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2022 -
Long-Term Fellowships - LTF

Experimental control over sleep cognition via transcranial focused ultrasound


. - Stichting Katholieke Universiteit, Radboudumc - nijmegen - NETHERLANDS

VERHAGEN Lennart (Host supervisor)
During sleep, people experience rich cognitive activity despite being unable to perceive their embedding environment. Untainted by concurrent external information, dreams uniquely reflect a person's underlying, unconscious models of the world. Still, the nature of this reflection is far from established, likely because sleep experience notoriously defies scientific methods such as experimental stimulus control (i.e., dream manipulation). To avoid therapeutic errors based on misinterpretations of the meaning of dreams, it is overdue to address this problem. Sleep and related cognitive processes are often influenced by brain structures that are inconveniently located deep below the surface (such as the thalamus and amygdala), which is why experimental modulation of their activity was long deemed impossible in healthy humans. Recently however, transcranial focused ultrasound (tFUS) has solved this problem of non-invasive deep brain stimulation. It has been shown that ultrasound applied to the scalp can safely modulate neuronal membrane potentials in real time. More importantly, this can be done with millimeter precision at any depth of the brain. tFUS as a revolutionary neuromodulatory method is therefore an excellent way to modulate the activity of deep brain areas known to regulate sleep and related cognitive activity.
2022 -
Grant Awardees - Program

Mapping gut-to-brain transmission of prion protein


Institute of Neuropathology - University of Zurich - ZURICH - SWITZERLAND


Dept. of Microbiology - University of Pennsylvania - Philadelphia - USA

Prion diseases are incurable neurodegenerative conditions. They are caused by PrPSc, an infectious form of the cellular prion protein PrPC. Upon ingestion, PrPSc causes misfolding of PrPC and successively propagates to the brain, where it causes a universally fatal spongiform encephalopathy. Inhibition of gut-to-brain transmission should theoretically prevent disease, but the detailed circuit by which PrPSc reaches the brain remains incompletely defined. We have recently used polysynaptic tracing in combination with single-nucleus RNA-sequencing to comprehensively map neuronal gut-brain pathways from the intestinal epithelium to the brain. We made the surprising discovery that a single such pathway, leading from enteroendocrine cells to the brainstem via the enteric nervous system, is characterized by expression of the endogenous prion gene Prnp in each component of the circuit. In this project, we aim at (I) determining the physiological function of PrP in this gut-brain circuit, as well as (II) elucidating if this pathway transmits PrPSc from the intestine to the brain and whether its inhibition can prevent prion disease. To achieve these goals, we will join forces between a lab that has pioneered the study of prion transmission (Aguzzi) and a lab that specializes in the investigation of gut-brain communication (Thaiss).
2022 -
Grant Awardees - Program

Spatial and deep neurolipidomics to reveal synapse diversity


Analytical Chemistry - University Vienna - Vienna - AUSTRIA


Molecular Horizons and School of Chemistry and Molecular Bioscience - University of Wollongong - Wollongong - AUSTRALIA


Center for Molecular Neurobiology - University Medical Center Hamburg-Eppendorf - Hamburg - GERMANY


Department of Cellular and Molecular Medicine - KU Leuven -University of Leuven - Leuven - BELGIUM

The astonishing capacity of the brain to process and store information crucially relies on properly functioning synapses. They provide the connecting entities within neural circuits and they properties define circuit function. The molecular composition of synapses can be very different, which has not been appreciated yet to the extent that would allow deeper insights into the molecular underpinnings of information processing in different circuits. While the role of proteins, as core components of the synaptic cell membrane and synaptic transmission has been addressed in certain detail it is unclear to what extent the molecular diversity of lipids can influence synaptic function. Based on new technologies allowing for the first time lipidomic studies at the level of different synapse types, the project aims at unveiling the molecular interactions between lipids and proteins. Newly developed analysis strategies as well as innovative lipid tagging and imaging approaches will enable us to determine the membrane composition of specific synapses with high resolution. This spatial lipidomics workflow will pave the way to studies on how aging and neurological diseases influence synaptic lipid composition with the prospect of therapeutic interventions.
2022 -
Long-Term Fellowships - LTF

An adaptive role of mammalian cortex in shaping innate visual behavior

ATLAN Gal (.)

