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Awardees

2021 -
Long-Term Fellowships - LTF

Algorithms and circuit mechanisms underlying distance estimation in larval zebrafish

VOIGT Fabian (GERMANY)

Department of Molecular and Cellular Biology - Harvard University - Cambridge - USA

ENGERT Florian (Host supervisor)
All species need to navigate, forage, and interact with other animals in a constantly changing threedimensional world. For such behaviors, vision is one of the most important senses as it allows animals to map their immediate surroundings from a distance which in turn helps coordinating ongoing and future motor actions. To construct such a map, the visual system uses a wide variety of depth cues such as object size, binocular disparity, texture, accomodation, shading, perspective, motion parallax, and occlusions. However, despite extensive research into the function of visual systems, currently, it still remains unclear what the exact perceptual algorithms and circuit mechanisms underlying depth perception are. Therefore, I propose to investigate how larval zebrafish process depth information and use such cues during hunting behavior. Given its small size, genetic tractability, optically accessible brain, and rapid development of visually driven behaviors, the larval zebrafish is an ideal vertebrate model system to tackle these questions. Starting at 5 days post fertilization, larvae visually hunt small protists. At the start of a hunting sequence, they almost invariably select the closest prey, which suggests that they posses a way of visually estimating distance. In order to investigate how larvae perform this feat, I plan to design and build a novel virtual reality system than can provide both monocular and binocular depth cues to a freely swimming or restrained zebrafish larva. Using this VR system, I then aim to determine which depth cues are utilized and investigate their neuronal representation using whole-brain two-photon imaging.
2021 -
Long-Term Fellowships - LTF

Mechanisms of 5´UTR-mediated translational dysregulation in cancer

WEBER Ramona (GERMANY)

Institute for Regenerative Medicine - University of Zurich - Zurich - SWITZERLAND

SENDÖL Ataman (Host supervisor)
The dysregulation of protein synthesis in favor of oncogenic proteins is a hallmark of cancer. Recent discoveries revealed that translation of upstream open reading frames (uORFs) within 5´ untranslated regions (5´UTRs) of oncogenic messenger RNAs (mRNAs) contributes substantially to increased oncogene synthesis during cancer initiation. Although we begin to understand the molecular mechanisms underlying the specific programs of protein synthesis, we lack a general picture of the order of events that lead to the remodeled protein synthesis in cancer. Here, I propose to develop, validate and apply a split-fluorescent uORF/mainORF (mORF) reporter system that recapitulates preferential oncogene translation in a squamous cell carcinoma (SCC) model. I aim at developing and characterizing this reporter system in order to record for the first time the translational remodeling in an in vivo mouse cancer model during transition from healthy tissue to different stages of tumor formation. In addition, this approach will enable me to screen for factors involved in the induction of oncogenic drivers by 5´UTR-associated mechanisms. Finally, I will also reveal the molecular mechanisms by which the newly identified factors drive translational reprogramming in cancer. My findings will substantially contribute to our understanding of protein synthesis pathways during health and disease and provide a foundation for the development of novel cancer therapies.
2021 -
Long-Term Fellowships - LTF

S1DZ neuronal representations during social behavior and the effect of cytokines on this activity

YARDEN RABINOWITZ Yasmin (ISRAEL)

Department of Brain and Cognitive Sciences - Massachusetts Institute of Technology - Cambridge - USA

CHOI Gloria B. (Host supervisor)
Maternal immune activation (MIA) in pregnant mice has been shown to induce phenotypes resembling those of Autism spectrum disorder (ASD) in offspring, among those are deficiencies in social interaction. A recent study showed social behavior deficits can be temporarily rescued by eliciting an inflammatory response. Specifically, it was shown that administration of lipopolysaccharide (LPS) induces interleukin-17a (IL-17a) or direct administration of IL-17a into primary somatosensory cortex dysgranular zone (S1DZ), promoted sociability in these mice. These results raise the following questions: (a) what is the role of S1DZ in sociability? And (b) how does IL-17a affect the neuronal activity in this brain area that rescues social behavior deficits? In my postdoctoral studies I plan to answer these questions by recording neuronal activity in S1DZ in freely moving MIA-affected and control mice during social interaction and characterize the neuronal representations in this brain area. Moreover, by administrating IL-17a I will study how this cytokine act as a neuromodulator affecting the neuronal activity in S1DZ. Identifying the role of S1DZ in social behavior and the underlying mechanisms increasing sociability that are prompt by the presence of IL-17a, will pave the way to design potential treatments for behavioral abnormalities manifested in ASD phenotypes.
2021 -
Long-Term Fellowships - LTF

Artificial intelligence-driven identification of in vivo RNA structure motifs in RNA degradation

