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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.
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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
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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.
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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.
Awardees
2021
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Grant Awardees - Program
How do malaria mosquitoes swarm and mate? The functional biology of mating swarms
MUIJRES Florian (NETHERLANDS)
Experimental Zoology Group - Wageningen University - Wageningen - NETHERLANDS
RIFFELL Jeffrey (USA)
Dept. of Biology - University of Washington - Seattle - USA
MUELLER Ruth (GERMANY)
Unit Entomology - Institute of Tropical Medicine Antwerp - Antwerp - BELGIUM
DIABATE Abdoulaye (BURKINA FASO)
Laboratoire de Parasitologie Entomologie - Institut de Recherche en Sciences de la Santé DRO - Bobo Dioulasso - BURKINA FASO
Malaria mosquitoes are world’s deadliest creatures. Despite our intensive vector-control efforts they still cause >400,000 human deaths each year. However, we know surprisingly little about the mechanisms that underlie their fecundity. Mosquitoes mate in-flight in complex 3D swarms of up to thousands of individuals of multiple sympatric species. It is thought that to avoid hybridization in such swarms, male and female conspecifics perform a mating dance by synchronizing their wingbeats. But interactions between freely-flying mosquitoes within a swarm have never been quantified.
Here, we propose to study the complex dynamics of mating swarms using an interdisciplinary approach by combining expertise from neuroscience, bio(fluid)mechanics, machine vision, behavioral ecology and medical entomology, from laboratories across three continents (Africa, Europe and N. America). Together, we aim to collaboratively study swarming behavior in lab, semi-field and field conditions. For this, we will develop two main research methodologies:
A. Dedicated machine-vision-based videography systems for tracking up to 300 mosquitoes flying in a swarm. These systems will be used to study the biomechanics and behavior of multi-species swarms in lab, semi-field and field conditions.
B. Novel tethered-flight electrophysiological assays to record the neural responses to approaching conspecifics and allospecifics. By placing this system within a swarm, we will study the neural bases of mate-swarming behavior.
By using these systems with a collaborative, multidisciplinary research approach, we aim to jointly answer our four main research questions:
Q1. How do mating-swarms form and keep their integrity?
Q2. How do individual swarming mosquitoes recognize potential mates?
Q3. How do swarming mosquitoes mate in-flight?
Q4. How does mosquito swarm dynamics affect mating success and hybridization?
This study will generate a new understanding of the functional neuro-mechanics of mating swarms, and provide crucial knowledge about the mechanisms that underlie the fecundity of malaria-vectors. We use the malaria mosquito as our model organism because its fecundity is particularly depending on swarming dynamics, and malaria is the deadliest mosquito-borne disease. Therefore, the project outcomes will directly support the development of malaria-vector control strategies/methods, such as gene-drive, acoustic lures, and monitoring. Swarming is currently an important topic in aerial robotics research; our study will provide novel bio-inspiration for flight control strategies, systems and algorithms of such swarming robots.
2021
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Grant Awardees - Program
Evolution of neural circuit dynamics and brain computations in Astyanax blind cave fish
SUMBRE German (ARGENTINA)
Dept. of Biology - Ecole Normale Superieure - Paris - FRANCE
KEENE Alex (USA)
Department of Biology - Texas A&M University - College Station - USA
GJORGJIEVA Julijana (MACEDONIA)
School of Life Sciences - Technical University of Munich - Freising - GERMANY
Environmental changes often drive drastic evolutionary changes in behavior and brain function. While genetic mapping studies have provided insight into the genetic basis of behavioral evolution, much less is known about the neural circuit dynamics and brain computations that drive this behavioral change. Across phyla, cave ecosystems provide the opportunity to examine how environmental change impacts the evolution of morphology, development and behavior. The Mexican tetra, Astyanax mexicanus is a leading model for studying genetic mechanisms underlying trait evolution. A. mexicanus consists of a surface (river) and several cave populations that independently evolved in largely isolated caves, allowing for comparative approaches to identify genetic and neural variants associated with behavioral evolution.
Cave populations of A. mexicanus exhibit prominent changes in sensory systems including loss of vision and expansion of smell, taste, mechanosensation and lateral line. Despite the robust changes in behavior and morphology, the shifts in processing sensory information within the brain has been unexplored. Here, we will apply an interdisciplinary approach that leverages newly developed genetic tools and synergistic interaction between PIs with expertise in behavioral evolution, functional imaging and theoretical modeling to investigate how changes in neural dynamics underlie the evolution of sensory systems to new environments with different sensory constraints. This synergistic collaboration will shed light on general evolutionary principles underlying the repurposing of neural circuit dynamics and computations of sensory systems that could have broad implications for understanding the evolution of brain function, plasticity and intra-species differences in sensory processing.
