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Awardees

2022 -
Long-Term Fellowships - LTF

Development of neural circuits for cooperative behavior in schooling fish

ZADA David (.)

. - The Regents of the University of California, San Diego - La Jolla - United States

LOVETT-BARRON Matthew (Host supervisor)
Throughout the natural world, many species behave in cooperation with their social groups. For example, individuals in a school of fish sense the actions of their neighbors to coordinate their actions. These complex sensory-motor behaviors emerge at the transition to adulthood, but it is unknown how the maturation of an individual’s neural circuits produces the capacity for social coordination. Here we propose a novel approach to study the functional development of neural circuits underlying social attention in schooling fish, using large-scale cellular-level calcium imaging and immersive virtual reality. We will apply these technologies to the micro Danionella translucida; glassfish remain small and transparent throughout their lifespan, allowing for whole-brain neural activity imaging in socially-mature animals. We will engage Danionella in a head-tethered virtual reality environment, where we can image neurons across the brain as fish move their tail to navigate a panoramic visual environment with an interactive group of computer-simulated schooling fish. We will record cellular-level calcium activity from across the visual-motor circuits of transgenic Danionella expressing a genetically-encoded calcium indicator in all neurons, and identify cells that encode the actions of others in the social group. By imaging from early development to mature adult, we will identify the developmental onset of socially-encoding neural circuits and schooling behavior. Overall, this new research direction will provide foundational insights into the function and evolution of the social brain, and identify how these abilities emerge from neural circuit development and maturation.
2021 -
Cross Disciplinary Fellowships - CDF

Cell migration in complex environments as a crucial step in the immune response

JAKUSZEIT Theresa (GERMANY)

Cell Biology and Cancer Department - Institut Curie - Paris - FRANCE

PIEL Matthieu (Host supervisor)

Cell migration has a crucial function in a variety of processes in the human body, e.g. dendritic cells explore tissues in search of pathogens, while cancer metastasis significantly decreases survival chances. Research over the last decade has shown that different migratory modes may be adaptations to changing extracellular conditions as experienced by immune cells migrating between tissues with different physicochemical properties. However, it remains unclear how cells integrate potentially competing physical and chemical cues to choose a path in complex environments such as dense tissue. To identify key cellular and extracellular factors that limit migration, we need to understand the underlying physical principles of migration under defined physical and chemical conditions. To this end, I will study dendritic cell migration in microfluidic channels with a high control over the microenvironment such as its porosity or gradients of chemokine. Collaborating with Prof. Voituriez, I will develop a mechanical understanding of the cytoskeleton dynamics in complex environments using active hydrodynamic models to study the interaction of cells with physical barriers. I will combine this cellular level of understanding with random walk models to analyse the large-scale dynamics of cell migration. To elucidate the physiological relevance, I will apply the theoretical framework to cells with migratory defects that display a primary immune deficiency. Thus, the interplay of experiment and theory will develop a quantitative understanding of how immune cells integrate physical and chemical cues to navigate complex environments, which is essential for an effective immune response.

2021 -
Long-Term Fellowships - LTF

Estimating male mutation bias across vertebrates

DE MANUEL MONTERO Marc (SPAIN)

Department of Biological Sciences - Columbia University - New York - USA

PRZEWORSKI Molly (Host supervisor)
In many species, the germline mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This observation is widely interpreted as resulting from the higher number of cell divisions that lead to male gametes compared to female gametes, and thus support the textbook view that germline point mutations stem mostly from errors in DNA replication. Recently, several lines of evidence call into question this interpretation: notably, the male bias has been reported to be stable with parental ages in humans and across a handful of mammals. In this proposal, we aim to fill in an important piece of the puzzle by estimating the extent of male mutation bias across a large number of vertebrates. To do so, we will employ a comparative genomics approach to infer neutral substitution rates in sex chromosomes and autosomes for different types of mutations. Importantly, we will use recent modelling that translates sex-to-autosome substitution rates into male-to-female mutation ratios taking into account sex-specific life histories. With this research design in mind, we thus aim to deepen our understanding of the genesis of germline mutations through the study of how male mutation bias arises and varies across species.
2021 -
Long-Term Fellowships - LTF

Programmable protease circuits to control vaccine immunogenicity

VLAHOS Alex (CANADA)