YU Haopeng (CHINA, PEOPLE'S REPUBLIC OF)

Department of Cell and Developmental Biology - John Innes Centre - Norwich - UK

DING Yiliang (Host supervisor)
RNA structure plays a crucial role in regulating gene expressions such as translation and RNA degradation. Considering the advance of high-throughput sequencing, researchers are currently able to access both in vivo RNA structures and RNA degradation information over tens of thousands of RNAs in one single experiment. However, it is still unclear which RNA structure feature/motif is generally responsive to RNA degradation in living cells. It is challenging for traditional analysis methods to process the emerging " big data" of RNA structure in vivo, and they are not able to assess the complexity of RNA structure features for the whole RNA, which is over thousands of nucleotides long on average. In this project, I aim to develop novel artificial intelligence (AI) frameworks incorporating deep learning and omics approaches to determine in vivo functional RNA structure motifs in RNA degradation. By integrated multi-omics data, I will construct deep learning models to establish the relationship between RNA structure and RNA degradation and consequently extract the potential RNA motifs. The combination of dry-bench and wet-bench methods will allow me to develop a prediction-validation working scheme to solve this multidisciplinary problem. Based on the identified functional RNA structure motifs, I will also establish corresponding web servers for the community to predict/design the RNA structure motifs for the RNA of interest. The proposed research will make major advances in our fundamental understanding of the RNA structure functionality in RNA degradation in living cells and the AI framework will enable further applications to the complex genomics dataset.
2021 -
Long-Term Fellowships - LTF

Elucidating the role of nuclear envelope budding as a non-canonical route for exporting large-RNPs

ZAGANELLI Sofia (ITALY)

Department of Molecular, Cellular and Developmental Biology - University of Colorado - Boulder - USA

VOELTZ Gia (Host supervisor)
For decades, the nuclear pore complex (NPC) has been considered the sole gateway between the nucleus and the cytoplasm, allowing transport of molecules across the nuclear envelope (NE). However, in recent years NE budding emerged as a non-canonical alternative route for nuclear export of viral nucleocapsids, as well as for large ribonucleoparticles (RNPs). Yet, very little is known about the significance of this unconventional export pathway. The project proposed here aims to elucidate the role of NE budding as a non-canonical route for exporting large-RNPs. The strategy I propose is to track and perturb NE budding transport of large-RNPs. In particular, I will study: (I) the relationship between NE budding and NPC canonical export pathway; (II) its potential involvement in nuclear quality control; and (III) I will test the hypothesis that lamin and Torsin protein families participate in NE budding of large cellular complexes. To follow RNP trafficking and image NE budding events, I will apply state-of-art RNA live-imaging techniques and use a combination of cryo-electron microscopy and tomography (cryo-EMT) and high-resolution live-cell microscopy. Moreover, I will apply biotin proximity ligation assay (BioID) to identify novel RNA and protein cargos transported through NE budding in a Torsin-dependent manner. The results stemming from the work proposed here will represent a significant step towards understanding NE dynamics, and may shift the current dogma of nuclear export.
2020 -
Grant Awardees - Program

Elucidating the mechanism of membrane fusion using DNA nanostructures

AKSIMENTIEV Aleksei (USA)

Dept. of Physics - University of Illinois at Urbana-Champaign - Urbana - USA

HOWORKA Stefan (AUSTRIA)

Dept. of Chemistry, Institute of Structural Molecular Biology - University College London - London - UK

ROY Rahul (INDIA)

Lab. for Nanobiology, Dept. of Chemical Engineering - Indian Institute of Science - Bangalore - INDIA

Lipid bilayer membranes define the outer boundary of a biological cell, protecting its internal volume from elements of the extracellular environment. To gain entry through these membrane barriers, some pathogens fuse their membranes with the membrane of the host cell in a process commonly known as membrane fusion. It is largely believed that placing two membranes near one another can lead to the spontaneous formation of a neck (stalk) joining the two membranes. The stalk eventually resolves into an opening (pore) for material exchange, followed by complete fusion of the two membranes into one. Dedicated proteins (fusogens) found in viruses and cell organelles accelerate this process by facilitating transitions between several intermediate states of the membrane fusion process. While our knowledge of the proteins involved in membrane fusion has steadily accumulated, much less is known about the actual mechanics of membrane fusion, as these processes occur too fast for conventional experimental approaches to capture them with sufficient resolution. This project aims to develop a new approach for studying membrane fusion mechanics by utilizing recent developments in the field of DNA nanotechnology, where molecules of DNA are reprogrammed to fold into well-defined structures of the same size as fusogenic membrane proteins. Using such DNA nanostructures as a type of a molecular scaffold, two membranes with different chemical and physical properties will be placed a prescribed distance away from one another to determine the likelihood of spontaneous fusion. Elements of fusogenic proteins will be incorporated within the DNA nanostructures to generate on-demand membrane fusion events. Advanced microscopy techniques will be combined with computer simulations to verify that such artificial DNA nanostructures can indeed capture the functionality of naturally occurring membrane fusion proteins. Finally, the method will be applied to induce and arrest fusion of a virus with a lipid membrane, providing a highly detailed view of the first step of viral infection. The fundamental insights into the mechanics of membrane fusion as well as the DNA nanotechnology platform to study such processes will open new avenues of investigations of various biological processes, from neuroscience to drug delivery.
2020 -
Grant Awardees - Program