2021
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Grant Awardees - Program
Friends with benefits? A holistic approach to diffuse mutualism in plant-pollinator interactions
SICARD Adrien (FRANCE)
Plant Biology department - Swedish University of Agricultural Sciences - Uppsala - SWEDEN
RISSE Benjamin (GERMANY)
Computer Vision and Machine Learning Systems Group - Faculty of Mathematics and Computer Science - Münster - GERMANY
GROZINGER Christina (USA)
Department of Entomology - Center for Pollinator Research - University Park - USA
Most flowering plant species benefit from the pollination services of animals, where the animal helps transport pollen between flowers and individual plants, thereby supporting seed and fruit production. In turn, plants provide nutritional resources to pollinators, include nectar (which serves as a source of carbohydrates) and pollen (which serves as a source of protein and fat). This plant-pollinator mutualism is essential to supporting terrestrial ecosystems and is also vital for human agricultural production. Declines in pollinator populations due to anthropogenic change (including habitat loss) endangers these ecosystems and threatens food security. Generalist pollination systems in which flowering plant species uses a broad spectrum of pollinators for pollination services, and pollinator species visit diverse plant species to meet their nutritional needs, can create robust and resilient plant-pollinator communities. Designing and restoring habitats with these generalist systems can serve to reduce or reverse pollinator decline, since multiple pollinator species will be supported. Yet, how such generalist and diffuse mutualisms are formed in an ecological community remains a mystery - primarily due to the lack of tools supporting high throughput monitoring of pollinator visitation patterns and the lack of plant systems where pollinator-attractive traits can be precisely genetically controlled. This interdisciplinary project combines computer vision with plant genetics and pollinator behavioral ecology to identify the mechanisms mediating plant-pollinator interaction networks in generalist pollination systems. In addition to generating novel, broadly accessible monitoring tools and experimental plant systems, this study will provide the first comprehensive characterisation of the plant traits that attract and reward different pollinator species and the pollinator behavioral strategies which optimise pollinator nutrient acquisition in ecological communities. By linking plant genetics, pollinator health and quantitative behavioral data, this project will generate novel concepts and approaches to mitigate pollinator decline in agricultural, urban and natural ecosystems.
2021
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Grant Awardees - Program
Assembling and recombining the Arabidopsis centromeres
HENDERSON Ian (UK)
Department of Plant Sciences - University of Cambridge - Cambridge - UK
SCHATZ Michael (USA)
Departments of Computer Science and Biology - Johns Hopkins University - Baltimore - USA
KAKUTANI Tetsuji (JAPAN)
Dept. of Biological Sciences - The University of Tokyo - Tokyo - JAPAN
Centromeres are essential to attach chromosomes to spindle microtubules during cell division. Despite this deeply conserved role, the DNA sequences underlying centromeres are extremely fast evolving, which is termed the ‘centromere paradox’. Many centromeres consist of highly repetitive satellite repeats, where individual repeats are often ~170-200 bp in length and occur in massive tandem arrays. Intriguingly, satellites show concerted evolution within and between chromosomes, indicating mechanisms of sequence exchange between the repeats. However, the recombination pathways that change satellite arrays, and their influence on centromere function, remain poorly understood. In this project, we will investigate genetic and epigenetic factors that control satellite dynamics and centromere function, using Arabidopsis thaliana. Accurate analysis of the Arabidopsis centromeres via short-read sequencing has been impossible, due to the high degree of satellite repetition. Long-read technology has created new opportunities to sequence and assemble the centromeres for the first time. We aim to harness nanopore technology to assemble the Arabidopsis centromeres and dissect the roles of meiotic recombination and epigenetic information. Our success requires interdisciplinary innovation via a combination of genetics, epigenetics and computer science. The Henderson and Kakutani groups will generate Arabidopsis nanopore data. Analysis of long-read sequencing data and repeat regions requires significant computational expertise, which is provided by the Schatz laboratory. They will perform new computer science research into the fundamental algorithms and data structures for the assembly, alignment and analysis of highly repetitive texts, including centromere sequences. The Henderson group will test the role of meiotic recombination on centromere stability, while the Kakutani group will test the role of epigenetic information. The Schatz group are using cutting-edge computational methods to map DNA methylation in nanopore data, which will synergize with our experiments testing the role of this epigenetic mark within the centromeres. The team’s combined computational and biological expertise is strongly complementary and synergistic. Our strategic aim is to provide fundamental insights into the genetic and epigenetic mechanisms that control centromere dynamics in eukaryotes.
2021
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Grant Awardees - Program
Structural damage to axons resulting from repetitive mechanical motion
HESS Henry (GERMANY)
Biomedical Engineering - Columbia University - New York - USA
SHEFI Orit (ISRAEL)
Faculty of Engineering - Bar-Ilan Institute of Nanotechnology and Advanced Materials - Ramat Gan - ISRAEL
KAKUGO Akira (JAPAN)
Faculty of Science - Hokkaido University / Graduate School of Science - Sapporo - JAPAN
RAFFA Vittoria (ITALY)
Department of Biology - Università di Pisa - Pisa - ITALY
Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. Biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. For example, “tensegrity” refers to the emergence of stability as a result of a balance of tensile and compressive elements in a mechanical structure. It was inspired by the human musculoskeletal system, applied to architectural designs, and returned to biology as a framework to understand cellular mechanics.
However, progress in the engineering discipline of mechanics also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures, and its origin in processes such as materials fatigue. Some tissues, such as the spinal cord, are formed from long-lived nerve cells which maintain their function over the entire lifetime of the organism. How do these cells maintain their operation despite being constantly subjected to mechanical stresses? How do the mechanical stresses degrade intracellular structures, and what mechanisms are activated to effect repair? These are the fundamental biological questions we aim to address.
