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Awardees

2022 -
Grant Awardees - Program

Assembly, mechanics and growth of plant cell walls

COEN Enrico (UK)

Dept. of Cell and Developmental Biology - The John Innes Centre - Norwich - UK

COSGROVE Daniel J. (USA)

Biology - Pennsylvania State University - UNIVERSITY PARK - USA

DURAND-SMET Pauline (FRANCE)

Matter and complex systems - Université Paris Cité - Paris - FRANCE

SVAGAN (HANNER) Anna (SWEDEN)

Fibre and Polymer Technology - Royal Institute of Technology - Stockholm - SWEDEN

The shape and architecture of every plant depends on how its cells grow. The outer membrane of every plant cell is surrounded by a wall made of cellulose fibres embedded in a matrix, and neighbouring cells are stuck together so they cannot move. Despite these constraints, plants can generate remarkable shapes, from orchid flowers to tree canopies. These forms arise through a dynamic process in which the pressure within each cell causes the walls to stretch irreversibly, a process known as creep. Wall thickness is maintained through synthesis of new layers of fibers at the cell membrane, and partitioning walls are also added, preventing cells from becoming too large. Although the pressure in each cell acts equally in all directions, the wall fibers are not randomly arranged, causing cells to creep more in some orientations than others. The secret of plant shape therefore lies in how the cell walls are structured to yield with specific rates and orientations. Although much progress has been made in understanding how genes control these processes, we still lack a quantitative understanding of how growth of even a single plant cell is controlled. One difficulty is that cell wall properties depend on their history of formation, which is usually unknown. A further problem is that growth is modified by mechanical constraints and signals from neighbouring cells. This project aims to circumvent these problems by exploiting a simplified system in which the formation of a new wall can be followed from scratch. Protoplasts are single plant cells in which the walls have been digested away. Under the right conditions, protoplasts will regenerate their walls and exhibit oriented growth. Using the state-of-the-art techniques, we will quantify and perturb different components of the wall as it is made and measure its mechanical properties as it strengthens and begins to undergo creep. We will also synthesize simplified artificial plant cells and cellulose nanofiber networks to test hypotheses for how walls acquire their mechanical properties and the feedback mechanisms involved. By exploring hypotheses through computational modelling, we will evaluate which best predict experimental results and thus arrive at an integrated quantitative understanding of cell wall synthesis, assembly, mechanics and growth that underpins plant development.
2022 -
Grant Awardees - Program

The social origins of rhythm

COOK Peter (USA)

Psychology - New College of Florida - Sarasota - USA

KING Stephanie (UK)

School of Biological Sciences - University of Bristol - Bristol - UK

MADSEN Peter Teglberg (DENMARK)

Dept. Of Biology, Section for Zoophysiology - Aarhus University - Aarhus - DENMARK

RAVIGNANI Andrea (ITALY)

Department Human Neurosciences - Sapienza University of Rome - Rome - ITALY

The enjoyment of music is ubiquitous across human societies and cultures. Among the (bio)cognitive underpinnings to process and enjoy music, rhythm plays a key role. In humans, musical beat processing intimately links perception and action when we entrain rhythmic movements to musical beats. In social settings, this leads to rhythmic actions within groups of people, such as dancing or marching in unison, but what selective pressures led to rhythmic behaviour to begin with, and why did the social use of rhythm evolve? The search for the origins of social rhythm is complicated because unlike other biological traits, rhythmic processing does not fossilize and humans only constitute one datapoint to build testable hypotheses on rhythm evolution. However, rhythmic processing is not unique to humans, with examples found across the animal kingdom. In this project, we will integrate approaches from field biology, comparative neuroscience, artificial intelligence, and speech sciences to test competing hypotheses on the evolutionary roots of rhythmic abilities. We will study a wide range of marine mammal species, known for their vocal flexibility but subject to differing social pressures, as a test-bench for evolutionary hypotheses on the origins of social rhythm in our own species.
2022 -
Grant Awardees - Early Career

Cellular and molecular basis of behavioural manipulation by viral infection

CRAVA Maria Cristina (ITALY)

Universitary Institute BIOTECMED - University of Valencia - Burjassot - SPAIN

GAMIR FELIP Jordi (SPAIN)

School of Technology and Experimental Sciences - University Jaume I of Castellon - Castellón de la Plana - SPAIN

PRIETO GODINO Laura Lucia (SPAIN)

Neural Circuits and Evolution lab - The Francis Crick Institute - London - UK

YON Felipe (PERU)

Laboratorios de Investigación y Desarrollo, Lab. 308 - Universidad Peruana Cayetano Heredia - Lima - PERU