Self-organization and biomechanical properties of the endosomal membrane

ANDO Toshio (JAPAN)

WPI Nano Life Science Institute - Kanazawa University - Kanazawa - JAPAN

GIZELI Electra (GREECE)

Institute of Molecular Biology & Biotechnology - Foundation for Research and Technology, Hellas - Heraklion - GREECE

SPAKOWITZ Andrew J. (USA)

Dept. of Chemical Engineering - Stanford University - Stanford - USA

ZERIAL Marino (ITALY)

Zerial Lab, Principles of cell and tissue organization - MPI of Molecular Cell Biology and Genetics - Dresden - GERMANY

Gaining insight into the structure and function of biological membranes is important for understanding cell organization. Yet, despite a great deal of progress with identifying lipids and proteins on biological membranes, we lack an understanding of their organization and movements. We propose to look at how proteins change shape during binding events using two innovative techniques. One technique uses acoustic waves to extract information of the size and shape of proteins determined by their hydrodynamic properties. The other, called atomic force microscopy, uses a miniature detector to rapidly scan a surface, similar to a finger reading braille text, to deliver a microscopic 3D view of the proteins and lipids and how their shapes change during binding events. Models of these events will be created to interpret how they are regulated and controlled. Cells have a complicated network of vehicles, called endosomes, which transport proteins and lipids to wherever they are needed at a moment’s notice. We study this endosomal network in fine detail to get a better idea of how it’s regulated. We build a simplified synthetic “endosome” containing some of the key lipids and proteins found on native endosomes. We monitor protein-lipid and protein-protein binding events to see how the proteins change their shape upon binding. By changing the density and patterns of the proteins on our synthetic “endosome” we seek to understand how a native endosome controls such critical events within the cell. The endosomal network impacts many diseases for example, Alzheimer’s and cardiovascular disease, as well as playing a role the entry of certain pathogens into cells. Also, drugs can be delivered to cells via the endosomal network. Thus, a better understanding of its regulation could impact human health and welfare.
2020 -
Cross Disciplinary Fellowships - CDF

Mycobacterium tuberculosis modulation of host, elucidated by super-resolution imaging and proteomics

ASHDOWN George (UK)

Division of Infectious Diseases and Immune Defence - Walter and Eliza Hall Institute of Medical Research - Melbourne - AUSTRALIA

COUSSENS Anna (Host supervisor)

Mycobacterium tuberculosis (Mtb) survival and replication within, or escape from, its phagocytic host requires molecular exploitation of host proteins and lipids. However, there are still large gaps in our understanding of bacterial survival and escape, particularly regarding quantitative analysis of interactions between host and Mtb derived proteins or lipids. Super-resolution fluorescence imaging has begun to yield unprecedented insight into biological processes including protein distribution at the nanometer scale and live dynamics of proteins, lipids and the cytoskeleton. However, these techniques have rarely been applied to Mtb research. Here, super-resolution imaging complimented with proteomics will allow the spatiotemporal analysis of membrane associated proteins, including pathogen derived proteins which interact with the intra- and extracellular milieu of primary human macrophages and neutrophils. Work will also utilise live-cell imaging sensitive to membrane composition to elucidate how the pathogen modulates host cell lipids for survival and replication. Additionally, how Mtb escapes its host for transmission is poorly understood. Mtb modulation of the host’s cytoskeleton, membrane and linker proteins using high- and super-resolution imaging, will clarify this process. Quantifying the distribution or disruption of host proteins and lipids through the host-pathogen lifecycle, and investigating whether Mtb proteins themselves present on the host plasma membrane will translate to application of therapeutics. This work will generate novel hypotheses for the Mtb field, and other pathogens, in the context of host immunity and disease equilibrium.