We will mimic the repetitive mechanical motion and study how it damages internal structural components in the long extensions of nerve cells and which repair mechanisms contribute to maintaining their health. Specifically, we will: (1) develop a novel experimental setup to exert thousands of cycles of stretching and bending deformations on the nerve cell extensions, (2) characterize the structural damage to them, (3) characterize the functional damage to them, (4) identify the repair mechanisms employed by the cell to mitigate and reverse the mechanical damage, and (5) integrate the obtained information into a coherent model.
The newly formed team is composed of experts in biomechanics, materials science and nanotechnology, neuroscience and regenerative medicine, and will combine experimental and modeling approaches. Overall, we take an engineering perspective and apply it to cell biology by asking not “How does it work?” but “How does it keep working for so long?”. The obtained insights will inform our understanding of the mechanical aspects of maintaining cellular health, inspire new biomimetic approaches to engineering, and yield a better appreciation of the cell as a “self-repairing machine”.
2021
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Grant Awardees - Program
Understanding the cellular mechanics of coral bleaching
HU Ke (CHINA, PEOPLE'S REPUBLIC OF)
Center for Mechanisms of Evolution - Arizona State University - Tempe - USA
INABA Kazuo (JAPAN)
Shimoda Marine Research Center - University of Tsukuba - Shizuoka - JAPAN
Mutualistic and parasitic intracellular symbionts have an enormous impact in the global ecosystem as well as on the health and behavior of their hosts. Coral bleaching, a major global ecological crisis, is caused by the massive loss of the symbiont dinoflagellate Symbiodinium from its coral hosts. Sustained coral bleaching leads to coral death, destroying an essential foundation of the marine ecosystem. While the importance of Symbiodinium spp in the marine ecosystem has long been established, the cellular mechanics of how the intracellular association with their hosts is established and dissolved is not understood. To tackle this problem, the joint team of the Hu Lab (Arizona State University, U.S.A.) and the Inaba Lab (Shimoda Marine Research Center, University of Tsukuba, Japan) will combine our expertise in cell biology, microscopy, parasitology, evolution biology and marine biology. We will use an evolution-guided strategy to test whether two seemingly incongruent processes - the exodus of Symbiodinium from cnidarians and the egress of apicomplexan parasites from mammalian cells- share a common evolutionary origin and cellular mechanics. Our work will reveal the nature of the force driving exodus of symbiont from coral, and develop molecular genetic tools that are essential for investigating the fundamental biology of the Symbiodinium-cnidarian partnership.
2021
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Grant Awardees - Program
Revealing the interplay of genetics and biomechanics underlying butterfly scale morphogenesis
KOLLE Mathias (GERMANY)
Department of Mechanical Engineering - Massachusetts Institute of Technology - Cambridge - USA
WILTS Bodo (GERMANY)
Department of Chemistry and Physics of Materials - University of Salzburg - Salzburg - AUSTRIA
NADEAU Nicola (UK)
Dept. of Animal and Plant Sciences - The University of Sheffield - Sheffield - UK
During the final stage of metamorphosis, butterfly wings sprout with hundreds of thousands of scales, each formed by a single cell and carrying precise nanostructural motifs. Delicate control of scale structure on the single-scale level determines multiple functions of the wing, including brilliant colors, water repellency, thermoregulation, and lift generation. Despite these functions being of great interest to biologists and engineers alike, we only have limited knowledge of the mechanisms underlying scale formation. This project aims to decipher the processes underlying butterfly scale morphogenesis using newly developed methods for observing the scales while they are forming in the chrysalis, combined with biomechanical modeling, molecular analysis, genetic manipulation of scale formation, and nano-scale electron-microscopic analysis of formed scale morphologies. To understand the coordination across different morphological features, the characterization of the temporal changes during stages of development is critical. By integrating these different approaches, we will shed light on the mechanical effects, biomolecular constituents, and genetic factors that drive the temporal and spatial coordination during wing scale development.
The result of this collaborative interdisciplinary effort between biologists, materials scientists, and engineers will be a complete time-resolved picture of scale structure formation, paired with information about the landscape of molecular constituents in critical developmental phases, a deeper understanding of the biomechanical phenomena, and a clearer view on the interplay between specific genetic components, their effect on the scales’ biochemistry and its influence on critical biomechanical interactions. We will test our understanding through genetic manipulation and through time-sensitive inhibition of structural components. The deeper understanding of biological formation of functional material architectures gained through this effort will form the basis for future targeted initiatives aimed at translating structure formation principles from biological systems into synthetic functional materials for applications in optics, sensing, biomedical devices and textile technology, sustainable paints and coatings, and augmented reality infrastructure.
2021
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Grant Awardees - Program
Teratology in microfossils as a proxy for understanding mass-extinctions through time
VANDENBROUCKE Thijs (BELGIUM)
Department of Geology - Ghent University - Ghent - BELGIUM
VAN DE SCHOOTBRUGGE Bas (NETHERLANDS)
Dept. of Earth Sciences - Utrecht University - Utrecht - NETHERLANDS
LOMAX Barry (UK)
Dept. of Agriculture & Environmental Science - University of Nottingham - Nottingham - UK
LOOY Cindy (NETHERLANDS)
Dept. of Integrative Biology - University of California, Berkeley - Museum of Paleontology - Berkeley - USA
Mass-extinction events in Earth history can provide us with crucial baselines by which ongoing biodiversity loss can be compared and its selectivity calibrated. All mass-extinction events are connected to extreme perturbations of the carbon cycle, including changes in greenhouse gas concentrations and associated global warming/cooling. These major changes in the carbon cycle are thought to be driven by interconnected episodes of widespread volcanism, rapid increase or burning of biomass, burial, erosion or oxidation of carbon, destabilization of methane from the seafloor and permafrost, and marine anoxia. A recently discovered phenomenon associated with mass-extinction events is an increase of teratological microfossils (pollen, spores, organic-walled phyto- and zooplankton) with aberrations in morphology and texture. These malformed fossils allow us to make direct inferences about the proximate mechanisms behind these biotic crises. Unique in the fossil record, these tell-tale signatures co-occur in, and can be recovered from both the marine and terrestrial realms, allowing for the integration of these records and a search for commonality.
