Awards | Human Frontier Science Program

Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
News & Impact
Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
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2022 -

Long-Term Fellowships - LTF

Regulation of phagosome dynamics in antigen cross-presentation by dendritic cells

BIRAM Adi (.)

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

REIS E SOUSA Caetano (Host supervisor)

Type 1 conventional dendritic (cDC1) cells play a major role in orchestrating anti-viral and antitumor immunity by cross-presenting antigens on major histocompatibility complex class I (MHCI) molecules to CD8+ T cells. cDC1 cells in both mice and human express dendritic cell natural killer lectin group receptor-1 (DNGR-1, encoded by Clec9a), which detects dead cells and supports cross-presentation of dead cell-associated antigens. Recent studies have shown that DNGR-1 favors cross-presentation by promoting phagosomal rupture upon ligand engagement, allowing the escape of phagosomal contents into the cytosol, where they access the MHC class I antigen processing pathway. Although DNGR-1 was shown to destabilize the phagosomal membrane, it is unclear how phagosomal rupture is regulated downstream of DNGR-1 signaling. Here, we will employ a genome wide high throughput screening approach to identify novel regulators of phagosomal rupture and integrity and examine their role in antigen cross-presentation and antitumor immunity. We will utilize multiple cellular assays to mechanistically evaluate the contribution

of potential regulators, followed by generation of in vivo mouse models to study their function. Using a multidisciplinary approach that combines cell biology and functional immunology, we aim to uncover important players in DNGR-1-mediated phagosomal rupture and study their roles in various cancer models. Our approach will provide new insights into the basics of antigen crosspresentation and open new avenues in the development of therapeutic strategies manipulating cross-presentation in cancer.

2022 -

Grant Awardees - Early Career

Crossing the barrier: horizontal gene transfer in synergistic protocells

O'FLAHERTY Derek (CANADA)

Department of Chemistry - University of Guelph - Guelph - CANADA

BONFIO Claudia (ITALY)

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

SPRUIJT Evan (NETHERLANDS)

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

ZOU Yimin (USA)

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

HJERLING-LEFFLER Jens (SWEDEN)

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

FUJIYAMA Fumino (JAPAN)

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

BOURNE James (AUSTRALIA)

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

WUTTKE Stefan (GERMANY)

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

BOXER Steven (USA)

Dept. of Chemistry - Stanford University - Stanford - USA

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?

GOORDIAL Jacqueline (CANADA)

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

BRADLEY James (UK)

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

TREMBATH-REICHERT Elizabeth (USA)

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

GREENING Chris (AUSTRALIA)

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

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)

The serotonin system is the most widely used pharmacological target for treating depression and anxiety. Despite its fundamental importance, the assembly of serotonin system during development and disrupted consequences remain unknown. Recent studies, leading by my postdoc supervisor Dr. Jing Ren, show that individual subpopulation of raphe nuclei serotonergic axonal fibres innervate specific brain regions, suggesting the significance of serotonin neuron subpopulations behind wiring specificity. These organized serotonin axonal projections modulate neuronal activities in innervated regions and their functions, but how are these projection patterns determined during development? With my strong background in molecular biology and super-resolution microscopy, I am pursuing the answer to this question, how do the synaptic wiring proteins, serotonin receptors and surrounding microenvironment interact to specify serotonin axonal projections? Firstly, I have profiled protein networks of serotonin terminals at different brain areas by proximity biotinylation-facilitated quantitative proteomics. Functions of protein candidates shall be verified in 3D culture and conditional knock-out models. Secondly, I shall investigate mechanical signals from the microenvironment on axon projection specificity, by manipulating substratum stiffness. Finally, serotonin circuitry conduction shall be studied by employing GFP knock-in 5HTR2A mice-derived culture via super-resolution imaging. This study will significantly advance our understanding of the developmental assembly of the serotonin circuitry, providing insights into the relationship between neurodevelopment and mental disorders.

2022 -

Grant Awardees - Program

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

CHICA Roberto (CANADA)

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

THOMPSON Michael (USA)

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

GREEN Anthony P. (UK)

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

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

COSGROVE Daniel J. (USA)

Biology - Pennsylvania State University - UNIVERSITY PARK - USA

DURAND-SMET Pauline (FRANCE)

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

SVAGAN (HANNER) Anna (SWEDEN)

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

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

2022 -

Grant Awardees - Program

The social origins of rhythm

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

COOK Peter (USA)

Psychology - New College of Florida - Sarasota - USA

RAVIGNANI Andrea (ITALY)

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

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

2022 -

Grant Awardees - Early Career

Cellular and molecular basis of behavioural manipulation by viral infection

CRAVA Maria Cristina (ITALY)

Universitary Institute BIOTECMED - University of Valencia - Burjassot - SPAIN

GAMIR FELIP Jordi (SPAIN)

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

PRIETO GODINO Laura Lucia (SPAIN)

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

YON Felipe (PERU)

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

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

2022 -

Long-Term Fellowships - LTF

Somatosensory processing in a cerebello-cortical loop for adaptive control

CROSS Kevin (.)