2020 -
Grant Awardees - Early Career

The mechanics and energetics of insect herbivory: from cutting `machines’ to ecosystem structure

BACCA Mattia (ITALY)

Dept. of Mechanical Engineering - University of British Columbia - Vancouver - CANADA

HOLT Natalie (UK)

Dept. of Biology - University of California, Riverside - Riverside - USA

LABONTE David (GERMANY)

Dept. of Bioengineering - The Imperial College of Science, Technology and Medicine - London - UK

Insect herbivores and their food sources comprise ~50% of biodiversity, and their interactions impact community structure, species’ geographical ranges, and food security. How insects choose their food sources, and how plants can defend themselves, are therefore questions of substantial ecological, evolutionary and economical relevance. However, the astounding diversity of herbivorous insects and their food sources renders them challenging to answer. We seek to address this problem by investigating an aspect of plant feeding that all herbivores have in common: the mechanical breakdown of tough plant material. Plant fracture requires the application of a force, the magnitude of which depends on the morphology of the fracturing tool, and the plant material properties. This force is generated by muscle, in a process that consumes energy. Feeding on plants is therefore both mechanically challenging and metabolically costly, to an extent defined by muscle physiology, mouthpart morphology, and plant tissue mechanical properties. We will build on this common, physical foundation to develop a mechanical and energetic framework that can be used to derive first-principles predictions of herbivore behaviour. Developing such a framework will require advances in the fields of solid mechanics and muscle physiology. We will expand fracture theory to describe the mechanics of thin sheet cutting, taking into account tool geometry, large deformations, and multi-axial stress states that occur during plant tissue fracture; and we will develop thermal imaging as a novel method to study muscle energetics. We will apply this framework to the leaf-cutter ants, iconic, polymorphic herbivores that feed on a diversity of plants and exhibit a complex foraging behaviour, making them a rich and multi-faceted model system. We will predict food preferences and cutting strategies in individual workers and ant foraging parties, and use machine learning and computer vision to test these predictions in large-scale, ecologically relevant experiments. This international, inter-disciplinary collaboration will not only (i) provide a quantitative theory to study individual as well as group feeding behaviour, (ii) advance our understanding of insect-plant co-evolution, but also (ii) have impact in other fields, from inspiration for small-scale cutting tools to developments in motor control theory.
2020 -
Grant Awardees - Program

Biological protein springs as allosteric modulators

BAHAR Ivet (USA)

Dept. of Computational & Systems Biology - University of Pittsburgh School of Medicine - Pittsburgh - USA

GORDON Reuven (CANADA)

Dept. of Electrical and Computer Engineering - University of Victoria - Victoria - CANADA

ITZHAKI Laura (UK)

Dept. of Pharmacology - University of Cambridge - Cambridge - UK

YANG Shang-Hua (CHINA, REPUBLIC OF (TAIWAN))

Dept. of Electrical Engineering - National Tsing Hua University - Hsinchu - CHINA, REPUBLIC OF (TAIWAN)

Over the last decade, humans have made extraordinary advances in our ability to synthetically adapt biology. We are in the midst of developing the tools that can reverse genetic disease by altering DNA, and we are creating proteins that do not exist in nature to perform new functions. Yet our understanding of the basic function of proteins and how this is influenced by design is extremely primitive. Even the basic understanding of binding-based signal transduction in proteins, allostery, is arguably far from complete: we are still a long way from being able to mimic nature’s sophistication in creating functional proteins and engineering allosteric functions into proteins – the difference between a mere description and a true understanding. Our mechanistic understanding of allostery has been hindered by a lack of experimental techniques that can probe single proteins within an ensemble and the gap between experimentally observed and computationally predicted quantities. We will tackle this problem by adopting new single molecule tools, in conjunction with protein design and multiscale theoretical modelling. To understand how protein design impacts allostery, we will use and further develop a combination of theoretical (based on Ising formalism, elastic network models (ENMs), and sequence coevolution analyses) and experimental (nanoplasmonic tweezers, extraordinary acoustic Raman (EAR) spectroscopy, and molecular characterization of folding/binding/function) methods. We choose as model system tandem-repeat proteins because of their simplicity and modularity, structural malleability and adaptability to new functions allosterically driven by alterations in interfacial interactions and assembly state. Using both natural and designed TR proteins (and their mutants), we seek to close the gaps between design, theory/computations and function. The goal is a deeper understanding of the biophysics of allostery that will inform our traverse into synthetic biology while also having a specific impact on TR proteins and their essential roles in cellular pathways. Notably, an important interdisciplinary impact of this work will be to quantify the interaction of electromagnetic waves with proteins in the >10 GHz frequency range, precisely where new 5G cellular phone standards are being developed and proteins are susceptible to disruption due to their elastic resonances.
2020 -
Grant Awardees - Early Career

Hormone delivery in plants: mechanisms and physiological roles of gibberellic acid transporters - RENEWAL APP

BAND Leah (UK)

Div. of Plant and Crop Science, School of Biosciences, - University of Nottingham - Loughborough - UK