With this interdisciplinary project we aim to test a set of interrelated hypotheses that link malformation to either metal toxicity (Hg, Cd, Ni, Pb), or increased UV-B radiation due to ozone loss, or to environmental stress related to climate change. Here, we propose to use these microfossils and their modern analogues in experimental and field settings to explore the true potential of teratology as a proxy to test, integrate and refine the many existing models for biotic crises across time and space. The deep time perspective is provided by work packages led by Ghent University and Utrecht University working on Paleozoic and Mesozoic events characterized by the presence of abundant malformed microfossils reflecting both marine and terrestrial ecosystems. Planned work will tease out the relative influence of metal toxicity related to marine anoxia and volcanic activity from geochemical and micropaleontological analyses of core and outcrop material complemented by studies of modern analogs. Work at UC Berkeley and University of Nottingham, focusing on the role of UV-B radiation, metals and temperature, will ground-truth observations from deep time via growth experiments using nearest living relatives.
2021
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Grant Awardees - Program
The aphrodisiac gut: defining the factors promoting yeast mating within insect intestines
STEFANINI Irene (ITALY)
Department of Life Sciences and Systems Biology - University of Turin - Turin - ITALY
POLIN Marco (ITALY)
Mediterranean Institute For Advanced Studies (IMEDEA) - CSIC-University of Balearic Islands - Esporles - SPAIN
NEW Elizabeth (AUSTRALIA)
School of Chemistry - University of Sydney - University of Sydney - AUSTRALIA
SEGRE' Daniel (ITALY)
Graduate Program in Bioinformatics - Boston University - Boston - USA
Saccharomyces cerevisiae (Sce) has seen widespread use by humans throughout history for winemaking, brewing, and bakery. However, a process fundamental for this yeast’s evolution still remains only partially understood: interstrain mating (outbreeding), which potentially results in strains bearing new genomic settings and fitness. While outbreeding is easily achievable in laboratory settings, it is extremely rare in nature. In fact, we have only recently discovered the first environment where it can occur: within wasp guts. Comprehending what makes the insect gut an environment suitable for Sce mating would provide us with a better understanding of Sce evolution and expand our knowledge beyond the unnatural lab settings. Outbreeding is achieved through a multi-step process encompassing sporulation, germination, ascus break, and mates encounter. These steps may be promoted within wasp guts thanks to the sequence of drastically different chemical and mechanical stresses peculiar to this environment. We have set up a team of experts in all the fields necessary to tackle this hypothesis: microbiology, genetics, chemistry, physics, and computational biology. We will carry out in vivo experiments to assess the wasp gut environment by using dedicated sensors and Sce genes fundamental for germination and sporulation in this environment. These data will be instrumental to develop a genome-scale mathematical model exploring yeast genetics, metabolic and environmental features favoring germination and sporulation. In vitro high-throughput assays assessing both the yeast response and metabolites measured by dedicated intra- and extra-cellular sensors will provide further data to calibrate the model. Physical forces required for Sce ascus break or mate encounter will be measured through up-to-date biophysical techniques: cylindrical Couette chambers, micropipette force sensors, and microfluidic droplets. We will bring together the information that we gather about each stage to develop microfluidic devices emulating the structure and physiology of wasp guts and investigate there the entire process leading to outbreeding. This project will unveil the key factors of Sce evolution by providing fundamental insights on the biological mechanisms leading to outbreeding in natural settings, thus potentially revolutionizing our current understanding of the process.
2021
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Grant Awardees - Program
Feathers as structures and sensors: understanding mechanosensing in bird flight
WINDSOR Shane (NEW ZEALAND)
Dept. of Aerospace Engineering - University of Bristol - Bristol - UK
PERKEL David (USA)
Dept. of Biology & Otolaryngology - University of Washington - Seattle - USA
WOOLLEY Sarah (USA)
Dept. of Biology - McGill University - Montreal - CANADA
Birds are extremely agile and robust flyers, able to cope with challenging gusty wind conditions and perform remarkable aerial manoeuvres. To do so, birds take advantage of the flexibility of their feathers, which vibrate as a function of airflow, stimulating the mechanosensory neurons in the skin, to provide information about the airflow over the wings. We aim to explore this complex sensorimotor loop, first to identify what aerodynamic information is available to birds to help control their flight and understand how birds’ wings can act both as aerodynamic surfaces and as a distributed airflow sensing array and then to understand how this aerodynamic information is encoded in the nervous system. Although airflow sensing is thought to be critical for efficient and agile flight, almost nothing is known about how changes in airflow translate to feather movement and subsequent neural signaling. Thus, this work addresses a broad biological question about sensory encoding of aerodynamic information.
