James (UK)
Department of Zoology - University of Cambridge - Cambridge - UK
FAN Dixia (CHINA, PEOPLE'S REPUBLIC OF)
Dept. of Sustainable and Environmental Engineering - Westlake University - Hangzhou - CHINA, PEOPLE'S REPUBLIC OF
JODIN Gurvan (FRANCE)
SATIE CNRS - ENS Rennes - BRUZ - FRANCE
Just as boats leave a wake as they travel over the surface of the water, underwater animals also leave a trail of water disturbance as they move through their environment. These trails, termed ‘hydrodynamic motion cues’, hold information about the size of the animal that was travelling through that location in the past, what type of animal it was, and how that animal was moving. In effect, these hydrodynamic motion cues represent a ‘liquid fingerprint’, holding information about the animal itself and and how it was travelling through that location in the past. Many species of fishes are able to detect the hydrodynamic pressure of these liquid fingerprint, however, we know little about how the hydrodynamic information detected by animals is used in their behavioural decision-making. In this project, we will test whether fishes that sense the hydrodynamic cues generated from the past movements of other animals use this information in different behavioural tasks. For example, some prey fishes may use these cues to find other group members, while other predatory species may use these cues to track their prey. Using a combination of behavioural experiments, modern sensing technology, and machine learning techniques, this project aims to understand how hydrodynamic motion cues are used by fishes in search and navigation tasks. This work will not only allow us to understand some of the extraordinary sensory and behavioral adaptations that animals have evolved in underwater environments, but will also be informative for engineering applications, including the design of autonomous sensing vehicles.
2022
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Grant Awardees - Program
The evolution of sperm cell shape and motion
HUMPHRIES Stuart (UK)
Physical Ecology lab., College of Science, School of Life Sciences - Lincoln Institute for Advanced Studies - Lincoln - UK
SNOOK Rhonda (USA)
Dept. of Zoology - Stockholm University - Stockholm - SWEDEN
FAUCI Lisa (USA)
Dept. of Mathematics - Tulane University - New Orleans - USA
Across the tree of life, sperm show an unrivalled diversity of shapes and sizes greater than any other cell type. The reasons for such diversity remain elusive. Most work has focussed on simple sperm shape found in externally fertilizing invertebrates and internally fertilizing vertebrates, yet most diversity is found in internally fertilizing invertebrates, especially insects. Therefore to truly understand how and why different sperm shapes have evolved, we need to shift away from these historically studied animals and focus on the evolution of insect sperm. In this project we will test how sperm shape and size variation has evolved and more specifically, how it allows sperm to perform their ultimate function – fertilisation. To do so, we will unite researchers from three differing disciplines: biophysics, evolutionary ecology, and mathematics. A biophysics approach will allow us to test how the sperm swim, and determine how the reproductive fluid and reproductive tracts they move in shape these movements. An evolutionary ecology focus will allow us to test how both large- and small-scale evolutionary variation in sperm shape is linked to coevolution with the fertilization environment of the female. The fundamental integration of mathematics across and within our projects will provide synthesis of empirical work and generate new predictions of how the combination of sperm shape and motion, reproductive tract structure, and competition between multiple sperm affect reproductive performance. Only by combining these three disciplines can we truly understand this sperm diversity for the first time. Novel experimental devices, microscale measurements of fluid properties, genetic studies and computational modelling will allow us to chart the evolution of sperm shape, understand how sperm form and female reproductive tracts evolved together, and to link all of these to predict and understand how sperm performance is determined.