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

HANTMAN Adam (Host supervisor)

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

2022 -

Long-Term Fellowships - LTF

Cell size-dependent sex determination

D'ARIO Marco (.)

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

LESLIE Andrew (Host supervisor)

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

2022 -

Grant Awardees - Program

Bacterial genome editing systems as a driver of cancer mutations

GALUN Eithan (ISRAEL)

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

DAGAN Tal (GERMANY)

Institute of Microbiology - Kiel University - Kiel - GERMANY

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

2022 -

Grant Awardees - Program

Unravelling the code of mitochondrial-nuclear communication

LEFKIMMIATIS Konstantinos (GREECE)

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

STÄDLER Brigitte (SWITZERLAND)

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

DASKALAKIS Nikolaos (GREECE)

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

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

2022 -

Grant Awardees - Early Career

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

PILOSOF Shai (ISRAEL)

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

DE DOMENICO Manlio (ITALY)

Dept. of Physics and Astronomy Galileo Galilei - University of Padua - Padova - ITALY

HALL James (UK)

Department of Evolution, Ecology and Behaviour - Institute of Infection, Veterinary and Ecological Sciences - Liverpool - UK

In a world fraught with human impact, predicting the response of organisms to environmental changes is a fundamental challenge. A dominant approach is to investigate how demographic and genetic factors determine the adaptability of a single taxon. However, organisms do not live in isolation. Hence, community ecologists investigate how the structure of species interaction networks affects community stability. While the interplay between species-level processes and community-level structures governs the response to environmental change, these two approaches have been disconnected. Moreover, how specific kinds of environmental heterogeneity and perturbations modulate this interplay is understudied. We propose to address these gaps by integrating theory and experiments using bacteria as a model organism. Bacteria are a dominant life form, colonizing almost every environment. In addition, genetic change in bacteria is partly driven by horizontal gene transfer (HGT)--a community-level process whose interplay with other interactions (e.g., competition) has not been studied at a community level. We will develop a theoretical framework to explore how species-level factors interact with the environment, affecting competitive ability and emerging community structures. We will use bacteria to experimentally test communities' responses to multiple kinds of environmental change, testing our theory. Our work will establish a framework for a mechanistic understanding of the interplay between species-level processes, community-level structures, and the environment. While targeted at bacteria, insights from this work will have broad implications for other organisms. This work is only achievable through a unique international collaboration that bridges ecology and evolution, microbiology, and statistical physics.

2022 -

Long-Term Fellowships - LTF

Understanding the role of mtDNA mutations and electron transport chain function in thyroid cancer

DE LA CALLE ARREGUI Celia (.)

. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States

MCFADDEN David (Host supervisor)

Cancer cells present altered metabolism to meet the bioenergetic and biosynthetic demands of high proliferation rates. Even though the mitochondrial genome (mtDNA) encodes key components of cellular energy homeostasis, and somatic alterations in mtDNA have been observed in many cancers, the functional significance of mtDNA mutations and alterations in the ETC remains incompletely understood. Previous research from Dr. McFadden’s lab has shown that the vast majority of the mtDNA in Hürthle cell carcinoma of the thyroid (HTC) harbored mutations in the complex I subunit of the electron transport chain (ETC). This loss of complex I function represents an early event in the progression of the disease and is maintained even during metastasis. This suggests that mtDNA mutations are a central driver in the pathogenies of this disease and opens the counterintuitive and exciting possibility that certain cancer types benefit from an impairment of mitochondrial respiration. Thus, I hypothesized that HTC represents an ideal disease outlier in which to interrogate the role of mtDNA alterations and ETC function in cancer. By using highly complementary approaches, I will first interrogate whether mtDNA mutations in humans predict impaired respiration and lead to altered metabolism. Then, I will study the mechanism by which mtDNA mutations confer a metabolic advantage in HTC in vitro, and finally, I will use novel genetically engineered mouse models to interrogate the role of complex I in thyroid tumorigenesis. To address these aims, I will use metabolomics, 13C tracer analysis, exome sequencing analysis, and in vitro and in vivo models of HTC. With this project, I will deliver a mechanistic and functional understanding of mtDNA mutations and complex I loss in HTC which will lead to insights more broadly applicable to tumors harboring mutations in mtDNA such as kidney and colorectal cancers.

2022 -

Long-Term Fellowships - LTF

Light induces lymph node activation via a sympathetic eye-to-lymph node pathway

DE VIRGILIIS Francesco (.)