This proposal represents an integrated, international collaboration to explore this question across multiple levels of organization, from the movements of feathers to neural activity during perturbed flight manoeuvres. Dr Windsor (University of Bristol, UK) is an expert in using computational image analysis to study animal dynamics and his team will use techniques from aerospace engineering to look at the aerodynamic and vibrational properties of feathered wings, including measurements of the wing motions of behaving birds. Dr Perkel (University of Washington, Seattle, USA), an expert in songbird neuroscience, will investigate the physiological mechanisms underlying the encoding of this mechanosensory information by the nervous system. His lab will record electrical signals from single neurons in the wing nerve and spinal cord of zebra finches and trace their neural pathways. Dr Woolley (McGill University, Montreal, Canada) is an expert in behaviour and neurophysiology. Her lab will map the regions of the brain responding to airflow stimuli based on insights gained from Dr Windsor’s and Dr Perkel’s groups and then measure neural responses in flying birds. By combining approaches from aerospace engineering and neuroscience we aim to understand the functional properties of wing mechanosensing that allow birds to “feel” their way through the air.
2021
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Grant Awardees - Program
The shaping of life by oxygen: from single cell to multicellular dynamics
RIEU Jean-Paul (FRANCE)
Institute of Light and Matter - University Claude Bernard Lyon 1 - Villeurbanne - FRANCE
SAWAI Satoshi (JAPAN)
Dept. of Basic Science - Graduate School of Arts and Sciences - Tokyo - JAPAN
WEST Christopher (USA)
Dept. of Biochemistry & Molecular Biology - University of Georgia - Athens - USA
A high level of oxygen in the atmosphere is taken for granted as it is indispensable for human and most animal life. Yet, life (bacteria and unicellular eukaryotes) evolved for over 2 billion years in a low oxygen environment. Oxygen became widely available only in the last 600 million years and was likely the main factor behind the rapid diversification of most complex multicellular life forms. For elaborate multicellular tissues to form, their overall shapes however must still satisfy oxygen demands of individual cells. Oxygen consumption will rapidly reduce the oxygen level within a few cell depth into the tissue. This becomes a problem in early embryonic development before respiratory and circulatory systems are established. Many cells still need to differentiate and migrate for long distances and place themselves at the right destination. It is largely unknown what makes the varying oxygen environment and the execution of their precise differentiation and navigation within a tissue compatible. The project aims at elucidating the common basis of oxygen dependency in morphogenesis by studying how the social amoeba Dictyostelium detects and reacts to oxygen at the molecular level and how this dictates cell migration and morphogenesis. Dictyostelium is an organism evolutionarily close to the branches of multicellular evolution, and presents enormous advantages to be easily cultured in the laboratory and reversibly switched from unicellular to multicellular states in less than a day. Amoeboid cells are able to change their state (by differentiation) and place themselves in more favorable conditions for foraging and respiration (by migration). An emphasis is placed on clarifying this most fundamental and primordial characteristic with a focus on the cross-scale quantitative relationship between oxygen, metabolic states, cytoskeletal machineries and migratory modes. New screening methods based on aerotaxis responses, oxygen sensors and 3D microscopy will be combined with molecular genetics of oxygen response pathways. The role of the new mechanism unearthed will further be tested for their roles in neural crest cell migration in zebrafish. They will be formulated into multi-scale mathematical models to clarify how the coupling between oxygen consumption, sensing and migration of individual cells gives rise to robust and collective morphogenetic movements.
2020
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Grant Awardees - Program
Elucidating the mechanism of membrane fusion using DNA nanostructures
ROY Rahul (INDIA)
Lab. for Nanobiology, Dept. of Chemical Engineering - Indian Institute of Science - Bangalore - INDIA
HOWORKA Stefan (AUSTRIA)
Dept. of Chemistry, Institute of Structural Molecular Biology - University College London - London - UK
AKSIMENTIEV Aleksei (USA)
Dept. of Physics - University of Illinois at Urbana-Champaign - Urbana - USA
Lipid bilayer membranes define the outer boundary of a biological cell, protecting its internal volume from elements of the extracellular environment. To gain entry through these membrane barriers, some pathogens fuse their membranes with the membrane of the host cell in a process commonly known as membrane fusion. It is largely believed that placing two membranes near one another can lead to the spontaneous formation of a neck (stalk) joining the two membranes. The stalk eventually resolves into an opening (pore) for material exchange, followed by complete fusion of the two membranes into one. Dedicated proteins (fusogens) found in viruses and cell organelles accelerate this process by facilitating transitions between several intermediate states of the membrane fusion process. While our knowledge of the proteins involved in membrane fusion has steadily accumulated, much less is known about the actual mechanics of membrane fusion, as these processes occur too fast for conventional experimental approaches to capture them with sufficient resolution.
This project aims to develop a new approach for studying membrane fusion mechanics by utilizing recent developments in the field of DNA nanotechnology, where molecules of DNA are reprogrammed to fold into well-defined structures of the same size as fusogenic membrane proteins. Using such DNA nanostructures as a type of a molecular scaffold, two membranes with different chemical and physical properties will be placed a prescribed distance away from one another to determine the likelihood of spontaneous fusion. Elements of fusogenic proteins will be incorporated within the DNA nanostructures to generate on-demand membrane fusion events. Advanced microscopy techniques will be combined with computer simulations to verify that such artificial DNA nanostructures can indeed capture the functionality of naturally occurring membrane fusion proteins. Finally, the method will be applied to induce and arrest fusion of a virus with a lipid membrane, providing a highly detailed view of the first step of viral infection. The fundamental insights into the mechanics of membrane fusion as well as the DNA nanotechnology platform to study such processes will open new avenues of investigations of various biological processes, from neuroscience to drug delivery.