2022
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Grant Awardees - Early Career
Reconstructing water to land transitions in arthropod evolution combining atoms, genes and fossils
FERNANDEZ Rosa (SPAIN)
CSIC - Institute of Evolutionary Biology - Barcelona - SPAIN
MUÑOZ-GARCIA Ana Belen (SPAIN)
Department of Physics "Ettore Pancini" - University of Naples Federico II - Naples - ITALY
ORTEGA-HERNANDEZ Javier (MEXICO)
Department of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA
Breathing has played a key role in all animal life since its origins more than half a billion years ago. Animals occupy all types of environments, ranging from mountain tops to the bottom of the oceans. Despite this enormous variability of lifestyles, all animals fall within one of three possible categories for breathing: those that breathe air, those that breathe underwater, or those that do a combination of both. The common denominator is that all animals breathe to consume oxygen, a chemical element that can either be a lethal toxin or a vital gas, depending on the circumstances. The transition from breathing underwater to breathing air represents one of the most important steps in animal evolution, as it allowed them to explore dry land for the first time approximately 420 million years ago. However, the precise mechanisms responsible for the water to air transition of breathing and oxygen consumption remain largely unknown due to the complexity of this drastic change in the mode of life of early animals. The objective of this project is to investigate the early evolution of air-breathing among arthropods, animals with jointed legs whose living representatives include arachnids, millipedes, crustaceans and insects. Arthropods represent ideal case studies because they are among the first animals that evolved air-breathing as informed by the fossil record, as well as having well-developed structures for oxygen exchange such as external and internal gills. To better understand how animals acquired the capacity to consume oxygen from breathing air, we will explore this question from three interdisciplinary approaches: 1) We will explore how hemocyanins (the respiratory pigments of arthropods) have evolved through time and will investigate if the oxygen-transporting function in different respiratory structures is due to similar or different genes. 2) We will use the excellent fossil record of arthropods to investigate how respiratory structures have changed over millions of years, from fully marine animals during the Cambrian Explosion, to the first land-dwelling species that show the earliest evidence of adaptations for air-breathing in the Silurian and Devonian. 3) We will use and develop micro- and macroscopic physico-chemical approaches to investigate hemocyanin reactivity and respiratory flux features for different respiratory architectures.
2022
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Long-Term Fellowships - LTF
Dynamic threat assessment and signal integration by innate immune signaling complexes
FISCH Daniel (.)
. - Boston Children's Hospital - Boston - United States
KAGAN Jonathan (Host supervisor)
Pattern-recognition receptors (PRRs) of the innate immune system sense threats arising from pathogens or tissue injury, respectively known as pathogen or damage-associated molecular patterns (PAMPs/DAMPs). Upon activation, PRRs induce formation of supramolecular organizing centers (SMOCs). SMOCs are the signaling organelles of the innate immune system controlling cytokine production and cell death. SMOC activities were commonly studied in reductionist systems, using pure ligands of individual PRRs. However, during microbial encounters multiple PAMPs are present and likely contribute to SMOC activity, raising the possibility of additive, synergistic or even antagonism responses.
To test this, I propose to examine the dynamics of SMOC formation, composition, localization and effector activities using a distinct model system to prior approaches. Specifically, I plan to create CRISPR knock-in macrophages for live cell imaging and spatial proteomics. To offer modularity for PRR stimulation, I plan to use beads as “minimalist microbes”. Their regular, circular shape (and isolation methods for bead-containing phagosomes) allows monitoring protein localization and activities on these minimalist microbes. Combined with the flexibility to attach defined PAMPs, I envision development of a powerful discovery platform. Findings from these synthetic approaches will be scrutinized using primary cells to understand how SMOC assembly with defined ligands in isolation or in combination controls signaling and effector functions. This work will help elucidate how innate immune cells perceive and compute threats in an inflammatory environment and how they decide on an appropriate response.