. - University of Geneva (Université de Genève) - Geneva - SWITZERLAND

SCHEIERMANN Christoph (Host supervisor)

Lymph nodes (LNs) are the lymphoid organs where the adaptive immune response is initiated, which makes them extremely interesting in the clinics. LNs are richly innervated and several studies reported a regulatory effect of sympathetic innervation on LN activity (1,2). Additionally, recent studies demonstrated how both the nervous and immune system, including LN and lymphocytes, possess diurnal oscillation associated with changes in environmental stimuli, such as light (3, 4). Together, these findings suggest the hypothesis that light stimulation could directly influence LN activity via a descending neuronal pathway. Specifically, I propose that light stimulates specific non-image producing receptors in the retina (ipRGCs) connected to the suprachiasmatic nucleus (SCN) in the hypothalamus, which relays this photic information to the sympathetic ganglia (SG), ultimately leading to SG activation and LN modulation. Therefore, here, using a combination of stepwise genetic, pharmacological and surgical approaches, I aim to dissect this eye-to-LN neuronal pathway and its function in regulating LN as well as to create a first cell-specific atlas of molecular signatures in the LN induced by environmental stimuli such as light stimulation. Together, these data will pave the way to unprecedented, non-invasive approaches to modulate the immune system in the clinics with light stimulation.

2022 -

Grant Awardees - Program

The walking fish: Integrating biomechanics, energetics and robotics to study water-land transition

DI SANTO Valentina (ITALY)

Department of Zoology - Stockholm University - Stockholm - SWEDEN

IIDA Fumiya (JAPAN)

Department of Engineering - University of Cambridge - Cambridge - UK

SHUBIN Neil (USA)

Department of Organismal Biology and Anatomy - The University of Chicago - Chicago - USA

The transition from water to land in vertebrates occurred over 370 million years ago, however many of the fundamental morphological and physiological traits necessary to life on land arose prior to the origin of land walking. Several groups of fully aquatic fishes walk underwater, raising the question of why and which traits fishes need to take advantage of this mode of locomotion. Unfortunately, no work to date has explored the energetic benefits of this fundamental behavior across different environments, hindering the capacity to test hypotheses on the performance of transitional forms found in the fossil record and to understand the ecology of many extant species. Moving over complex and three-dimensional structures of the natural environment requires adaptive locomotor behaviors, and it is unclear how fishes during their growth might take advantage of the complexity of the substrate of the oceans and littoral zones. How do walking fishes achieve these versatile locomotor behaviors when moving over substrates of different complexity? Is there an ontogenetic shift in walking performance? What is the cost of walking and how does it compare to swimming? Here, we propose a study on the effect of environmental plasticity of walking behavior and fin anatomy of a fish, Polypterus, reared under different substrate types (flat and 3D), underwater and semi-terrestrial. We will combine anatomical measurements, developmental biology, biomechanical and physiological analyses, and robotic platforms to show how energetically efficient it is for a fish to walk and swim over different substrates and media. Experimental data will guide the design of a robotic platform capable of both walking and swimming. We will develop the bioinspired soft robotic model (the “robofish”) to understand the relationship between mechanical features and how they interact with motor patterns to form adaptive behaviors over different substrates at different body sizes. The performance of the robofish will be compared to that of real fish across treatments, and this will form the basis to create a platform to compare locomotor efficiency and plasticity of extant and extinct species of fish and their closest relatives.

2022 -

Long-Term Fellowships - LTF

Circuits for perception of state of self and others

DOLENSEK Nate (.)

. - The Regents of the University of California, Berkeley - Berkeley - United States

TSAO Doris (Host supervisor)

Our faces and the information they exhibit are crucial for the formation and continued functioning of human relationships and communities. Facial features enable us to accurately determine a person’s identity, and facial expressions enable us to judge their internal state and attempt to predict their intentions. Interestingly, this reliance on facial information is not unique to humans. Highly social primate species such as rhesus macaques also exhibit facial expressions in social contexts and possess sophisticated neural machinery for face processing. However, while much is known about how areas in the superior temporal sulcus (STS) process face identity, we know less about processing of expression, except that it is separate from the former. We further know that people interacting aren’t passively waiting for their turn, but synchronize their gaze, pupil size and mimic each other’s facial expression, with an inability to do so possibly underlying social dysfunction in autism. I aim to study how the brain assigns internal state to self and others by combining visual and interoceptive information, enabling dynamic social contact. I will first create a novel machine vision-based quantitative description of macaque orofacial movement. Next, I will employ NexGen fMRI whole-brain imaging combined with Neuropixels probes to investigate the circuits involved in facial expression detection of self and others, centering on the motion sensitive parts of STS and connected regions (insula, anterior cingulate). Finally, I will perturb neural activity of each component of the identified circuit and quantitatively assess its impact on facial expression, gaze, and other behavior.