Viruses and other pathogens can dramatically modify animal behaviour by altering the host’s nervous system. Famous examples include the zombie ants infected by fungi, or the neurological effects of rabies virus. How pathogens have evolved to exquisitely manipulate host behaviour, and the molecular and cellular bases behind this manipulation are poorly understood. Furthermore, the host-pathogen interactions are almost exclusively addressed in the laboratory under controlled conditions, excluding other players that can shape them in the real world. Tackling these complex, multidisciplinary questions requires in-depth knowledge of the ecology and biology of both the host and the pathogen and the ability to genetically manipulate all three ends; the virus, the host and the ecological settings to gain mechanistic insights. Here, we propose to address how viruses alter animal behaviour using as a model the triangle-like interaction between baculovirus, Spodoptera exigua caterpillars and tomato plants where this latter feed. We will couple genetic manipulation of the three biological systems with transcriptomics, molecular virology, neurophysiology, metabolomics, greenhouse ecological observations and bioassays. We will analyse how baculovirus alter a suit of caterpillar behaviours with a special focus on odour-guided behaviours and how these interact with ecological factors. Our results will shed light on which host’s biological processes are hitchhiked by the virus to ensure its maximal dispersal and the neuronal and molecular mechanisms behind this manipulation.
2022 -
Long-Term Fellowships - LTF

Somatosensory processing in a cerebello-cortical loop for adaptive control

CROSS Kevin (.)

. - The University of North Carolina at Chapel Hill - Chapel Hill - United States

HANTMAN Adam (Host supervisor)
Somatosensation is critical for preparing and executing motor actions as somatosensory impairments severely impact even basic motor function. Theories predict somatosensory feedback is monitored to correct for unexpected errors during a motor action and update internal models of the body to improve future motor actions. Motor cortex plays an important role in generating adaptive motor behaviours and is reciprocally coupled with subcortical circuits involved with sensory processing including the cerebellum forming the cerebello-cortical loop. Somatosensory feedback is a major input to the cerebello-cortical loop, however, how somatosensory feedback is transformed across this loop and how processing in this loop impacts adaptation across multiple timescales during motor actions are largely unknown but are critical for understanding adaptive control. To address these questions, we will develop novel optogenetic tools to stimulate somatosensory afferents projecting from muscles. These tools will be combined with high-density silicon electrode recordings in mice trained to perform goal-directed reaching movements. We will analyse how mice adapt to somatosensory stimulation across different behavioural timescales including within trial, across trials and across days and explore how adaptation across these timescales are reflected in the dynamics of the cerebello-cortical loop. We will also investigate how somatosensory feedback may be flexibly routed through the cerebello-cortical loop in accordance with the behavioural goal. These results will provide insight into how cortical and subcortical circuits coordinate to process and adapt sensory information for motor actions.
2022 -
Long-Term Fellowships - LTF

Cell size-dependent sex determination

D'ARIO Marco (.)

. - Stanford University School of Medicine - Stanford - United States

LESLIE Andrew (Host supervisor)
Sex-associated size differences have evolved independently across the tree of life. Size is often regarded as a consequence of sex when linked to chromosomal inheritance, but sex determination due to cell size occurs in many plants. Post meiotic abortion in plants causes enlargement of some gamete cells, ultimately resulting in a shift to female functionality. But exactly how size dictates sex determination remains a mystery. The aim of this project is to investigate size-dependent sex determination in plants by understanding the development of spores via a novel experimental framework. We will use cutting-edge microscopy techniques combined with cellular laser ablation to visualize and manipulate spore development in vivo. By artificial abortion of male gametes, we will be able to test the long-standing hypothesis that size promotes sex differentiation via nutrient availability. At the same time, we will use transcriptomics of developing spore tissue to characterize genetic differences associated with sex determination. This combined approach will generate a novel 4-dimensional dataset of developing spores and an understanding of the physical and genetic components behind size-dependent sex determination. This work will focus on the lycopsids, an early plant group that has evolved size-dependent sex determination in some lineages, including the well-established model organism Selaginella moellendorffii. Ultimately, determination of the biological processes that unite size and sex determination will further our understanding of their evolutionary relationship and allow future investigations on the molecular mechanisms of size-dependent sex determination.
2022 -
Grant Awardees - Program

Bacterial genome editing systems as a driver of cancer mutations

DAGAN Tal (GERMANY)

Institute of Microbiology - Kiel University - Kiel - GERMANY

GALUN Eithan (ISRAEL)

Director, Goldyne Savad Institute of Gene Therapy - Hadassah Hebrew University Hospital - Jerusalem - ISRAEL