KAWATE Toshimitsu (JAPAN)

Dept. of Molecular Medicine - Cornell University - Ithaca - USA

NOUR-ELDIN Hussam Hassan (DENMARK)

Dept. of Dynamic Molecular Interactions - Institute of Plant and Environmental Sciences - Frederiksberg - DENMARK

SHANI Eilon (ISRAEL)

School of Plant Sciences and Food Security - Tel Aviv University - Tel Aviv - ISRAEL

Plants are sessile organisms whose growth and development rely on finely-tuned signaling mediated by plant hormones (phytohormones). One of the pivotal phytohormones, gibberellic acid (GA), promotes a wide range of developmental processes in plants, such as seed germination, root and shoot elongation, fiber and cambium development, flowering time and fruit patterning. It is therefore crucial for plants to tightly regulate the distribution of GA throughout their lifespan. Our original HFSP team, in parallel to colleagues in the field, demonstrated that a class of nitrate/peptide transporters (NPFs) actively transport GA and play major roles in GA delivery and response. However, we still do not know the mechanism by which the GA transporters select and move their substrates. One of the major impediments is the lack of high-resolution structures. Also, functional redundancy severely hampers genetic studies to investigate the contribution of each transporter in plant growth. To understand the mechanisms of active GA transport in plants, our team will address the following three objectives: 1) Uncover the molecular mechanisms of key novel NPF GA transporters using a combination of structural and functional studies; 2) Investigate the physiological functions of active GA transport in root development and fiber formation using genetic, cellular, and systems biology approaches; and 3) Identify novel GA transporters, beyond the NPF family. These objectives will require innovative techniques, for instance, we will overcome functional redundancy using our unique multi-targeted forward-genetic cell-type-specific transportome-scale screening. Our comprehensive studies on GA delivery at multiple levels—from the molecular and cellular mechanisms of individual transporters to the GA-trafficking protein network in the plant body—will greatly facilitate the design of GA-transporter specific modulators and deliver crucial knowledge on the mechanisms of active GA transport in plants. As genetic manipulation of GA biosynthesis and perception drove the first Green Revolution in world agriculture, controlling GA delivery through manipulation of GA transporters has the potential to generate a second Green revolution to improve agricultural traits.
2020 -
Grant Awardees - Early Career

Chance or curse? The consequences of hybridization in a changing world

BANK Claudia (GERMANY)

Institute of Ecology and Evolution, Division Theoretical Ecology and Evolution - University of Bern - Bern - SWITZERLAND

ROCHMAN Chelsea (USA)

Dept. of Ecology and Evolutionary Biology - University of Toronto - Toronto - CANADA

SCHUMER Molly (USA)

Dept. of Biology - Stanford University - Stanford - USA

SOUSA Vitor C. (PORTUGAL)

Centre for Ecology, Evolution and Environmental Changes - University of Lisbon - Lisboa - PORTUGAL

Hybrids are offspring produced from mating events between two different species. Once thought to be rare, we now know that hybridization is quite common, and evidence for it is found across the tree of life, including in our own species. There has been a longstanding debate about the importance of hybridization because it can have both beneficial and harmful effects. Hybridization can help organisms adapt, but it can also drive extinction by generating harmful combinations of genes. Past work has proposed that in stressful environments, the benefits of hybridization may outweigh the costs, but this idea has not been clearly tested. How this tug-of-war between the positive and negative impacts of hybridization resolves is unknown and is an outstanding puzzle in several fields of biology. Moreover, understanding these dynamics has become more pressing as rates of hybridization have increased due to the stresses of rapidly changing environments. We will combine research approaches from mathematics to environmental chemistry to address this fundamental question. We will ask how hybrids respond to multiple environmental stressors, and what genetic tools they use to do so. To characterize the costs of hybridization we will develop new computational tools to identify gene combinations that may be harmful or helpful to hybrids. Finally, we will integrate results to build mathematical models to predict the possible consequences of hybridization. Together, this work will reveal the consequences of hybridization and allow us to predict its impacts in our changing world.
2020 -
Long-Term Fellowships - LTF

Clonal dynamics and architecture of the blood stem cell niche

BARON Chloe (FRANCE)