. - The Regents of the University of California, San Francisco - San Francisco - United States

SCANZIANI Massimo (Host supervisor)
A fundamental property of the nervous system is its adaptive capability. This allows organisms to flexibly reconfigure sensorimotor processing to correct for perturbations that cause performance errors or for unreliable sensory input(1,2). Some species are less adaptable than others, with debilitating consequences. This was demonstrated elegantly in classical experiments by Sperry, in which he rotated the eyes of amphibians by 180 degrees. This resulted in a permanent shift of visuomotor responses that prevented the animals from capturing prey, as they would direct their tongue in the opposite direction(3). Beyond motor deficits, eye rotation affected the camouflage of newts, which became inverted. Normally mirroring the lower half of the visual field (the ground), their backs had become light, mirroring the overhead lighting instead(4). In stark contrast to amphibians, mammals such as humans and primates show high levels of adaptability to distortions of the visual field. This is most often induced via goggles containing a prism(5–7). Helmholtz and Stratton were the first to note that humans quickly adapt to an inverted visual world during prism adaptation(8,9). In a series of classical experiments, Erismann and Kohler demonstrated that after wearing the goggles for several consecutive weeks, subjects could adapt to perform tasks as complex as riding a bicycle(6,10). Thus, mammals can compensate for sensory perturbations by adjusting how sensory input translates to action. The key difference enabling behavioral adaptation in mammals may be the evolution of the neocortex. Many innate behaviors can be generated via direct sensory input to evolutionary-conserved subcortical centers. Mammals have evolved an additional pathway to the subcortex, through corticofugal projections. In the early 20th century Ludwig Edinger suggested that the expanded mammalian cortex allows for “a subordination of reflexes and instincts to associative and intelligent actions”(11). In other words, that corticofugal pathways have evolved to provide additional control over innate behavior. However, this suggestion remains unresolved. In this proposal, I wish to utilize advanced neural techniques in mice to test the hypothesis that corticofugal projections from the visual cortex play a critical role in remapping sensorimotor transformations during behavioral adaptation. The significance of this work is twofold. First, it will provide novel insights into the mechanisms of visual adaptation, contributing to a better understanding of neurological disorders in which adaptive behavior is impaired, such as autism(12). Secondly, leveraging the established framework of the visual system, this work aims to uncover the principles of corticofugal communication. Such principles could be extended to other cortical modalities, thereby shedding light on the fundamental evolutionary advantage gained by the expansion of the mammalian cortex.
2022 -
Grant Awardees - Program

Unravelling the mechanisms of brain and behavioral elaboration in ecologically diverse butterflies


Life Sciences - Universidad Regional Amazónica Ikiam - Tena - ECUADOR


Department of Behavioral Physiology & Sociobiology - University of Wuerzburg - Wuerzburg - GERMANY


Department of Biological Sciences - The George Washington University - Washington - USA


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

How does the brain encode adaptive behavior? And how do neural systems facilitate behavioral elaboration? Answering these questions requires integrating evolutionary perspectives of ecology and neurobiology in taxa that display behavioral diversity and innovation. To do so, we need new investigative tools that allow us to look deeper into the brain, and to experimentally manipulate brain development and function. Developing new tools for specific groups of organisms is a major investment, and careful consideration should be given to which species to target. We present Heliconiini butterflies as a system where investment is clearly justified. The rich ecological diversity of Heliconiini has been studied for 150 years, but only recently has the extent of neuroanatomical variation been revealed, with some brain regions varying in size by over 25X. Our rich understanding of these taxa, combined with their experimental tractability presents new opportunities for an integrative understanding of neural variation. However, the current lack of established investigative tools inhibits our ability to understand this neural diversity. To address this, we will: 1) visualise and quantify neural diversity; 2) link neural activity to behavior in a nature-based virtual reality setup; 3) optimise genetic tools to manipulate brains and behavior; and 4) identify molecular controls of behavioral maturation. Developing this toolkit will unlock the potential of this system as a model for understanding brain and behavioral elaboration.
2022 -
Long-Term Fellowships - LTF

Assembly, dynamics, and plasticity of plastid translocon biogenesis

BAG Pushan (.)