2022 -

Long-Term Fellowships - LTF

Glucose regulation in nectarivorous birds

DOMER Adi (.)

. - The Regents of the University of California, Berkeley - Berkeley - United States

DUDLEY Robert (Host supervisor)

Birds, naturally hyperglycemic, can maintain approximately twice the blood-glucose concentration of mammals at equivalent size. Furthermore, they do so with only 10% of mammalian insulin levels, as they lack the primary insulin-regulating glucose transporter. It has been known for decades that glucose regulation in birds must accordingly differ from that of mammals. Birds have been previously proposed as a model system for the study of type II diabetes. However, avian regulation of glucose levels is understudied. As part of my Ph.D. on stopover ecology, I discovered correlations between glucose levels and myo-inositol (MI). MI is known to have important functions in metabolism, particularly relative to insulin mimetic activity and plasma-glucose utilization, but also in other core biochemical pathways potentially of high relevance to birds. During my postdoctoral studies I propose to further examine the role that MI, along with other key metabolites, play in avian blood glucose regulation. Moreover, I intend to quantify behavioral responses, metabolic consequences, and patterns of gene regulation which track sugar ingestion, and which underlie these hypothesized regulatory mechanisms. The hypotheses of this study will be assessed using different avian models, according to logistical limitations associated with each species. This work will assess the major metabolites which play a key role in glucose regulation in birds, their molecular and physiological mechanisms of action and associated whole-animal behavioral responses and will thus address a long-standing conundrum in avian metabolism and provide new insights into the physiology of metabolic syndromes in humans.

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Awardees

Regulation of phagosome dynamics in antigen cross-presentation by dendritic cells

BIRAM Adi (.)

REIS E SOUSA Caetano (Host supervisor)

Abstract

Crossing the barrier: horizontal gene transfer in synergistic protocells

O'FLAHERTY Derek (CANADA)

BONFIO Claudia (ITALY)

SPRUIJT Evan (NETHERLANDS)

Abstract

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

ZOU Yimin (USA)

HJERLING-LEFFLER Jens (SWEDEN)

FUJIYAMA Fumino (JAPAN)

BOURNE James (AUSTRALIA)

Abstract

Modeling electric fields at the heart of enzyme catalysis and function

WUTTKE Stefan (GERMANY)

BOXER Steven (USA)

Abstract

The atmosphere: a living breathing ecosystem?

GOORDIAL Jacqueline (CANADA)

BRADLEY James (UK)

TREMBATH-REICHERT Elizabeth (USA)

GREENING Chris (AUSTRALIA)

Abstract

The Molecular Machinery behind the Wiring Specificity of Serotonin Axonal Projections

CHAN Chui kuen (.)

REN Jing (Host supervisor)

Abstract

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

CHICA Roberto (CANADA)

THOMPSON Michael (USA)

GREEN Anthony P. (UK)

Abstract

Assembly, mechanics and growth of plant cell walls

COEN Enrico (UK)

COSGROVE Daniel J. (USA)

DURAND-SMET Pauline (FRANCE)

SVAGAN (HANNER) Anna (SWEDEN)

Abstract

The social origins of rhythm

KING Stephanie (UK)

MADSEN Peter Teglberg (DENMARK)

COOK Peter (USA)

RAVIGNANI Andrea (ITALY)

Abstract

Cellular and molecular basis of behavioural manipulation by viral infection

CRAVA Maria Cristina (ITALY)

GAMIR FELIP Jordi (SPAIN)

PRIETO GODINO Laura Lucia (SPAIN)

YON Felipe (PERU)

Abstract

Somatosensory processing in a cerebello-cortical loop for adaptive control

CROSS Kevin (.)

HANTMAN Adam (Host supervisor)

Abstract

Cell size-dependent sex determination

D'ARIO Marco (.)

LESLIE Andrew (Host supervisor)

Abstract

Bacterial genome editing systems as a driver of cancer mutations

GALUN Eithan (ISRAEL)

DAGAN Tal (GERMANY)

Abstract

Unravelling the code of mitochondrial-nuclear communication

LEFKIMMIATIS Konstantinos (GREECE)

STÄDLER Brigitte (SWITZERLAND)

DASKALAKIS Nikolaos (GREECE)

Abstract

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

PILOSOF Shai (ISRAEL)

DE DOMENICO Manlio (ITALY)

HALL James (UK)

Abstract

Understanding the role of mtDNA mutations and electron transport chain function in thyroid cancer

DE LA CALLE ARREGUI Celia (.)

MCFADDEN David (Host supervisor)

Abstract

Light induces lymph node activation via a sympathetic eye-to-lymph node pathway