Stem Cell Program - Boston Children's Hospital - Boston - USA

ZON Leonard (Host supervisor)
Hematopoietic stem cells (HSCs) are responsible for the production of all blood cells throughout life. In vivo, HSCs reside within heterogeneous microenvironments or niches able to promote their function. Understanding the mechanisms responsible for the niche ability to support HSCs is required to expand our knowledge of HSC-niche interaction in vivo in healthy conditions and after niche injury induced by chemotherapy. Additionally, it will pave the way to create in vitro niches allowing for HSC reprogramming, maintenance and expansion for therapeutic purposes. Using zebrafish, a powerful model due to its similarity to human developmental processes, hematopoietic master regulators and disease inducing mutations, I will: Aim 1: Unravel the cellular and molecular mechanisms providing niche cells the ability to support HSC using live imaging and single-cell multiomics. a- Characterize the 3D structure and the cellular dynamics of the HSC niche using live imaging of a newly generated multicolor zebrafish reporter line in healthy conditions and after cell-specific ablations. b- Decipher the niche transcriptional code responsible for HSC support combining single-cell RNA-seq, single-cell ATAC-seq and spatial transcriptomics. Aim 2: Characterize the clonal dynamics of HSCs and niche cells in the marrow in perturbed conditions using genetic lineage tracing. a- Analyze the clonal origin of HSCs and niche cells in the healthy marrow using the scGESTALT barcoding technology. b- Expose animals to sublethal irradiation and characterize the clonal dynamics of niche recovery after injury.
2020 -
Grant Awardees - Program

Uncovering the OS of trees: Environmental information processing and the control of bud dormancy

BASSEL George (GREECE)

School of Biosciences - University of Warwick - Coventry - UK

BAYER Emmanuelle (FRANCE)

Lab. of Membrane Biogenesis UMR5200 - University of Bordeaux (CNRS) - Villenave d'Ornon - FRANCE

BHALERAO Rishikesh (SWEDEN)

Dept. of Forest Genetics and Plant Physiology - The Swedish University of Agricultural Sciences - Umea - SWEDEN

WALKER Sara (USA)

School of Earth and Space Exploration - Arizona State University - Tempe - USA

Plants have a remarkable ability to undergo transitions during their life in a robust and synchronized fashion. They are able to achieve this despite the environment they are in being highly variable, and not having sophisticated information processing systems like brains. A striking example of how plants use variable signals such as temperature to time a critical developmental transition is the breaking of bud dormancy in in long-lived trees that grow in boreal and temperate regions of the world. In these trees, growth stops in the autumn and a state of dormancy is established that prevents reactivation of leaf formation which is timed to coincide with the advent of spring. The timing of dormancy break so the growth can be restarted is highly critical decision since a premature release from dormancy exposes plants to damage from sudden frosts in the early spring, whereas restarting growing too late will compromise fitness and productivity due to reduction in the length of their growing season. How trees accurately time the break of bud dormancy so that growth can start again in spring is question that has puzzled biologists for over 100 years, and will be addressed in this project. This will be achieved by exploring parallels between how human engineered computers process information, and the cells in tree buds process temperature. The genes which control bud dormancy have recently been described, yet how they operate within the multicellular context of a bud tissue remains unknown. We propose that controlled communication between cells plays a central role in the release from bud dormancy, and their ability to generate robust responses. A synergistic combination of biological experiments, computer modelling, physics and 3D image analysis, will provide unprecedented insight into how tree buds process temperature information. The project will lead to the identification of algorithms invoked by trees and the molecular and cellular logic used by trees to control bud dormancy, thereby revealing the operating system used by a plant to control its growth over the course of its life cycle.
2020 -
Grant Awardees - Program

Adaptive asexual evolution in cancer, corals and seagrasses - ADAPTASEX

BAUMS Iliana (GERMANY)

Dept. of Biology - Pennsylvania State University - University Park - USA

REUSCH Thorsten (GERMANY)

Dept. of Marine Evolutionary Ecology - GEOMAR Helmholtz Centre for Ocean Research Kiel - Kiel - GERMANY

WERNER Benjamin (GERMANY)

Barts Cancer Institute - QMUL - London - UK

All multicellular organisms are genetic mosaics, composed of different cell populations that have acquired somatic mutations due to mitotic errors. It is generally assumed that this intra-organismal genetic heterogeneity is detrimental for organismal fitness and results in disease such as cancer and senescence. The goal of ADAPTASEX is to unite studies on the dark side of such genetic heterogeneity with an exploration of possible beneficial adaptive effects. In doing so, we are analyzing parallels in modular organisms that occur frequently among the plant and animal kingdom. Corals and seagrasses, as examples, grow asexually to very large size, resulting in clones (=genets) of hundreds of m2. Our research is motivated by preliminary, genetic marker based observations of within-genet heterogeneity (corals, seagrasses), its transfer to the germline, and the increasing recognition of the importance of genomic heterogeneity for predicting cancer etiology, dynamics and treatment. We will describe somatic genetic heterogeneity at the genome level of model coral and seagrass species, and compare patterns to available cancer data. For the free-living species, we perform experimentation to assess fitness effects of somatic genetic variants, and study the transfer of somatically generated variation to the sexual cycle. We hypothesize that the emergent multi-level selection contributes to adaptive dynamics and may purge deleterious genetic variation at the cell population level, explaining delayed senescence and reduced mutational load in modular species. Our interdisciplinary team will develop a joint modeling approach to follow adaptive dynamics of the observed intra-organismal genetic heterogeneity in diverse asexually evolving systems ranging from cancer to modular plant and animal genets and gain synergistic insights into the role of cell population competition and spatial structure for asexual selective sweeps. We will develop protocols to validate low frequency genetic variants, and to predict adaptive dynamics depending on localization, level of selection, and effects of somatic mutations. We expect to contribute to the unification of biological theory by establishing a framework for the study of somatically derived genetic variation from humans to plants, its evolutionary dynamics and fitness effects.
2020 -
Cross Disciplinary Fellowships - CDF