Department of Chemical Engineering - Stanford University - Stanford - USA

GAO Xiaojing (Host supervisor)
The development of vaccines to prevent morbidities from infectious diseases remains one of medicine’s greatest achievements. However, many successful vaccines have been developed empirically and vaccine efficacy is highly variable. Rationally differentiating immune cells to specific fates such as memory T cells to improve long-term vaccine efficacy is limited by current methods for controlling differentiation, in part due to inadequate quantitative and temporal control of cytokines. In this work, we propose to overcome these limitations by using engineered cells to function as programmable tools that can respond to combinatorial environmental inputs and produce controlled responses for interrogating basic biology of memory formation and its application in vaccination in an entirely human-derived system. I propose to construct a generalized platform (CHOMP-sec) to detect and secrete proteins using synthetic protein circuits. This platform will be used to systematically scan the effect of IL-2 expression and dynamics on driving the differentiation of memory CD8+ T cells using patient-derived tonsil organoids. The proposed work will provide the field of Immunology with tools to quantitatively control cytokine secretion and a new framework for exploring immune cell differentiation for additional applications, such as inducing tolerance by biasing regulatory T cell responses to engineered tissues.
2021 -
Grant Awardees - Program

Maintenance, homeostasis and heredity of mitochondria and their genomes

BADRINARAYANAN Anjana (INDIA)

National Centre for Biological Sciences - TIFR - Bangalore - INDIA

MANLEY Suliana (USA)

Dept. of Institute of Physics - Ecole Polytechnique Federale de Lausanne (EPFL) - Lausanne - SWITZERLAND

MARSHALL Wallace (USA)

Dept. of Biochemistry and Biophysics - University of California San Francisco - San Francisco - USA

PAULSSON Johan (SWEDEN)

Dept. of Systems Biology, HMS - Harvard University - Boston - USA

Mitochondria are central to modern eukaryotic life. As self-reproducing organelles with their own DNA, they must prevent damage and fluctuations in copy number from accumulating, while their network is locally sculpted through fission and fusion. Yet, even the most basic mechanisms of control are largely unknown, leaving many key questions unanswered. What mechanisms exist to ensure inheritance of genetic material between mitochondria, and mitochondria between cells in the face of segregation errors and noise? Self-replication is dynamically unstable in the absence of feedback control, and multilevel segregation requires multilevel control. How does the mitochondrial genome maintain its integrity? Genotypic selection of a heteroplasmic population of mitochondria post-mutation reflects a process similar to the neutrally stable dynamics behind mutual exclusion in ecological systems. How do mitochondria within a single cell maintain or modulate their size distribution or overall network size? Local decisions to divide or fuse must propagate up to the scale of the network. These decisions should adapt in response to damage, to protect the viability of the network. At present, these questions remain open, in part because they transcend standard sub-disciplines of biology. Finding answers thus requires a quantitative interdisciplinary approach, combining molecular biology, theoretical and quantitative analysis, modeling, and precision microscopy measurements. With our research team, we will develop novel molecular tools to specifically induce mtDNA damage, follow single nucleoids and count single copies (AB), image hundreds of cells to resolve their mitochondria and mtDNA at resolutions of 10-100 nm (SM), use microfluidics devices to follow 10^5 - 10^6 mutants and interpret fluctuations in copy number using stochastic theory (JP), and perturb, characterize and synthesize our observations into geometric models of cellular architecture (WM). On a fundamental level, we wonder why mitochondria form dynamic networks. Many have asked how mitochondrial dynamics or network morphologies contribute to cellular health through optimized energy production, ion buffering, or myriad other important roles. We hypothesize that the mitochondrial network, and the dynamic processes that produce it, exist largely to support the life cycle of the mitochondria as an endosymbiont, allowing its genome to be stably propagated in an intact form.
2021 -
Grant Awardees - Early Career

The bacterial biofilm as a multicellular organism: from molecules to populations

BERGERON Julien (FRANCE)

Randall Division of Cell and Molecular Biophysics - King's College London - London - UK

DURHAM William (USA)

Dept. of Physics and Astronomy - University of Sheffield - Sheffield - UK

TSENG Boo Shan (USA)

School of Life Sciences - University of Nevada Las Vegas - Las Vegas - USA

WHITNEY John (CANADA)