. - The University of Tennessee Knoxville - Knoxville - United States

BRUCE Barry (Host supervisor)
Evolution, on its millennial course, gave rise to eukaryotes from prokaryotes when bilayer organelles, mitochondria, and plastids, evolved from free-living prokaryotes engulfed via endosymbiosis. These organelles retained a fraction of their ancient genome by moving large parts to the nucleus. Hence, they rely heavily on importing nuclear-encoded, cytosolically-synthesized preproteins for >95% of their proteome[1]. Most organelle targeted preproteins have a short N-terminus sequence, named transit peptide(TP). TPs are essential for targeting and recognition of multi-protein translocon machineries present in both outer(TOC) & inner membrane(TIC), which select, sort, and translocate preproteins into the plastid[2]. During evolution, with increasing cellular compartmentalization, new regulatory subunits emerged to control the translocation process[3]. However, a fundamental question remains; how and where did the translocons came from? In plants, plastids are named for their plasticity in form and function. Different plastids are found in various tissues and are often responsible for coloration of leaf, flowers, and fruits[4]. In plants plastid biogenesis is an essential developmental step and mostly occurs from proplastid (premature) that has very few or no pre-existing translocons[5],[6]. Such as, in rapid greening upon germination or leaf re-emergence in spring. First proplastids replicate and later light exposure transforms them into chloroplasts[7]. Based on environmental conditions (dark/light), developmental state, or tissue type; proplastids can develop into non-green plastids or chloroplasts[6],[8]. Thus maturation of plastid is multidirectional, transitioning into other sub-types, such as from chloroplast to chromoplast in fruit ripening[11] or vice versa upon regreening of citrus fruits[12] or green plastid turning in gerontoplasts upon aging[13]. Given this complexity of plastid development, it is obvious that the composition and regulation of translocons must change during a plant’s life cycle, to support and regulate the high diversity of preproteins translocation. Although accepted that different translocon structures exist with different regulatory subunits, only limited research efforts have focused on developing plastids and hence their evolution remains elusive[14]. One limiting factor is the inability to make genetically “knocked out” viable mutants. Hence, understanding the evolution of core translocon “design” and assembly steps remains a major challenge. To alleviate these, range of model systems, that are simple to complex in tissue structure and photoheterotrophic (permitting nonlethal translocon mutations) to autotrophic in growth needs to be studied. Hence, I propose a comparative study of translocon biogenesis in complex plant(pea), simple plant(duckweed) and a lower non-flowering moss to disentangle the evolutionary ontology of how early eukaryotes transported proteins across plastid membranes with limited translocons.
2022 -
Grant Awardees - Program

Good vibes: how do plants recognise and respond to pollinator vibroacoustic signals?


Life Sciences and Systems Biology - Turin University - Turin - ITALY


Program for Systems Biology of Molecular Interactions and Regulation/Group of 'Transcriptional Orchestration of Metabolism' - Institute for Integrative Systems Biology (I2SYSBIO), Joint Centre University of Valencia (UV), Spanish Research Council (CSIC) - Paterna, Valencia - SPAIN


Faculty of Engineering and IT, Centre for Audio, Acoustics and Vibration - University of Technology Sydney - Sydney - AUSTRALIA

A finely-tuned communication is crucial for maintaining plant-pollinator interactions. So far, this complex association has been investigated primarily by focusing on visual and olfactory cues. Recent studies have suggested vibroacoustic (VA) signals as an additional communication channel eliciting plant responses, however, the extent and ultimate roles of VAs in plant interactions are largely unexplored. In the context of plant-pollinator associations, VA signalling has only been scantily addressed, mainly in buzz-pollinated species, neglecting airborne components and without delving into the underlying molecular mechanisms involved. Our project aims at dissecting the molecular and physiological mechanisms of plant responses to distinct VAs emitted by approaching insects, using snapdragon as a model. Since Antirrhinum flower visitors have unequal efficiency as pollinators and emit characteristic VAs, we hypothesise that plants are able to recognise effective pollinators by sensing their specific VA signatures. We also postulate that VA-elicited snapdragon responses affect pollinator behaviours, with effects on pollen transfer, and consequently on plant reproductive fitness. Our project will test these hypotheses by a multidisciplinary approach combining ethology, plant molecular biology, and physics-informed data science. VAs of legitimate and illegitimate flower visitors will be recorded and engineered signals will be played back to test plant early and late electrophysiological, metabolic and transcriptomic responses. We will generate flower-shape and receptor-sensing mutants by CRISPR-Cas gene editing to analyse VA-sensing processes and structural features potentially evolved to enhance plant VA transmission. Behavioural assays will test flower visitors’ preferences to assess if plant responses triggered by VAs can be considered adaptive in the context of pollination. Multidisciplinary data will be interwoven in an evidence-based mathematical model tracing a roadmap to help understanding the origins of phyto-vibroacoustics: why vibroacoustic communication has evolved in plants. By tackling complex dynamics in plant-pollinator systems from a totally new angle, we endeavour to revolutionise our understanding of how plants interact with the biotic and abiotic components of the environment.
2022 -
Long-Term Fellowships - LTF

Identifying genes contributing to trait variations throughout vertebrate evolution and development

BARUA Agneesh (.)