Global Neuronal Network theory vs Integrated Information Theory

BENDTZ Katarina (SWEDEN)

Children's Hospital - Harvard University - Boston - USA

KREIMAN Gabriel (Host supervisor)

Understanding how consciousness arises from neural activity in the human brain remains one of the greatest scientific challenges of modern times. Two of the most influential theories of the neural correlates of consciousness (NCC) are Global Neuronal Workspace (GNW) theory and Integrated Information Theory (IIT). GNW posits that what we experience as a conscious state is the global broadcasting of information in an interconnected neuronal network. IIT instead defines a measure for integrated information, known as phi (f), which can theoretically be used to locate this physical substrate within the brain. The empirical research on these theories have been focused on the visual modality alone, even though the theories make predictions of the full conscious experience, where all sensory modalities necessarily must be included. For example, very little attention has been directed towards the auditory modality. These theories have also been developed separately without much interaction between them and the empirical research has been focused on testing each theory individually, rather than contrasting them to evaluate their explanatory and predictive power. The research question of this project is which of these two theories better explains the NCC, using an adversarial and multi-modal approach designed to cover a maximal space of the testable predictions of these models. It is adversarial in the sense that the strongest advocators for both theories are involved in the project, and it is multi-modal in the sense that all experiments are tested in both the visual and the auditory modality.

2020 -
Grant Awardees - Program

Sounds and pheromones: neural networks merging olfactory and acoustic cues in sexual imprinting

BOVETTI Serena (ITALY)

Dept. of Life Sciences and Systems Biology - University of Turin - Turin - ITALY

GIGAN Sylvain (FRANCE)

Lab. Kastler-Brossel - Sorbonne Université, UPMC-ENS - Paris - FRANCE

PENN Dustin (USA)

Konrad Lorenz Institute of Ethology - Veterinary Medicine University, Vienna - Vienna - AUSTRIA

Sexual imprinting is a process of instinctive learning occurring during early postnatal development, through which many animal species acquire memories of the odor, vocalizations, and other characteristics of their parents (or siblings), and then utilize this information to select their mates as adults. Sexual imprinting has evolved in many taxa, and yet surprisingly almost nothing is known about the neural mechanisms controlling this type of learning. What neural circuits are involved in this process? How is information from multiple sensory modalities integrated, and do they have synergistic effects on female preferences? Laboratory mice have proven to be useful models to investigate sexual imprinting, but do these findings generalize to outbred, wild house mice? To answer these questions and decipher whether sexual imprinting represents a general mechanism guiding mate selection in females, we will take a multidisciplinary approach using behavioral, neuroanatomical and advanced optical imaging techniques. We will conduct cross-fostering experiments, and apply whole brain activity pattern reconstruction and in vivo functional imaging to address several specific aims: i) experimentally test the synergistic effects of acoustic and olfactory cues on sexual imprinting; ii) reconstruct the brain regions activated by sexual imprinting; and iii) functionally trace the circuits that influence female mating preferences. To address these aims we created a novel collaboration between three research groups with very different expertise. The multidisciplinary research capitalizes on recent advances in optical imaging and neuroanatomy, including light-sheet whole-brain imaging and highly innovative in vivo technology for simultaneous imaging on multiple brain regions. We aim to reveal the organization of the circuits that are shaped during postnatal development to form memories of conspecific that are recalled in adults, which enhance inbreeding avoidance and reproductive success.
2020 -
Cross Disciplinary Fellowships - CDF

Pathways of neural information transfer along the gut-brain axis

BOYS Alexander (USA)

Department of Chemical Engineering and Biotechnology - University of Cambridge - Cambridge - UK

MALLIARAS George (Host supervisor)