Dept. of Biochemistry - McMaster University - Hamilton - CANADA

Most bacteria live in surface-attached communities called biofilms, where they play profound roles in many important processes in infection, industry, agriculture, and the natural environment. A number of different genetic pathways have been demonstrated to impact biofilm formation at the aggregate level, typically by showing that the amount of biofilm produced by mutants lacking these pathways is either reduced or abolished altogether. However, we know very little about the how these pathways contribute to biofilm architecture at the scale of single cells, nor how these pathways interact with one another during biofilm development. This is because biofilms are three-dimensional, translucent structures, which makes it difficult to visualize what is happening deep inside of them. This project will use transformative new approaches to understand how bacteria work together to assemble biofilms. We hypothesize that multicellular biofilms undergo a series of developmental processes analogous to those observed in animals, where different pathways exhibit complex patterns of gene expression. These processes allow a single cell to transform into a multicellular biofilm, where genetically identical cells perform different roles and functions. Because we cannot currently visualize cells deep inside a mature biofilm, we will use microfluidic devices to approximate a two-dimensional cross-section through a mature biofilm, allowing us to directly visualize the behavior of individual cells and measure the expression of multiple genetic pathways simultaneously over long time periods. We will then use cell tracking and mutants to understand how each of these pathways control the behavior of individual cells within the 2D biofilm. These results will be validated in 3D biofilms, using separate microfluidic devices formed with fluid walls, which will allow us to extract fully intact biofilms for subsequent analysis by novel electron microscopy assays and by single-cell transcriptomics. By quantifying how each pathway contributes to biofilm assembly, and how each of these pathways interact with one another, we will provide an unprecedented view of the sequence of processes that play out in space and time during biofilm development. Such insights hold the key for developing new strategies for both rationally engineering beneficial biofilms and eradicating harmful biofilms.
2021 -
Grant Awardees - Program

Decoding acoustic communication in mosquitoes: from distortion products to vector control

ALBERT Joerg (GERMANY)

Ear Institute - University College London - London - UK

BOZOVIC Dolores (USA)

Dept. of Physics and Astronomy - University of California Los Angeles - Los Angeles - USA

CHEN Chun-Hong (CHINA, REPUBLIC OF (TAIWAN))

Institute of infectious diseases and Vaccinology - National Health Research Institutes - Zhunan - CHINA, REPUBLIC OF (TAIWAN)

KAMIKOUCHI Azusa (JAPAN)

Graduate School of Science - Nagoya University - Nagoya - JAPAN

As mosquitoes become an increasingly common part of daily life for millions of people worldwide, so too do the diseases they transmit. The rapid global spread of mosquitoes is placing billions at risk of infection from dengue, malaria and Zika, with current control methods unable to control the increased threat. New control tools, with novel mechanisms of action, are necessary to prevent public health resources from being overwhelmed. Mosquito ears are potentially the most sensitive in the insect world; this sensitivity is necessary for males to locate the faint sound of an individual female flying through the crowd of males that compromises a mosquito swarm. Although this male attraction to the noise of a female’s wing beat has been studied for decades, tools which manipulate this attraction effectively in the wild have still not been developed. We aim to address this problem by comprehensively studying every aspect of mosquito hearing-related anatomy and behaviour. We will describe the mosquito ear itself in detail and identify the individual components which underly the hearing process. By creating new mosquito mutants, we will be able to describe exactly which components allow males to locate females within noisy environments. We will then test which sounds specifically stimulate these components, before applying these sounds to groups of caged male mosquitoes. We will model the reaction of these groups – and their ears - to different sounds using ground-breaking mathematical models, which will feed into further experiments to identify an ‘ideal song’ to attract males. A particular focus of our project will be on the role of ‘phantom tones’, which males can generate in their own ears (and which are very similar to female flight tones) to support their hearing process. In other words, we want to understand how ‘making up’ the sound of a female can help males to find a real one. Finally, we will test the identified optimized sounds in the field to assess their attractiveness in the real world. To this end, we will attach speakers to mosquito traps to test whether ‘making the right noises’ can indeed increase the number of captured males. Our project aims to provide a clearer answer as to how mosquito hearing works, and whether the use of sound is a feasible path for controlling wild mosquito populations.
2021 -
Grant Awardees - Program

Understanding how genetic and physical fluidity drive adaptive behavior in a multinucleate organism

ALIM Karen (GERMANY)

Physics Department - Technische Universität München - Garching b. Munich - GERMANY

ROPER Marcus (UK)

Department of Mathematics - University of California, Los Angeles - Los Angeles - USA

ROZEN Daniel (USA)