. - University of Lausanne - Lausanne - SWITZERLAND

ROBINSON-RECHAVI Marc (Host supervisor)
Biological systems are constantly changing. The scales vary, from the development change during an organism's lifetime to evolutionary change taking millions of years. A common feature of both is the coordination of various processes to bring about change. Studying the ways discrete processes interact and how they change biology is vital to our understanding of the very fundamentals of life. One of the most impactful changes occurs in traits that determine how an organism interacts with its environment-- life-history traits. Life-history traits are important for adaptation, which in turn orients evolution. Therefore, variations in genes and processes that bring about life history transitions can play a crucial role in forming adaptions and creating diversity in form and function. This strong phenotypic effect of life-history transitions provides the perfect premise for characterising genotype-phenotype relationships and identifying genes linked with phenotypic variation. I hypothesise that genes and processes involved in life-history transitions have large phenotypic effects that lead to interspecies trait variation. To test my hypothesis, I will functionally characterise one of the most drastic transitions in vertebrates, metamorphosis; and study its role in trait evolution. Common throughout the animal kingdom, metamorphosis comprises ecological, morphological, and physiological changes influenced by an animal’s environment[1]. Changes during metamorphosis are drastic, with stark differences between larva and adult stages. Additionally, environmental conditions strongly affect metamorphosis, making it an excellent system for studying how varying environments can influence biological processes to produce different phenotypes. Insects are well-studied models of metamorphosis, however, their basic biology is very different from vertebrates. Similarly, amphibians are also classical models of metamorphosis, and much of our early knowledge of metamorphosis comes from studying amphibians. In contrast, our knowledge of metamorphosis is limited for the most abundant and phenotypically diverse group of vertebrates, teleost fish[2]. Some fish undergo subtle metamorphosis akin to fetal-adult transformation in mammals, while some experience spectacular metamorphosis comparable to that in frogs[2]. This feature makes fish an ideal system to study how differential regulation of the same genes can have varying phenotypic effects. Due to their extensive diversity, we know little about the major genes regulating teleost metamorphosis or how groups of genes bring about drastic character changes. However, this knowledge gap is exciting because it allows for the identification of genes previously not associated with vertebrate development or the origin of phenotypic traits. Lastly, novel genes involved in metamorphosis can be functionally verified in experimental models such as zebrafish providing a robust genotype to phenotype relationship.
2022 -
Grant Awardees - Program

Dynamics of multilayer epithelial structures: Integrative mechanical characterization of epidermis

BI Dapeng (USA)

Physics - Northeastern University - Boston - USA


TCIS, Collective Cellular Dynamics Lab - Tata Institute for Fundamental Research Hyderabad - Hyderabad - INDIA


Department of Physics - LMU Munich - Munich - GERMANY

How single layer tissues transform into multilayer systems to become building blocks of organs and organisms is one of the unresolved riddles in biology. An intriguing example of this process is the formation of the most important barrier layer, the skin epidermis, which protects our body from the external environment and withstands large external stresses. During its development, the epidermis starts as a single layer of cells, which proliferate, move outward, and stack-up to build the multilayered epithelium. Understanding epidermal development is critical for understanding, preventing, and curing numerous skin defects, painful blistering, and skin cancers. To this end, skin epidermis development has traditionally been tackled via 3D imaging of fixed tissue, collected mainly from mouse embryos. With this scheme, however, the dynamics of epidermal development cannot be revealed. Besides, progress in research using animal models are limited by the time required to induce genetic perturbations and ethical considerations. Even where it is possible to pinpoint few molecular players using an animal model, the dynamic biophysical mechanism that dictates cell movements in a developing skin dermis remains unexplored. Funded by the HSFP, we will overcome these limitations by developing a stem cell-derived skin model, termed skin organoid. Furthermore, we will introduce a mechano-biological platform to measure tissue mechanics in 3D, and build a predictive 3D model of epidermis. In essence, our strategy is to build a bottom-up system that grants simple access to experimental parameters via biophysical measurements, genetic perturbations, and mathematical modeling, while retaining the physiological relevance. Taken together, owing to the interdisciplinary nature of our team, we plan to use a unique combination of disciplines and technologies, which will enable us to take a radically different approach for tackling the question of how a single layer epithelium transform into a multilayer tissue.
2022 -
Long-Term Fellowships - LTF

Antigen recognition machineries of gamma delta T cells in the skin during health and disease

BIRAM Adi (.)