The gut-brain axis allows for information transfer between gut microbiota and the brain. The microbiome influences brain health, with links to autism, anxiety, and depression. However, pathways of communication between gut and brain have not been fully established. This study focuses on neural information transfer along the gut-brain axis. The enteric nervous system of the gut consists of parallel nerve plexi running along the gut. The enteric nervous system sends and receives signals through the vagus nerve which connects to the brain, thus providing a route of communication between gut microbiota and the brain. The exact pathways of information travel, regarding locality and extensivity of given microbial cues, are not well understood. This study utilizes a tissue engineered neural probe, consisting of a 3D network of recording sites within a cell-seeded collagen gel. These structures are designed to integrate into the gut, allowing for long-term implantation and recording. To determine locality of signals originating from the gut microbiome, probes will be tested in vitro on a population of gut epithelial cells followed by ex situ implantation into a gut explant model. After improving device efficacy, probes will be implanted into live mice. Bacteria will be injected into the gastrointestinal tracts of mice, and neural signals will be recorded from multiple locations along the gut to determine signal locality and route. Overall, this study focuses on a quickly developing area of research in examination of mechanisms by which the gut communicates with the brain, while generating a new form of neural probe for integrating with the nervous system.

2020 -
Grant Awardees - Program

Covalent modification and regulation of proteins by CO2 using Chlamydomonas as a model system

CAMPBELL Robert E. (CANADA)

Dept. of Chemistry, School of Science - The University of Tokyo - Tokyo - JAPAN

SMITH Alison G. (UK)

Dept. of Plant Sciences - University of Cambridge - Cambridge - UK

VOCADLO David (CANADA)

Depts. of Molecular Biology & Biochemistry and Chemistry - Simon Fraser University - Burnaby - CANADA

Carbon dioxide (CO2) has been present in the atmosphere and dissolved in water throughout the almost four billion years over which life has evolved. Over this time, CO2 has emerged as the primary carbon source for all life on earth through its assimilation by plants and bacteria to form carbohydrates and other organic molecules that are the building blocks of life. Consistent with its abundance in the atmosphere and its ability to diffuse through membranes, many organisms are well known to sense and respond to CO2. Despite the clear physiological importance of CO2 and its prevalence within the environment, remarkably little is known about the potential of CO2 to directly regulate protein function and how it may thereby serve as a metabolic signaling molecule within organisms. We hypothesize that reversible carboxylation of specific lysine residues by CO2 within various proteins, in a manner that is sensitive to cellular CO2 levels, can alter protein function in vivo and thereby serve as a mechanism for organisms to sense and respond to varying levels of CO2. We believe that several difficulties have limited progress in addressing this fundamental question. Principally, the rapidly reversible nature of lysine carboxylation makes it notoriously difficult to detect CO2 modified residues and to characterize the functional consequences of this protein modification. Here we propose to work as a team to develop a series of technologies to enable investigation of protein carboxylation by CO2 and its role in sensing within the microalgae Chlamydomonas. Chlamydomonas is an ideal model system because it shows clear physiological responses to CO2 and can be readily genetically engineered. Using these new research tools we will test the hypothesis that fluctuations in CO2 levels are sensed by Chlamydomonas through modification of the lysine residues of various cellular proteins. Finally, we will use targeted genetic engineering of Chlamydomonas to validate our understanding of this system.
2020 -
Long-Term Fellowships - LTF

Uncovering the molecular link between regeneration and aging in Hydra

CAMPOS RODRIGUEZ Sergio Esteban (MEXICO)

Department of Molecular and Cellular Biology - University of California - Davis - USA

JULIANO Celina (Host supervisor)
The decline in regenerative potential that follows aging is associated with organ failure ultimately leading to frailty and death. Understanding the mechanisms underlying the loss of regeneration with age may unlock novel therapies for treating age-related disease. The freshwater cnidarian Hydra vulgaris is capable of whole-body regeneration and appears to lack senescence. The closely related Hydra oligactis displays these features when cultured in normal conditions, but chemical treatment or temperature reduction induces an aging phenotype, which is accompanied by a decrease in regenerative potential. Interestingly, H. vulgaris does not age or lose regenerative potential when subjected to the same treatments. Thus, these two Hydra species present a valuable opportunity to use comparative approaches to uncover the mechanisms linking aging to a loss of regenerative potential. To accomplish this, I will use RNA-seq to profile regenerating tissue in aging and non-aging H. oligactis, and in H. vulgaris. In addition, I will profile aging H. oligactis treated with the anti-aging drug Rapamycin which promotes regeneration in aging H. oligactis. Together, these experiments will allow me to identify genes that are activated in regenerating H. vulgaris and non-aging H. oligactis, but not in aging H. oligactis after injury. I hypothesize that these genes are essential for regeneration, which I will test by knocking them down in H. vulgaris and assaying regenerative potential. The results of this proposal will contribute to understand the mechanisms of regeneration during aging and uncover potential molecular targets for the development of new anti-aging therapies.