Institute of Biology - Leiden University - Leiden - NETHERLANDS

The giant cellular compartments of syncytial organisms can harbor millions of nuclei. In Physarum polycephalum plasmodial fusion can produce complex nuclear-level interactions, including selective killing of nuclei after somatic fusion. At the same time, the shared plasmodial cytoplasm traffics resources and information, allowing the entire organism to gain resistance to antibiotics even when only a fraction of its nuclei carries resistance genes. Working at the interface of physics, evolutionary biology, and applied mathematics, we will uncover how cooperative and competitive dynamics between nuclei interact to produce emergent organism-scale behaviors. We exploit three key features of Physarum: 1. Diverse genotypes can be integrated into a single chimeric plasmodium via cellular fusion, 2. Flows of cytoplasm and nuclei can be dynamically tracked throughout the plasmodial network, 3. A rich, and poorly understood, repertoire of organismal behaviors, including learning and distributed intelligence. The project requires the combined skills of the PIs to: 1. Generate chimeric plasmodia in which nuclei have different complementary phenotypes (e.g. antibiotic resistance and sensitivity) and mapping and modeling shifts in nuclear proportions and spatial distributions when confronted by selective conditions. 2. Mechanistic study of how cytoplasmic flows can break down nuclear-division synchrony, allowing nuclear proportions to change in response to the environment. 3. Quantification and modeling of how nuclear dispersal and proliferation feed back on morphological changes and thus behaviors of the plasmodial network. Our quantitative understanding of nuclear interactions, bridging the scale from few nuclei interacting in a single plasmodial tube to the population dynamics of nuclei across the entire syncytial organism, will provide unprecedented insight into how nuclear interactions control and are controlled by network architecture, energy and information flow across the organism. We will give new insight on the mechanisms controlling Physarum’s surprisingly complex behaviors and revolutionize our understanding of the evolution of multinucleate cells, which occur in all biospheres and across all kingdoms of life.
2021 -
Grant Awardees - Early Career

Multi-scale functional investigations into mechanosensing response in archaea

ALVA KULLANJA Vikram (INDIA)

Dept. of Protein Evolution - Protein Bioinformatics Group - Max Planck Institute for Developmental Biology - Tuebingen - GERMANY

BHARAT Tanmay (UK)

Sir William Dunn School of Pathology - University of Oxford - Oxford - UK

BISSON Alex (BRAZIL)

Department of Biology - Brandeis University - Waltham - USA

Cells sense and respond to their physical surroundings using organized molecular machinery that is tightly regulated in space and time. From single cells to bacterial communities to multicellular organisms, biological systems employ tailored solutions to detect and physiologically feedback mechanical stimuli. Only recently understood to be distinct from bacteria, Archaea comprise a microbial branch within the same domain as eukaryotes. While Archaea phylogenetics has been extensively used to advance our understanding of the origin of complex life, the gap in the archaeal cell biology field makes them the least explored organisms in nature. To bridge our knowledge of mechanosensing at the nexus of prokaryotic and eukaryotic lifestyles, this project gathered a team of scientists from the USA, the UK, and Germany to address the unexplored molecular basis of how archaeal cells interact with their physical environment. We will use an interdisciplinary approach involving bioinformatics, biophysics, cell, and structural biology to elucidate how archaeal cells respond to mechanosensation in a molecular level. As well as improving our understanding of archaeal cell biology, our research represents a comprehensive understanding of their evolution, leading to clues on the origin of mechanosensing in eukaryotes.
2021 -
Long-Term Fellowships - LTF

Pex ex machina: the cell biological mechanics of locally-controlled peroxisome biogenesis

AMEN Triana (RUSSIA)

Global Health Institute - EPFL - Lausanne - SWITZERLAND

VAN DER GOOT Françoise Gisou (Host supervisor)
D'ANGELO Giovanni (Host supervisor)
The peroxisome is a widely underappreciated regulator of cellular metabolism. It is often credited solely with being a metabolic detoxifier of reactive oxygen species. Peroxisomes, however, are much more than antioxidant filters. Among their multiple capabilities, peroxisomes provide intermediates for gluconeogenesis and amino acid synthesis, enable cells to synthesize complex molecules like penicillin, degrade fatty acids, and synthesize lipids essential for brain development. Peroxisomes are unique organelles in that their many functions are governed primarily by ad hoc local biogenesis. Within the accepted model peroxisomes form by fission of pre-existing organelles or de novo, from the cellular endo-membranes. However, although de novo peroxisome biogenesis explains the formation of peroxisomal membranes, we do not know how peroxisomes expand their membranes during division. Additionally, little is known about the different molecular factors that trigger peroxisome biogenesis. This proposal will examine the molecular mechanisms of peroxisome biogenesis. My goal is to gain mechanistic understanding of the early events of peroxisome formation driven by diverse conditions and identify the autonomous regulation of the partitioning of the peroxisomal membranes. That will allow us to design targeted therapies for a range of peroxisome biogenesis disorders.
2021 -
Long-Term Fellowships - LTF

Structural and functional characterization of Plasmodium falciparum rhoptries and its proteins

ANTON Leonie (SWITZERLAND)

Microbiology and Immunology - Columbia University Irving Medical Center - New York - USA