. - The Francis Crick Institute Ltd - London - United Kingdom

REIS E SOUSA Caetano (Host supervisor)
The ability of the immune system to provide protection against invading pathogens relies on its capacity to recognize foreign components and execute an appropriate cellular immune response. T cells play a major role in this process, and broadly respond to pathogens through the diversity of their T cell receptor, comprised of either alpha-beta (ab) or gamma-delta (gd) chains. Although ab and gd T cells originate from common thymic precursors, the activation and regulation of these cell subsets differ substantially1. While the recognition of self and foreign peptides through MHC molecules by ab T cells was intensively characterized, the mechanisms by which gd T cells sense and respond to antigen are not clear. The lack of a generalized antigen recognition mechanism allowed the development of diversified gd T cell responses, which provide a rapid first line of defense and maintain barrier integrity at mucosal surfaces2. gd T cells are highly heterogeneous lymphocytes present in the blood, skin, intestine and lung3. The activation of various gd T cell subsets was shown to involve tissue-specific cues provided by the surrounding cells or sensed directly from the environment. For example, Butyrophilin and butyrophilin-like molecules, which are broadly expressed in lymphoid and non-lymphoid tissues were found to shape gd T cell compartments in both mice and humans4. gd T cells were long considered to contribute to ongoing immune responses mainly through cytokine secretion. Recent studies have suggested a role for engagements of cognate gd TCRs and co-stimulatory molecules in exerting different functions under distinct conditions2,5. Nonetheless, only few molecules were shown to bind the gd TCR and elicit a gd T cell response, and examples of direct recognition of microbial antigens remain scarce2. The skin niche comprises of several tissue-resident gd T cell subsets that sense and respond to the skin microbiota and environmental stimuli6. Apart from its role in homeostasis, gd T cells were shown to activate in various acute and chronic skin inflammations such as psoriasis and atopic dermatitis7,8. Studies from the Cyster and Weninger labs and subsequently additional groups identified dermal gd T cells, and determined their local functions in the skin, as well as cues guiding their migration to draining lymph nodes and distant skin sites7,9–21. Specifically, attempts to analyze the gd TCR repertoire in the draining lymph node has revealed dominant clonotypes18. Moreover, it was shown that mice which fail to develop a specific subset of dermal gd T cells, are protected from psoriasis-like skin manifestations, emphasizing the role of this cell population in psoriasis development8. Despite recent progress, how gd T cells recognize antigens in the skin and by what means these mechanisms contribute to disease progression are unclear. Here, I will develop a platform to identify unknown TCR-ligand interactions and study its role in skin inflammation.
2022 -
Grant Awardees - Early Career

Crossing the barrier: horizontal gene transfer in synergistic protocells


Laboratory of Supramolecular Biochemistry - Supramolecular Science and Engineering Institute (ISIS) - Strasbourg - FRANCE


Department of Chemistry - University of Guelph - Guelph - CANADA


Physical Organic Chemistry - Radboud University Nijmegen, Institute for Molecules and Materials - Nijmegen - NETHERLANDS