2022
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Grant Awardees - Program
Multi-omic reconstruction of flow across the distributed metabolism of early-branching Dracula ants
LEBOEUF Adria (USA)
Department of Biology - University of Fribourg - Fribourg - SWITZERLAND
FISHER Brian Lee (USA)
Entomology - California Academy of Sciences - San Francisco - USA
TEUSINK Bas (NETHERLANDS)
Amsterdam Institute of Molecular and Life Science (AIMMS) - VU University Amsterdam - Amsterdam - NETHERLANDS
Many successes in life are based on collaboration – this extends to the molecular level, where life is fueled by the chemical processes collectively called metabolism. Microorganisms exchange nutrients through cross-feeding, and multicellular organisms are made up of tissues with different metabolic roles and needs. Social insects, where the notion of self is distributed over multiple individuals, take this collaboration still further: Many ant colonies engage in social exchanges of experimentally accessible fluids that contain both exogenously sourced and endogenously produced materials. Larvae of many social insects have been purported to be a ‘digestive caste.’ They are fed exogenously sourced food by adults and return a nutritious fluid whose metabolic functions remain unestablished. The mode of transmission from larvae to adults varies across ant species: In some, larvae voluntarily secrete fluids, while in early-branching ‘Dracula’ ants, adults non-destructively drink larval hemolymph. Such socially exchanged fluids can be analysed to monitor the fluxes of distributed metabolism, making ant colonies apt model systems to study the molecular mechanisms of inter-system communication and division of metabolic labor. We address three key questions (i) what is being exchanged? (ii) what are the functional implications of these exchanges? and (iii) how did these modes of exchange evolve? We combine behavior observations with detailed molecular analyses of four species representing different social feeding modes and evolutionary lineages. We perform proteomics and metabolomics on each colony-tissue and exchanged fluid. Based on genomes and gene expression, we reconstruct metabolic networks for advanced multi-omic data integration to identify active pathways. Novel community-scale metabolic modeling will be used to probe colony-level functionality of social exchange. Critical pathways will be validated with fluorescent metabolite probes in an automated colony- and transmission-tracking system and by genetic or feeding perturbations. This project offers new ways to view social behavior, evolutionary biology, metabolism and the physics of collective behavior. Ultimately, this work will innovate by elucidating the functional role of distributed metabolism, probing its evolution, and providing new tools to study community-level metabolic interactions.
2022
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Long-Term Fellowships - LTF
Dopaminergic basis of learning temporal regularities in perceptual decisions
FRITSCHE Matthias (.)
. - University of Oxford - Oxford - United Kingdom
LAK Armin (Host supervisor)
Learning from past decisions and their outcomes allows us to make predictions about the future, thereby improving subsequent decisions. Some predictions are formed based on the stability of the world in which past successful decisions tend to remain successful (stable predictions), while others rely on foreseeable dynamic changes in the environment (dynamic predictions). How does the brain learn to make these distinct predictions? I propose to address this question by combining cutting-edge behavioural, neurobiological and computational tools in mice. I will investigate whether the neurotransmitter dopamine, a central component of the brain’s learning circuits, plays a role in this learning process. Specifically, I hypothesize that dopamine regulates distinct prediction strategies through the modulation of neural circuits in two brain areas: the striatum and prefrontal cortex. I will first identify the behavioural signatures of stable and dynamic prediction strategies by training mice to perform visual decisions in environments affording both types of predictions, and will develop computational models of decision-making that capture mouse behaviour. I will then investigate the roles of dopamine in this learning by measuring the release of dopamine in prefrontal cortex and striatum using novel imaging techniques. Finally, I will determine the causal role of dopamine by manipulating dopamine signals in the two brain areas, using optogenetic tools. This research will provide fundamental insights into the neural bases of decision-making, and could shed light on clinical conditions that compromise decision-making and cognition.
2022
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Grant Awardees - Early Career
Biofilm heterogeneity as an evolutionary mechanism for resilience to complex environments
FUSCO Diana (ITALY)
Physics - University of Cambridge - Cambridge - UK
TROPINI Carolina (CANADA)
Dept. of Microbiology and Immunology and School of Biomedical Egineering - University of British Columbia - Vancouver - CANADA
RUIZ PESTANA Luis (SPAIN)
Civil, Architectural, and Environmental Engineering - University of Miami - Coral Gables - USA
Biofilms are structured communities of bacteria that grow at interfaces and have a remarkable ability to adapt and thrive in a tremendous diversity of hostile environments, including antibiotic-impregnated prosthetic implants. As such, biofilms are the most pervasive life-form on Earth. Our understanding of how biofilms achieve and have evolved this amazing resilience is woefully incomplete, as evidenced by our inability to disrupt detrimental biofilm formation. We hypothesize that phenotypic plasticity and biofilm morphology are coupled and have coevolved to promote optimal adaptation and survival in fluctuating hostile environments. We formulate this hypothesis based on 1) the correlation between biofilm morphology and phenotypic spatial organization 2) the widespread phenotypic heterogeneity among bacterial species, and 3) the multiple mechanisms through which functional and phenotypic diversity may confer advantages to biofilms. While isolated parts of this problem have been investigated, the intrinsic coupling between the mechanics, microbiology and evolution across multiple scales has not yet been explored. Our overall goal is to understand the feedback between cell-to-cell phenotypic heterogeneity, local physico-chemical conditions, and macroscale biofilm morphology, and to elucidate its evolutionary path and role on the amazing resilience of biofilms. Our research plan consists of three aims. First, we will learn the microscopic rules that govern the interplay between mechanical forces and gene expression. Second, we will determine whether and how phenotypic plasticity and associated biofilm morphology in the wildtype confers a fitness advantage to the biofilms. Third and last, we will elucidate how phenotypic heterogeneity could have spontaneously evolved. Our approach consists of a synergistic combination of a bottom-up multiscale modeling framework to map the mechanisms that control the feedback and co-evolution between phenotypic heterogeneity and biofilm morphology, in-vitro microfluidics and top-agar setups to inform and validate the computational models, directed evolution experiments, and in-vivo characterization of gut microbial biofilms to corroborate and revise our in silico understanding of biofilm behavior. The completion of this work will enable an integrated model of the role of heterogeneity in establishing biofilm resilience.