HO Chi-Min (Host supervisor)
Malaria is caused by the protozoan parasites of the Plasmodium species, which during their lifecycle infect human erythrocytes. Like all apicomplexan parasites, P. falciparum has specialized organelles that are essential for infectivity. One of these organelles are the rhoptries, which eject proteins, lipids and membranes into the erythrocyte, contributing to invasion and enabling the parasite to acquire the nutrients necessary for intracellular replication. The molecular processes mediating rhoptry content expulsion and nutrient acquisition have been poorly understood. The aim of this proposal is to use recent advances in structure biology and genome-editing methods to uncover the molecular mechanisms underlying rhoptry function. Using cryo-electron tomography and cryo-focused ion beam milling, I aim to obtain sub-nanometer ultrastructure information of rhoptry organelles of P. falciparum before, after and during invasion of erythrocytes. Furthermore, I aim to determine the structure of the high-molecular-weight complex RhopH, which inserts into the erythrocyte membrane and is essential to nutrient uptake. By taking advantage of CRISPR-Cas gene manipulation tools, I will purify the RhopH complex from infected erythrocytes and use cryo-electron microscopy and single particle analysis to obtain a near-atomic 3D reconstruction. The proposed research will bring novel methods for structure elucidation to malaria research and thereby increase knowledge on the molecular processes of invasion and intracellular infection. Understanding the mechanisms of this essential step in the parasite life cycle, contributes to finding new ways for drug mediated interventions.
2021 -
Cross Disciplinary Fellowships - CDF

Engineered collagen fibrils through controlled microfluidics and DNA directed processes

ARNON Zohar (ISRAEL)

Department of Chemical Engineering and of Applied Physics and Materials Science - Columbia University - New York - USA

GANG Oleg (Host supervisor)

Collagen plays a major structural role in various connective tissues, such as tendons, skin, bones, hair and more. Due to the diverse natural utilization of collagen fibers in the different tissues, synthetic and recombinant collagens are used for numerous applications, specifically, in the fields of biomaterials science and medicine. Yet, the ability to fabricate and assemble continuous collagen fibrils across length scales is still an unmet need. Here, we aim to establish a methodology for the fabrication of designed collagen organization, with control on multiple scales, which cannot be attained by current fabrication methods. Designed DNA nano-vessels can be coordinated into a guided 3D pattern. Molecular recognition sites within the nano-vessels will induce collagen formation with precise spatial specifications. Microfluidic techniques will allow the rapid and immediate adjustment of the assembly environment, enabling investigation of various parameters and their effect on the formation process. We intend to study the relationship between collagen architectures and their mechanical properties, in order to rationally design desired end-product attributes. We believe that the Gang group exceptional expertise with DNA nanotechnology together with my own experience with microfluidic techniques and self- and co-assembly mechanisms will produce a fertile conceptual ground for a fruitful study. Elucidating key elements in the relationship between the structure and mechanical properties will enable the regular use of collagen-based biomimetic materials for numerous applications, including drug delivery systems, tissue regeneration platforms, reinforcement scaffolds and more.

2021 -
Long-Term Fellowships - LTF

Bioelectric patrolling: the role of the local membrane potential in immune cell migration

AVELLANEDA SARRIO Mario (SPAIN)

Laboratory of Cell Biology and Immunology - Institute of Science and Technology Austria - Klosterneuburg - AUSTRIA

SIXT Michael (Host supervisor)
Many cells rely on chemotactic motility – the ability to sense and follow external molecular cues – to explore their environment, perform their tasks or merely survive. Chemotaxis is central to immune cells, as they need to efficiently navigate through the body to locate and eliminate threats. Yet, how these cells can respond and reconfigure their steering machinery so fast upon changes in the chemoattractant gradients is not fully understood. In the recent years, ion channels and the membrane potential have gained increasing attention, as they appear to play an important yet unclear role in chemotaxis. Studying the link between bioelectricity and migration is particularly difficult for non-excitable cells like immune cells, since there are no action potentials to propagate the electric signal throughout the cell. Instead, changes in the membrane potential likely occur locally, i.e. in a confined section of the membrane. Moreover, the continuous motion of migrating cells constitutes an additional challenge. Until recently, membrane polarization has been measured using voltage cell clamps, a highly invasive technique that cannot locally probe different sections of the cell simultaneously, and that inevitably disrupts migration. Here I propose to use recently developed optical voltage sensors to study how local membrane polarization affects and is affected by cell steering and chemotactic activity. Migration mechanisms are highly conserved across many different cells, so understanding the role of the membrane electric polarization in immune cell steering will be relevant for many other physiological processes such as cancer metastasis, regeneration and development.
2021 -
Grant Awardees - Early Career

How life got moving: reconstructing and re-evolving the bacterial flagellar motor, piece-by-piece

BAKER Matthew (AUSTRALIA)

School of Biotechnology and Biomolecular Science - University of New South Wales - Kensington - AUSTRALIA

KACAR Betul (USA)

Dept. of Bacteriology - University of Wisconsin Madison - Madison - USA

MATZKE Nicholas (USA)

School of Biological Sciences - University of Auckland - Auckland - NEW ZEALAND

MCNALLY Luke (IRELAND)