2020
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Grant Awardees - Program
Self-organization and biomechanical properties of the endosomal membrane
GIZELI Electra (GREECE)
Institute of Molecular Biology & Biotechnology - Foundation for Research and Technology, Hellas - Heraklion - GREECE
ZERIAL Marino (ITALY)
Zerial Lab, Principles of cell and tissue organization - MPI of Molecular Cell Biology and Genetics - Dresden - GERMANY
ANDO Toshio (JAPAN)
WPI Nano Life Science Institute - Kanazawa University - Kanazawa - JAPAN
SPAKOWITZ Andrew J. (USA)
Dept. of Chemical Engineering - Stanford University - Stanford - USA
Gaining insight into the structure and function of biological membranes is important for understanding cell organization. Yet, despite a great deal of progress with identifying lipids and proteins on biological membranes, we lack an understanding of their organization and movements. We propose to look at how proteins change shape during binding events using two innovative techniques. One technique uses acoustic waves to extract information of the size and shape of proteins determined by their hydrodynamic properties. The other, called atomic force microscopy, uses a miniature detector to rapidly scan a surface, similar to a finger reading braille text, to deliver a microscopic 3D view of the proteins and lipids and how their shapes change during binding events. Models of these events will be created to interpret how they are regulated and controlled. Cells have a complicated network of vehicles, called endosomes, which transport proteins and lipids to wherever they are needed at a moment’s notice. We study this endosomal network in fine detail to get a better idea of how it’s regulated. We build a simplified synthetic “endosome” containing some of the key lipids and proteins found on native endosomes. We monitor protein-lipid and protein-protein binding events to see how the proteins change their shape upon binding. By changing the density and patterns of the proteins on our synthetic “endosome” we seek to understand how a native endosome controls such critical events within the cell. The endosomal network impacts many diseases for example, Alzheimer’s and cardiovascular disease, as well as playing a role the entry of certain pathogens into cells. Also, drugs can be delivered to cells via the endosomal network. Thus, a better understanding of its regulation could impact human health and welfare.
2020
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Grant Awardees - Program
Biological protein springs as allosteric modulators
ITZHAKI Laura (UK)
Dept. of Pharmacology - University of Cambridge - Cambridge - UK
BAHAR Ivet (USA)
Dept. of Computational & Systems Biology - University of Pittsburgh School of Medicine - Pittsburgh - USA
GORDON Reuven (CANADA)
Dept. of Electrical and Computer Engineering - University of Victoria - Victoria - CANADA
YANG Shang-Hua (CHINA, REPUBLIC OF (TAIWAN))
Dept. of Electrical Engineering - National Tsing Hua University - Hsinchu - CHINA, REPUBLIC OF (TAIWAN)
Over the last decade, humans have made extraordinary advances in our ability to synthetically adapt biology. We are in the midst of developing the tools that can reverse genetic disease by altering DNA, and we are creating proteins that do not exist in nature to perform new functions. Yet our understanding of the basic function of proteins and how this is influenced by design is extremely primitive. Even the basic understanding of binding-based signal transduction in proteins, allostery, is arguably far from complete: we are still a long way from being able to mimic nature’s sophistication in creating functional proteins and engineering allosteric functions into proteins – the difference between a mere description and a true understanding. Our mechanistic understanding of allostery has been hindered by a lack of experimental techniques that can probe single proteins within an ensemble and the gap between experimentally observed and computationally predicted quantities.
We will tackle this problem by adopting new single molecule tools, in conjunction with protein design and multiscale theoretical modelling. To understand how protein design impacts allostery, we will use and further develop a combination of theoretical (based on Ising formalism, elastic network models (ENMs), and sequence coevolution analyses) and experimental (nanoplasmonic tweezers, extraordinary acoustic Raman (EAR) spectroscopy, and molecular characterization of folding/binding/function) methods. We choose as model system tandem-repeat proteins because of their simplicity and modularity, structural malleability and adaptability to new functions allosterically driven by alterations in interfacial interactions and assembly state. Using both natural and designed TR proteins (and their mutants), we seek to close the gaps between design, theory/computations and function. The goal is a deeper understanding of the biophysics of allostery that will inform our traverse into synthetic biology while also having a specific impact on TR proteins and their essential roles in cellular pathways. Notably, an important interdisciplinary impact of this work will be to quantify the interaction of electromagnetic waves with proteins in the >10 GHz frequency range, precisely where new 5G cellular phone standards are being developed and proteins are susceptible to disruption due to their elastic resonances.
2020
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Grant Awardees - Program
Uncovering the OS of trees: Environmental information processing and the control of bud dormancy
BASSEL George (GREECE)
School of Biosciences - University of Warwick - Coventry - UK
BHALERAO Rishikesh (SWEDEN)
Dept. of Forest Genetics and Plant Physiology - The Swedish University of Agricultural Sciences - Umea - SWEDEN
WALKER Sara (USA)
School of Earth and Space Exploration - Arizona State University - Tempe - USA
BAYER Emmanuelle (FRANCE)
Lab. of Membrane Biogenesis UMR5200 - University of Bordeaux (CNRS) - Villenave d'Ornon - FRANCE
Plants have a remarkable ability to undergo transitions during their life in a robust and synchronized fashion. They are able to achieve this despite the environment they are in being highly variable, and not having sophisticated information processing systems like brains.