2022
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Long-Term Fellowships - LTF
Microtechnology-based limbic-cortex axis in 3D: modeling human neurodevelopment and disease
GARONE Maria giovanna (.)
. - Murdoch Childrens Research Institute - Parkville - AUSTRALIA
VELASCO Silvia (Host supervisor)
Stem cell-derived 3D organoid models hold great promise for studying processes of human brain development that would not otherwise be experimentally accessible. The amygdala is the component of the limbic system that regulates emotion and behavior, making extensive connections with the cerebral cortex and hippocampus. Its alterations have recently been highlighted as hallmarks of neurodevelopmental diseases, such as autism spectrum disorder (ASD). Despite recent advances in the generation and characterization of 3D systems replicating brain regions in vitro, models of the amygdala are still missing. Therefore, I propose to develop an innovative method to differentiate human induced pluripotent stem cells (iPSC) into amygdala-like brain organoids (hAmyOs). By using microtechnology-based methods to improve nutrient delivery and exchange, I aim to establish a next-generation 3D system to recapitulate the mutual interactions among the human cortex, amygdala, and hippocampus. By taking advantage of this novel 3D hiPSC-derived cortex-amygdala-hippocampus assembloid system, I will explore aspects of neuronal biology and function involved in human brain development and disease. I will focus on ASD mutant 3D systems to investigate defects of connectivity among defined brain regions with long-term live imaging and functional assays. Moreover, I will leverage single-cell-omics technologies to unbiasedly discover cell-type specific abnormalities and pathogenic mechanisms associated with mutation of ASD genes. Our research will provide a platform to study limbic-cortex connections involved in human development and for modeling circuit organizations and neurodevelopmental diseases.
2022
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Long-Term Fellowships - LTF
Metabolic and cell–cell interactions of Helicobacter pylori and stem cells of the gastric glands
GEIER Benedikt (.)
. - Stanford University School of Medicine - Stanford - United States
AMIEVA Manuel (Host supervisor)
Virulent strains of the global pathogen Helicobacter pylori (Hp) significantly increase the risk of developing gastric cancer. Recently, Hp has been described to form clonal microcolonies directly on the epithelial surface deep within the gastric glands, where they affect the proliferation and gene expression of epithelial stem cells.
My aim is to reveal the molecular details of how these gland-associated Hp strains shape this niche and how virulent strains promote gastric cancer.
To study metabolic interactions in situ I have developed an approach combining fluorescence labeling and high-resolution mass spectrometry imaging. I will to translate my approach for analyzing how different Hp strains and epithelial stem cells change their metabolome during colonization of the gastric gland microniche. To reveal the metabolic heterogeneity of Hp microcolonies that grow on the epithelia and to understand the underlying cell-cell interactions, I propose to integrate metabolite imaging with 3D correlative light and electron microscopy. Two experimentally tractable infection models developed by the host lab will serve me as study systems: a chronic Hp infection model of murine stomachs, and a human organoid model that mimics different regions of the gastric gland epithelium. I will infect both systems with genetically modifiable, isogenic Hp strains to show how virulence factors modulate the site-specific metabolism and ultrastructure of epithelial stem cells.
Here, I plan to develop a framework to investigate fundamental interactions between microbial strains and human epithelia to shed light on how Hp promotes gastric cancer by colonizing the microniche of the gastric glands.