School of Biological Sciences - University of Edinburgh - Edinburgh - UK

Many organisms move, but the origin of the first motility is not known. We focus on the oldest propellers: flagellar motors. Remarkably, these evolved twice: the bacterial flagellar motor (BFM) and the archaeal flagellar motor (AFM). Both require dozens of cooperating proteins to function, and both are partially homologous to secretion systems. BFM function and assembly has been researched for decades, however the key question of: ‘how did such functional complexity first arise?’ has only been addressed, in outline, in a handful of publications. We hypothesize that the earliest proto-flagella evolved by coupling secretion systems to power sources (BFM: ion pumps; AFM: ATPases), providing a small, yet selectively advantageous, improvement in dispersal ability. We will test this hypothesis by reconstructing, resurrecting, and examining possible ancestor-like proteins. We will do this one-component-at-a-time, and then in combinatoric fashion using high-throughput motility screens. We will measure the biophysical characteristics of proto-motors in hosts over which we have genetic control. We will measure chemotaxis parameters to model what selective benefits are gained, at what cost, as the proto-motor adapts to optimise for efficiency in assembly and function. Our ultimate target is to recreate, in the lab, the moment where suitable machinery was co-opted to impart a selective advantage (motility) to an ancestral organism. To prepare to tackle this ambitious goal, we will comprehensively characterise the evolution and differentiation of the ion-powered stator units. Our team comprises experts in the complementary areas this project requires: Bayesian statistical phylogenetics; biophysics of the flagellar motor, ancestral sequence reconstruction and experimental evolution; and theoretical eco-evolutionary microbiology. Our project outcomes will characterise how flagellar motors adapt to improve motility in different conditions, and determine plausible pathways for how motility first emerged.
2021 -
Grant Awardees - Program

Memory – from material to mind

BARAK Omri (ISRAEL)

Faculty of Medicine and Network Biology Research Laboratories - Technion - Israeli Institute of Technology - Haifa - ISRAEL

DIAMOND Mathew (ITALY)

Tactile Perception and Learning Lab - International School for Advanced Studies (SISSA) - Trieste - ITALY

KEIM Nathan (USA)

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

The brain’s capacity to store and retrieve information is the target of enormous research efforts. Seemingly unrelated research in physics has begun to focus on information storage and retrieval in non-living systems. For instance, a crumpled nickel-titanium wire spontaneously reconfigures into its remembered shape – a paperclip – upon heating. Our proposal posits that the memory dynamics being discovered in non-living systems are less remote from brain memory than might be supposed. Through our experimental neuroscience expertise (DIAMOND), we will train rats in perceptual memory behaviors. To uncover fundamental rules that extend beyond a single paradigm, we will use one stimulus set as the external drive from which the brain generates multiple distinct percepts; furthermore, we will train rats to act upon these percepts in a diverse library of tasks. Through our soft matter physics expertise (KEIM), we will chart out a general framework for memory storage and retrieval aimed at replicating key rat findings, such as the interaction between short-term and longer-term memories. Materials that extract and store information, such as driven suspensions, can be arranged in a flexibly interacting network to serve as a physical model of brain networks. Our computational neural networks expertise (BARAK) will act as the bridge. In a feedback loop within the project, BARAK will characterize materials networks in a language that can be applied to experimental neuroscience. By converting materials network properties into biological mechanisms, such as persistent firing patterns, BARAK will provide DIAMOND with quantitative predictions for the neuronal population states across a network of cortical regions (analogous to the network of materials). Removal of a single module from the materials network might be analogous to optogenetic suppression of a single cortical region; the team, together, will interpret parallel experiments of this sort. While not neglecting what makes the brain qualitatively different from an inanimate material, our identification of common motifs between material and mind engenders a new approach that envisions behavior as the task-dependent configuration of a repertoire of fundamental memory properties.
2021 -
Grant Awardees - Program

The biology of left-right asymmetry - linking structural determinants to ecology and evolution

BARRETT Spencer C.H (CANADA)

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

DEINUM Eva (NETHERLANDS)

Dept. of Mathematical and Statistical Methods (Biometris) - Wageningen University & Research - Wageningen - NETHERLANDS

ILLING Nicola (SOUTH AFRICA)

Dept. of Molecular and Cell Biology - University of Cape Town - Rondebosch - SOUTH AFRICA

LENHARD Michael (GERMANY)

Institute for Biochemistry and Biology - University of Potsdam - Potsdam - GERMANY