A striking example of how plants use variable signals such as temperature to time a critical developmental transition is the breaking of bud dormancy in in long-lived trees that grow in boreal and temperate regions of the world. In these trees, growth stops in the autumn and a state of dormancy is established that prevents reactivation of leaf formation which is timed to coincide with the advent of spring. The timing of dormancy break so the growth can be restarted is highly critical decision since a premature release from dormancy exposes plants to damage from sudden frosts in the early spring, whereas restarting growing too late will compromise fitness and productivity due to reduction in the length of their growing season. How trees accurately time the break of bud dormancy so that growth can start again in spring is question that has puzzled biologists for over 100 years, and will be addressed in this project.
This will be achieved by exploring parallels between how human engineered computers process information, and the cells in tree buds process temperature. The genes which control bud dormancy have recently been described, yet how they operate within the multicellular context of a bud tissue remains unknown. We propose that controlled communication between cells plays a central role in the release from bud dormancy, and their ability to generate robust responses.
A synergistic combination of biological experiments, computer modelling, physics and 3D image analysis, will provide unprecedented insight into how tree buds process temperature information. The project will lead to the identification of algorithms invoked by trees and the molecular and cellular logic used by trees to control bud dormancy, thereby revealing the operating system used by a plant to control its growth over the course of its life cycle.
2020
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Grant Awardees - Program
Adaptive asexual evolution in cancer, corals and seagrasses - ADAPTASEX
REUSCH Thorsten (GERMANY)
Dept. of Marine Evolutionary Ecology - GEOMAR Helmholtz Centre for Ocean Research Kiel - Kiel - GERMANY
BAUMS Iliana (GERMANY)
Dept. of Biology - Pennsylvania State University - University Park - USA
WERNER Benjamin (GERMANY)
Barts Cancer Institute - QMUL - London - UK
All multicellular organisms are genetic mosaics, composed of different cell populations that have acquired somatic mutations due to mitotic errors. It is generally assumed that this intra-organismal genetic heterogeneity is detrimental for organismal fitness and results in disease such as cancer and senescence. The goal of ADAPTASEX is to unite studies on the dark side of such genetic heterogeneity with an exploration of possible beneficial adaptive effects. In doing so, we are analyzing parallels in modular organisms that occur frequently among the plant and animal kingdom. Corals and seagrasses, as examples, grow asexually to very large size, resulting in clones (=genets) of hundreds of m2. Our research is motivated by preliminary, genetic marker based observations of within-genet heterogeneity (corals, seagrasses), its transfer to the germline, and the increasing recognition of the importance of genomic heterogeneity for predicting cancer etiology, dynamics and treatment. We will describe somatic genetic heterogeneity at the genome level of model coral and seagrass species, and compare patterns to available cancer data. For the free-living species, we perform experimentation to assess fitness effects of somatic genetic variants, and study the transfer of somatically generated variation to the sexual cycle. We hypothesize that the emergent multi-level selection contributes to adaptive dynamics and may purge deleterious genetic variation at the cell population level, explaining delayed senescence and reduced mutational load in modular species. Our interdisciplinary team will develop a joint modeling approach to follow adaptive dynamics of the observed intra-organismal genetic heterogeneity in diverse asexually evolving systems ranging from cancer to modular plant and animal genets and gain synergistic insights into the role of cell population competition and spatial structure for asexual selective sweeps. We will develop protocols to validate low frequency genetic variants, and to predict adaptive dynamics depending on localization, level of selection, and effects of somatic mutations. We expect to contribute to the unification of biological theory by establishing a framework for the study of somatically derived genetic variation from humans to plants, its evolutionary dynamics and fitness effects.
2020
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Grant Awardees - Program
Sounds and pheromones: neural networks merging olfactory and acoustic cues in sexual imprinting
BOVETTI Serena (ITALY)
Dept. of Life Sciences and Systems Biology - University of Turin - Turin - ITALY
GIGAN Sylvain (FRANCE)
Lab. Kastler-Brossel - Sorbonne Université, UPMC-ENS - Paris - FRANCE
PENN Dustin (USA)
Konrad Lorenz Institute of Ethology - Veterinary Medicine University, Vienna - Vienna - AUSTRIA
Sexual imprinting is a process of instinctive learning occurring during early postnatal development, through which many animal species acquire memories of the odor, vocalizations, and other characteristics of their parents (or siblings), and then utilize this information to select their mates as adults. Sexual imprinting has evolved in many taxa, and yet surprisingly almost nothing is known about the neural mechanisms controlling this type of learning. What neural circuits are involved in this process? How is information from multiple sensory modalities integrated, and do they have synergistic effects on female preferences? Laboratory mice have proven to be useful models to investigate sexual imprinting, but do these findings generalize to outbred, wild house mice? To answer these questions and decipher whether sexual imprinting represents a general mechanism guiding mate selection in females, we will take a multidisciplinary approach using behavioral, neuroanatomical and advanced optical imaging techniques. We will conduct cross-fostering experiments, and apply whole brain activity pattern reconstruction and in vivo functional imaging to address several specific aims: i) experimentally test the synergistic effects of acoustic and olfactory cues on sexual imprinting; ii) reconstruct the brain regions activated by sexual imprinting; and iii) functionally trace the circuits that influence female mating preferences.