Replication is a key property of living systems and must have played a central role in the origin of life. However, current models of protocells do not support an autonomous cycle of replication: membraneless organelles (coacervates) can sequester nucleic acids, but lack stability and impede proper base pairing important to RNA biochemistry, while membrane-bound structures (liposomes) can host prebiotic RNA biochemistry without being able to take in the required substrates. Our team suggests that the advent of life resulted from the emergence of a prebiotic ecosystem of synergistically interactive protocells rather than individual self-sustaining systems. Whereas RNA-based coacervates and liposomes have been studied separately, we innovatively propose that cooperative interactions between protocells might overcome major obstacles for replication in minimal cells. Inspired by symbiosis in biology, we envision that protocell synergy helped overcome this issue by enabling the primitive horizontal gene transfer (pHGT) between protocells, in order to unlock critical processes important to life. In living cells, liposomes and coacervates coexist, while performing different tasks. Similarly, their primitive versions might have had different, yet synergistic, roles in supporting RNA-based biochemistry, leading to a prebiotic scenario of increased complexity (introducing new functionalities) and diversity (improving fitness and efficiency). By elucidating the conditions required for coexistence, interaction and transfer between coacervates and liposomes, we will establish symbiosis as a novel factor in the origin of life, and at the same time gain a better understanding of the interactions between membraneless organelles and membranes in modern biology. The investigation of these three-way interactions between RNA, liposomes and coacervates constitutes a key innovative element, and will allow us to answer several questions fundamental to biology. We will illuminate i) how protocell recognition/interaction occur and ii) how genetic material is stored by and transferred between protocells, to build co-operative systems capable of pHGT. This unique opportunity will capitalize on each member’s set of expertise (Bonfio – membranes, O’Flaherty – nucleic acids, Spruijt – coacervates), that would otherwise be impractical without each member’s key contributions.
2022 -
Grant Awardees - Program

Transition and reconstruction of Central Nervous System due to aging and disease


Cellular and Cognitive Neurodevelopment - National institute for mental health - Bethesda - USA


Laboratory of Histology and Cytology, Faculty of Medicine and Graduate School of Medicine - Hokkaido University - Sapporo - JAPAN


Dept. Medical Biochemistry and Biophysics - Karolinska Institutet - STOCKHOLM - SWEDEN

ZOU Yimin (USA)

Neurobiology - University of California, San Diego - La Jolla - USA

What is aging? Getting old is not always bad, but it can be difficult both mentally and physically. Brain aging is a universal phenomenon in all mammalian species and continues to be a fundamental biological question. Although there has been much effort to understand brain aging and its many manifestations, including shrinkage and cognitive decline, it largely remains a mystery. With the increased life span of humans and neurodegenerative disorders on the rise, understanding normal aging will have a tremendous societal impact. Contrary to aging, much more is known about brain development. In the past several decades, tremendous progress has been made in deciphering the molecular program responsible for the development and maturation of neurons. Recent advances in genome science have led us to speculate that the very same factors that control fundamental developmental events are repurposed in adulthood to control synapse biology. It is known that the characteristic EEG rhythm decreases as aging. Therefore, we study the potential function of key factors and signalling molecules, which plays a pivotal role in developing the brain, on the formation, maintenance and function of the synapses formed by specific cortical neurons, which are essential for rhythm generation. We postulate that deregulation of these vital developmental factors might have a fundamental role in not only synaptic loss but also synaptic function when the cognitive decline starts in the aging brain. We will take a comparative approach to identify common mechanisms between the non-human primate model and a rodent model and test the functions of the aging program. This proposal relies on multilateral collaborations from distinct expertise in broad areas of neuroscience. Collaborations have made this proposal highly innovative as these questions are otherwise not accessible to researchers from each of the areas these investigators represent. When the issue of "what is aging" is clarified by our multidisciplinary team, it will be a great light not only for the mechanism of aging in healthy humans but also for the treatment and rehabilitation of diseases.
2022 -
Grant Awardees - Program

Modeling electric fields at the heart of enzyme catalysis and function

BOXER Steven (USA)

Dept. of Chemistry - Stanford University - Stanford - USA


Basque Center for Materials, Applications and Nanostructures - Ikerbasque Foundation - Leioa - SPAIN

The synthesis and degradation of nearly all components of living systems are controlled by enzymes. Enzymes can accelerate the rate of biosynthetic processes to a remarkable degree while retaining a high level of specificity. We aim to understand the origin(s) of this rate enhancement by creating synthetic enzyme mimics. Our underlying hypothesis is that the active site elements of enzymes are organized to create large electric fields that interact non-covalently with the substrate bonds undergoing charge displacement during catalysis. If the field is large and oriented correctly, this interaction can make a substantial contribution to lowering the transition state free energy and accelerating the reaction. This concept is called electrostatic catalysis, and while some computational and experimental evidence exists to support this hypothesis, the non-covalent interactions at the heart of this concept have not been recapitulated or their fields measured in synthetic systems. This is a grand challenge at the interface of biology and chemistry. This proposal brings together a group that is expert in the synthesis of molecularly defined porous materials with a more biological group that has developed methods to measure electric fields within organized systems, specifically naturally occurring enzymes, and to connect those fields to the lowering of the activation free energy. By using metal-organic frameworks (MOFs) to precisely install the key functional groups of molecules in apposition to each other, the electric fields created by their non-covalent interactions will be measured for the first time. The synthetic scaffold offers a tremendous diversity of chemical functionality; specific MOF structures that mimic a wide range of enzyme active site geometries that lead to diverse function are proposed. While motivated by enzyme catalysis, electrostatic interactions due to non-covalent interactions are an essential feature of the assembly of living systems on all length-scales, so we expect this work to have both fundamental and applied impact in diverse fields. We build on this fundamental information to create enzyme-like architectures that should, if our hypothesis is correct, be capable of accelerating the rate of chemical transformations as is found in living systems.
2022 -
Grant Awardees - Early Career