Consistently telling left from right is no small feat, and how developing organisms do so to form left-right (LR) asymmetric structures is a fascinating question in biology. While the molecular mechanisms involved are known in some detail in the case of LR asymmetric internal-organ placement in vertebrates, a number of key issues remain poorly understood. These include the questions (1) how symmetry is initially broken in a consistent manner; (2) how this is translated into asymmetric organ growth; (3) what the functional importance of LR asymmetries is; and (4) how they evolved. Here, we will work towards an integrative understanding of LR asymmetries by answering the above questions for mirror-image flowers as a highly suitable model. In mirror-image flowers, the upper part of the female reproductive organ, the style, is bent away from the midline that runs from the top to the bottom of the flower, either to the left or to the right. Conversely, one of the male organs, the anthers, is bent in the opposite direction. While in some species individuals carry both left- and right-styled flowers, in others each individual has either only left- or only right-styled flowers, and this difference in orientation between the individuals is controlled by a single gene. This arrangement means that pollen from a left-styled individual (with its anthers on the right) should be deposited on a pollinating insect in such a way that it can be efficiently transferred to the female organs on a right-styled individual, and vice versa. As such, mirror-image flowers are thought to promote outcrossing. In this project, we will use the genetic control of left/right orientation in mirror-image flowers to identify the responsible genes and study how the encoded proteins break the left-right symmetry and cause the style to bend. Experimental studies will be complemented by computational modelling to understand the minimum requirements for consistent organ deflection. Using field experiments we will test the prediction that mirror-image flowers promote efficient outcrossing. We will also study the evolution of mirror-image flowers and compare the results about the orientation-determining genes between the three independently evolved cases of genetically controlled mirror-image flowers. This will indicate whether each of them found a unique solution to the problem of telling left from right, or whether the same mechanism is used repeatedly. As a result, this project will provide an integrated understanding of left-right asymmetry.
2021 -
Grant Awardees - Early Career

Conferring carnivorous plant-like traits by single gene transfers

BAUER Ulrike (GERMANY)

School of Biological Sciences / Mechanical Ecology Lab - University of Bristol - Bristol - UK

FUKUSHIMA Kenji (GERMANY)

Department of Botany I - University of Würzburg - Würzburg - GERMANY

RENNER Tanya (USA)

Department of Entomology - The Pennsylvania State University - University Park - USA

In principle, all botanical research, regardless of the species studied, will ultimately contribute to human welfare, by, for example, providing useful knowledge and genetic materials to improve crops. A key challenge is to efficiently select genes that have a high chance of achieving predicted trait modifications. Because the same mutations led to the same evolutionary outcomes among different organisms, convergently evolved traits based on the same genetic changes may be less dependent on the genetic background, and thus more easily transferable. Here, we test this idea with carnivorous plants, which evolved multiple fascinating traits in disparate groups of flowering plants. To achieve this goal, we will combine bioinformatics, biomechanics, and experiments involving live plants, insects, and pathogens to evaluate the performance of crop plants into which carnivorous plant genes are transferred. Carnivorous plants are a source of many potentially useful traits that may enhance crop production when transferred. These plants produce highly modified leaves that serve as prey traps. Those with flypaper-type and pitcher-type trapping mechanisms are popular ornamentals. The traps themselves are armed with biochemical and biomechanical weapons to repel pathogens and insects. For example, many carnivorous species secrete hydrolytic cocktails to digest prey, which contain enzymes derived from pathogenesis-related proteins. Additionally, carnivorous plants with pitcher-type traps can have digestive fluids that are highly viscoelastic, aiding in prey retention, as well as sophisticated surface microstructures that prohibit insect attachment. When successfully transferred, these traits can help increase crop production under exposure to pathogens and herbivorous insects. Because independent lineages of carnivorous plants have been confirmed to have functionally important genes that have been modified through similar evolutionary pathways, they are ideal systems to perform a proof-of-concept study of efficient trait transfers by taking advantage of convergently evolved genes. This project will result in novel insights into how to prioritize genes for trait transfers, as well as how carnivorous traits can enhance crop health and production.
2021 -
Grant Awardees - Program

Darwin rwinDa: rewinding and rerunning evolution to study innovation in action

BEEBY Morgan (UK)

Department of Life Sciences - Imperial College London - London - UK

CARY Craig (NEW ZEALAND)

Thermophile Research Laboratory - University of Waikato - Hamilton - NEW ZEALAND

HOCHBERG Georg Karl Albert (GERMANY)

Evolutionary Biochemistry group - Max Planck Institute for Terrestrial Microbiology - Marburg - GERMANY

PEDACI Francesco (ITALY)

Dept. of Biophysics and Bioengineering/Centre de Biochimie Structurale - CNRS UMR 5048 - UM - INSERM U 1054 - Montpellier - FRANCE