As life expectancy increases in the world, the likelihood that any individual will be diagnosed with cancer, or die from cancer related illness is high. Cancer development is associated with the occurrence of mutations, that develop in specific cell types in our body during aging. These mutations are the drivers of cancer development. Although we have a substantial knowledge as for the effect of mutations in specific genes on cancer propagation in the specific organs, we have no understanding why these specific genes are mutated and how mutations emerge. Our skin, gut and respiratory systems, are habitats to diverse bacteria that can interact with our organs. We know that bacteria can enter cells in our body in different organs. We also know that bacteria can secret different types of genetic cargo elements that can enter normal cells. The interaction between bacteria and human has been implicated in various states of health and disease. Here we aim to investigate whether bacteria and bacterial secreted elements may play a role in the emergence of cancer mutations. Our focus is on bacterial defense systems against their natural enemies: bacteriophages. To defend themselves against invading phages, bacteria evolved various mechanisms to cut and degrade phage DNA. Such systems have been adopted and utilized by scientists in order to engineer the genome of animals, plants and microorganisms with high precision. Bacteria that are associated with humans, also harbor such mechanisms; however, whether the DNA stored in our cells may be sensitive to bacterial defense systems is currently unknown. Can bacteria in the human microbiome manipulate our genome and initiate cancer development? In this program, two teams that never collaborated before, resolved to meet the challenges put forth by this hypothesis. The expertise of these teams are in very different scientific fields essential for investigating this project. The Dagan team in Kiel is a microbiological research group with knowledge in bacterial genetics and genomics, who will collaborate with the Galun team in Jerusalem that has the knowledge to establish cancer models in cell culture and mice. Together, the two teams will establish an experimental system to investigate the role of bacteria as drivers of mutagenesis in human tissues. Neither team alone is capable to conduct this program solely.
2022 -
Grant Awardees - Program

Unravelling the code of mitochondrial-nuclear communication

DASKALAKIS Nikolaos (GREECE)

NeuroGenomics & Translational Bioinformatics Laboratory - McLean Hospital/ Harvard Medical School - Belmont - USA

LEFKIMMIATIS Konstantinos (GREECE)

Department of Molecular Medicine - University of Pavia - Pavia - ITALY

STÄDLER Brigitte (SWITZERLAND)

Interdisciplinary Nanoscience Center (iNANO) - Aarhus University - Aarhus - DENMARK

The energetic status of mitochondria often defines the outcomes of complex cellular responses. However, the modalities through which mitochondria-derived signals (retrograde signalling) are perceived by the nucleus and translated into specific transcriptional responses are poorly understood. A major roadblock in studying the crosstalk between these two organelles is our inability to isolate the messages they exchange from the background signalling events constantly taking place within the cell. We propose to overcome this issue with a bottom-up approach in which we will attempt to develop a synthetic, matrix-sustained two-organelle unit and use it as a platform to address a number of questions fundamental to mitochondrial and nuclear biology. By incorporating biosensors for small compounds that participate in mitochondria-nucleus crosstalk both, in the matrix and organelles, we will be able to identify the signalling molecules employed by these organelles under specific conditions (from nutrient availability to mitochondrial DNA damage). Similarly, by employing next generation single nucleus RNA sequencing we plan to identify the specific transcriptional signatures triggered by distinct mitochondrial changes in nuclei of the same background. We designed a collaborative research plan that builds across all three fields of expertise and combines cutting-edge techniques with conceptual perspectives. Städler, a materials chemistry expert, will develop the inter-organelle communication matrixes (IOCMs) and optimize the encapsulation of mitochondria and nuclei. Lefkimmiatis, a cell physiologist, will develop the biosensors, validate their functional incorporation in the support matrix and organelles, and will perform the imaging experiments for the identification of organelle-derived signals. Finally, Daskalakis, an expert in transcriptomics, will employ single nucleus RNA sequencing and bioinformatic analysis for recognizing the transcriptional signatures coupled to specific mitochondrial conditions. By working together, we will paint a comprehensive picture of how mitochondria and nuclei communicate as well as provide the scientific community with a platform that offers a controlled environment optimal for investigating complex communication pathways in the absence of background “signalling noise”.
2022 -
Grant Awardees - Early Career

How do ecological network dynamics mediate the response of organisms to novel environments?

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

PILOSOF Shai (ISRAEL)

Department of Life Sciences - Ben Gurion University of the Negev - Beer-Sheva - ISRAEL

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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
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 -
Grant Awardees - Program

Bridging biophysics and evolution: impact of intermediate filament evolution on tissue mechanics

EXTAVOUR Cassandra (CANADA)

Dept. of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA

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

TOMANCAK Pavel (CZECH REPUBLIC)

Max Planck Institute of Molecular Cell Biology and Genetics - Max Planck Society - Dresden - GERMANY

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 -
Grant Awardees - Early Career

How fishes use historical hydrodynamic motion cues in search and navigation tasks

FAN Dixia (CHINA, PEOPLE'S REPUBLIC OF)

Dept. of Sustainable and Environmental Engineering - Westlake University - Hangzhou - CHINA, PEOPLE'S REPUBLIC OF

HERBERT-READ James (UK)

Department of Zoology - University of Cambridge - Cambridge - UK

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 -
Grant Awardees - Program

The evolution of sperm cell shape and motion

FAUCI Lisa (USA)

Dept. of Mathematics - Tulane University - New Orleans - USA

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

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.