The atmosphere: a living breathing ecosystem?


School of Geography - Queen Mary University of London - London - UK


School of Environmental Sciences - University of Guelph - Guelph - CANADA


Biomedicine Discovery Institute - Monash University - Clayton, Melbourne - AUSTRALIA


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

The atmosphere is the Earth’s largest potential habitat, yet the least understood. Microscopic organisms (microbes) are transported between land and water through the atmosphere in a process that shapes global biodiversity and influences disease transmission. Yet little is known about the nature or activities of these microbes. Are airborne microbes simply passively blown through the atmosphere? Or is the atmosphere a ‘true’ ecosystem, with active microbes utilizing atmospheric gases for energy? Through this collaborative study, we will resolve these questions by systematically studying the composition, capabilities, and activities of atmospheric microorganisms. We will carry out a global genetic survey of microbial composition and traits, thus establishing whether the atmosphere hosts structured and adapted microbial communities. In parallel, we will conduct highly sensitive activity assays to determine whether airborne communities and single cells can metabolise atmospheric substrates. In addition, we will integrate empirical data with theoretical modelling to determine whether the energy available in the atmosphere through trace gases and other sources is sufficient to sustain life. Achieving this ambitious program depends on integrating multiple advances developed by our research team, including cutting-edge techniques (e.g., single-cell tagging and NanoSIMS measurements), theoretical approaches (e.g., bio-energetic single-cell and planetary-scale modelling), and recent major discoveries (e.g., that bacteria can live on atmospheric energy sources). The proposed research directly applies to the HSFP mandate to understand the fundamental mechanisms of life. If the atmosphere is found to be ecologically structured and metabolically active, it would result in the discovery of the largest active biosphere on Earth, and could broaden how (and where) we may search for life on other planets.
2022 -
Long-Term Fellowships - LTF

The Molecular Machinery behind the Wiring Specificity of Serotonin Axonal Projections

CHAN Chui kuen (.)

. - MRC Laboratory of Molecular Biology - Cambridge - United Kingdom

REN Jing (Host supervisor)
One in four adults experiences at least one diagnosable mental illness in any given year. Mental illnesses represent the largest single cause of disability worldwide. Depression is a common mental disorder, affecting more than 264 million people worldwide [1]. An imbalance in serotonin (5-HT) levels may disrupt emotions, consequentially leading to depression and anxiety [2]. 5-HT neurons in the central nervous system are spatially clustered in the brainstem. 5-HT neurons of the dorsal raphe (DR) and median raphe (MR) collectively innervate the entire forebrain and midbrain, directly regulating nearly every aspect of human behaviour. DR is the predominant source of serotonergic innervation of the forebrain, controlling diverse physiological and behavioural functions in health and diseases. The DR 5-HT system was conventionally concepted as a single, homogenous population highly collateralized for volume transmission, with limited wiring specificity. However, this idea is toppled by a recent study led by Dr Jing Ren. It was found that at least two parallel subsystems of DR 5-HT neurons differ in input and output connectivity, physiological response properties, and behavioural functions. This suggests heterogeneity of 5-HT neurons at the raphe nucleus [3]. Interestingly, two subpopulations of serotonergic fibres from DR preferentially innervate different brain regions [4], suggesting wiring specificity dictated by 5-HT neuron subpopulation at the nuclei. Communication by 5-HT neurons stands as a duality, which remains widely uncovered. Most 5-HT neurons do not involve synaptic connectivity, known as volume transmission. On the other hand, a minority of 5-HT neurons establish synaptic connectivity, known as wired transmission [5]. Despite spectacular progress over the past decade on molecular guidance-instructed axon projection, it is greatly centralized upon synaptic transmission but not volume transmission. Thus, despite its fundamental importance, the precise developmental assembly of the 5-HT system and the disrupted consequences remain unknown. In this proposed project, I shall investigate the molecular mechanisms regulating the specific assembly of 5-HT axonal projections. Specifically, how volume transmission-capable 5-HT projections reach their destination and stabilise. As a highly-targeted neuronal circuitry for psychiatric disorders, current antidepressants primarily rely on inhibiting 5-HT reuptake. Yet, the developmental mechanisms of the 5-HT system remains poorly understood for complex therapeutics to be based upon, with regard to the diverse behavioural deficits. Thus, a better understanding of the molecular architecture of the 5-HT system would enhance our ability to comprehend the aetiology of these disorders and provide novel and enhanced therapeutic strategies.
2022 -
Grant Awardees - Program