How does evolution create novelty? The underpinning of evolution is molecular; cells are filled with molecular machines whose origins involved evolution of many new components. Understanding how evolution created such novelty is a substantial gap in evolutionary theory. Current understanding, however, is limited by the absence of a molecular fossil record and challenges in determining the structures and functions of molecular machines from diverse species. We propose a study to overcome these limitations by combining breakthroughs in metagenomics, evolutionary biology, structural biology, and single molecule biophysics to provide a description of the evolutionary path of a molecular machine. We will experimentally rewind evolution of the high-torque flagellum from epsilon-proteobacteria (ePB), an ideal model system which incorporated several new proteins as it evolved higher torque. We will determine when new proteins were added from protein phylogenies (HOCHBERG) aided by metagenomics-informed environmental sampling of uncultured diversity in sparse parts of the tree (CARY). We will infer the structure of motors along this trajectory by imaging motors in situ at crucial branches with cryoelectron tomography and microscopy (BEEBY) and infer their selective benefits by biophysically measuring motor output (PEDACI). Our work will reveal whether the evolution of molecular machines follows traditional gradualist theories of evolution, or whether their construction from discrete proteins necessitates discontinuous evolutionary leaps. We will address how initially merely useful accessory proteins became completely essential using ancestral sequence reconstruction (HOCHBERG), genetic manipulation of newly isolated bacteria (BEEBY and CARY), and experimental evolution (BEEBY). Lastly, we will use resurrected ancestral flagellar proteins (HOCHBERG) together with experimental evolution (BEEBY) to test whether receptivity of the motor or the availability of suitable proteins limits protein recruitment. Our work will reveal whether nature’s nanomachines come from efficient evolutionary optimization or whether historical accidents have introduced gratuitous complexity. More generally, we will extend the reach of comparative evolutionary biology to the nanomachines that drive cells and make a first step in uncovering the rich molecular natural history of the cell.
2021 -
Grant Awardees - Program

Adaptation of photosynthetic membranes to environmental change

BENNETT Doran (USA)

Department of Chemistry - Southern Methodist University - Dallas - USA

CROCE Roberta (ITALY)

Dept. of Physics and Astronomy/Biophysics of Photosynthesis - Vrije Universiteit Amsterdam - Amsterdam - NETHERLANDS

ENGEL Benjamin (USA)

Helmholtz Pioneer Campus - Helmholtz Zentrum Munich - Neuherberg - GERMANY

Photosynthetic organisms convert sunlight into biochemical energy, thereby sustaining most of the life on Earth. Changing light conditions present a fundamental challenge for these organisms, which must find a balance between increasing productivity and avoiding damage caused by overexciting the photosystem protein complexes embedded within their thylakoid membranes. Regulatory mechanisms such as state transitions and non-photochemical quenching are proposed to involve major remodeling of the thylakoid membranes and their embedded light-harvesting protein complexes. However, despite decades of intense research activity providing indirect supporting evidence, the molecular adaptation of thylakoids has never been directly observed, and there remains a disconnect between the relatively slow membrane remodeling steps and the ultrafast process of light harvesting. In our newly-formed team, we have assembled a novel combination of multidisciplinary expertise and innovative technology aimed at breaking through this longstanding barrier in the field.
2021 -
Long-Term Fellowships - LTF

Dissecting tissue specific antibody mediated immunity to Rotavirus infection

BERNSHTEIN Biana (ISRAEL)

- Ragon Institute of MGH, MIT and Harvard - Cambridge - USA

ALTER Galit (Host supervisor)
Our immune system efficiently fights pathogens by recruiting and activating immune cells within the infected tissue to clear out the infection. Antibody mediated immune response is a critical part of this process. In my postdoctoral studies, I plan to study the role of antibodies in orchestrating the immune response through interactions with innate immune cells within the tissue. As a model system I propose Rotavirus (RV), a devastating enteropathogen causing pediatric gastroenteritis worldwide. A vaccine against RV infection prevented millions of hospitalizations worldwide, however it is insufficient to provide protection in young children in developing countries. While vaccine induced antibody levels serve as a biomarker of vaccine response, the precise immunological mechanisms of vaccine-mediated protection remain undefined, rendering improved vaccine design challenging. Here I aim to systematically probe the antiviral functions of RV vaccine-induced antibodies. Using the Alter lab’s systems serology platform, I will study the ability of antibodies to directly block RV infection, as well as to recruit the innate immune system. The protective signatures defined in the human vaccine study will be mechanistically dissected in an in-vivo RV infection model. Ultimately, I aim to define the rules by which antibodies direct mucosal immune cells to fight RV, potentially unlocking novel roles for antibody-innate immune cell interactions. These studies will expand our understanding of the role of antibodies in guiding innate immune function in the intestinal mucosa, paving the way towards developing efficacious vaccines against additional enteropathogens or diseases of the gut.