A bottom-up approach to understand how enzyme structural fluctuations accelerate multistep reactions


Department of Chemistry and Biomolecular Sciences - University of Ottawa - Ottawa - CANADA

GREEN Anthony P. (UK)

Department of Chemistry - Manchester Institute of Biotechnology - Manchester - UK


Department of Chemistry and Biochemistry - University of California, Merced - MERCED - USA

Enzymes are a type of protein found within all living cells. Often called biocatalysts, enzymes speed up the rate of biochemical reactions to help support life. Their unique structure imparts certain characteristics and makes them reactive to specific substrates, analogous to a lock and key model. The structure of enzymes is amenable to change, however it is not clear how structural changes in enzymes affect their efficiency (speed of reaction). Our team of interdisciplinary experts is proposing a unique approach to study the effect of structural changes in enzymes on their behavior by using a combination of state-of-the-art time-resolved X-ray crystallography and substrate engineering. This study will allow us to evaluate the link between structural changes and the catalytic efficiency of enzymes for various complex and multistep chemical reactions. The knowledge accrued through these experiments will enable us to predict the role of structural fluctuations in enzyme catalysis, and set the stage for the rational design of efficient artificial enzymes for applications in medicine and industry.
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


Biology - Pennsylvania State University - UNIVERSITY PARK - USA


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


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


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


School of Technology and Experimental Sciences - University Jaume I of Castellon - Castellón de la Plana - 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)
We take for granted how easily mammals can move and adapt to the environment. Simply reaching for an object requires the generation of motor commands to precisely coordinate the dozens of muscles spanning the upper limb. Further complications arise as repeating the exact same motor commands are liable to generate different reaching movements due to noise inherent to the neuromuscular system along with changes to the properties of the limb. These problems highlight an important role for sensory feedback as a way to identify errors during a motor action. In particular, somatosensory feedback is a critical sensory modality for performing skilled and precise motor actions and encompasses several modalities including proprioception. Proprioception is largely composed of feedback about changes in muscle properties (e.g. length, velocity, forces) which can be used to infer the state of the limb (Tuthill and Azim 2018). Ablation of proprioception causes a devastating reduction in performance for even basic motor actions with movements appearing uncoordinated and in some cases ablation may prevent movement altogether despite the motor system remaining intact. However, despite the obvious importance of proprioceptive feedback to adaptive control, our understanding of the neural processes that give rise to adaptive motor responses remains poor. One limitation has been the lack of a conceptual framework by which to interpret proprioceptive feedback and neural activity. The dynamical systems framework is a recent approach to understand neural processing and has been successful at predicting many features of neural processing (Vyas et al. 2020). This approach models neural activity as a dynamical system where neural activity (dx(t)/dt=A(x(t))+B(U(t)); where x(t) is a vector of neural firing rates) follows a low-dimensional trajectory in state space with dynamics generated from two main factors: from autonomously generated dynamics such as the dynamics generated by connections between neurons (A(x(t)), A is the transition function), and from external inputs to the network such as sensory input (B(U(t)) where U is a vector of sensory inputs and B is the input function that maps inputs to neural activity). However, most studies in the field have focused on the influence of autonomously generated dynamics reflecting in part the difficulty with estimating the influence of external inputs on neural networks. In theory, inputs could alter the neural trajectories in any number of ways including: translating, rotating and/or stretching the trajectories. Thus, in this project we aim to develop new tools to understand how external inputs from proprioceptive feedback influences dynamics in the cerebello-cortical loop, a circuit critical for adaptive motor control.