To address these aims we created a novel collaboration between three research groups with very different expertise. The multidisciplinary research capitalizes on recent advances in optical imaging and neuroanatomy, including light-sheet whole-brain imaging and highly innovative in vivo technology for simultaneous imaging on multiple brain regions. We aim to reveal the organization of the circuits that are shaped during postnatal development to form memories of conspecific that are recalled in adults, which enhance inbreeding avoidance and reproductive success.
2020
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Grant Awardees - Program
Covalent modification and regulation of proteins by CO2 using Chlamydomonas as a model system
VOCADLO David (CANADA)
Depts. of Molecular Biology & Biochemistry and Chemistry - Simon Fraser University - Burnaby - CANADA
SMITH Alison G. (UK)
Dept. of Plant Sciences - University of Cambridge - Cambridge - UK
CAMPBELL Robert E. (CANADA)
Dept. of Chemistry, School of Science - The University of Tokyo - Tokyo - JAPAN
Carbon dioxide (CO2) has been present in the atmosphere and dissolved in water throughout the almost four billion years over which life has evolved. Over this time, CO2 has emerged as the primary carbon source for all life on earth through its assimilation by plants and bacteria to form carbohydrates and other organic molecules that are the building blocks of life. Consistent with its abundance in the atmosphere and its ability to diffuse through membranes, many organisms are well known to sense and respond to CO2. Despite the clear physiological importance of CO2 and its prevalence within the environment, remarkably little is known about the potential of CO2 to directly regulate protein function and how it may thereby serve as a metabolic signaling molecule within organisms.
We hypothesize that reversible carboxylation of specific lysine residues by CO2 within various proteins, in a manner that is sensitive to cellular CO2 levels, can alter protein function in vivo and thereby serve as a mechanism for organisms to sense and respond to varying levels of CO2.
We believe that several difficulties have limited progress in addressing this fundamental question. Principally, the rapidly reversible nature of lysine carboxylation makes it notoriously difficult to detect CO2 modified residues and to characterize the functional consequences of this protein modification. Here we propose to work as a team to develop a series of technologies to enable investigation of protein carboxylation by CO2 and its role in sensing within the microalgae Chlamydomonas. Chlamydomonas is an ideal model system because it shows clear physiological responses to CO2 and can be readily genetically engineered. Using these new research tools we will test the hypothesis that fluctuations in CO2 levels are sensed by Chlamydomonas through modification of the lysine residues of various cellular proteins. Finally, we will use targeted genetic engineering of Chlamydomonas to validate our understanding of this system.
2020
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Grant Awardees - Program
Time-resolving the mechanism of exocytosis in situ
GALLEGO Oriol (SPAIN)
Dept. of Experimental and Health Sciences - Pompeu Fabra University - Barcelona - SPAIN
CASTANO-DIEZ Daniel (SPAIN)
BioEM Lab, Biozentrum - University of Basel - Basel - SWITZERLAND
DE MARCO Alex (ITALY)
Dept. of Biochemistry and Molecular Biology - Monash University - Clayton - AUSTRALIA
Exocytosis is a conserved vesicle trafficking pathway responsible for the delivery of biomolecules to the cell surface and to the extracellular media. While regulated exocytosis is present only in secretory cells (i.e. neurotransmission or hormone release), constitutive exocytosis is generally present in all eukaryotes, where it regulates cell growth, cell progression, cell polarity and it is involved in multiple human pathologies including cancer and neurological disorders. Our goal is to time-resolve the molecular mechanism of constitutive exocytosis (i.e. exocytosis).
Understanding complex and multi-step processes such as the exocytosis requires a complete overview of the structure-function relationships and the dynamics of the protein machinery involved. Exocytosis is regulated by an extensive network of macromolecules organized in protein complexes, regulatory proteins and membranes with specific compositions. Despite it has been long studied, the complexity and dynamism of the mechanism of exocytosis could not be reconstituted in vitro. This and other technical constraints limited the characterization of the cellular machinery in charge of performing this function. To investigate this further, we have gathered an international team of scientists to resolve the global mechanism controlling exocytosis through the concerted application of advanced imaging techniques. The team includes experts in biology, mathematics and engineering of instrumentation for microscopy. We intend to decipher the molecular mechanism of exocytosis by addressing the system with all of its complexity, including its topology, dynamics and function. We will combine live-cell imaging, the development of imaging instrumentation and advanced mathematical computation to build an enhanced setup capable of reconstructing the cellular machinery beyond current technical constraints. Together we will embark on a comprehensive approach to solve the long-standing question of how the cell is capable to coordinate such a massive and dynamic protein machinery in charge of driving exocytosis.
2020
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Grant Awardees - Program
How plant heat stress will influence global warming this century
FRANKS Peter (AUSTRALIA)
School of Life and Environmental Sciences - University of Sydney - Eveleigh - AUSTRALIA
SCHROEDER Julian (USA)
Div. of Biological Sciences, Cell and Developmental Biology Section - University of California, San Diego - La Jolla - USA
COX Peter (UK)
College of Engineering, Mathematics and Physical Sciences - University of Exeter - Exeter - UK
Our objective is to elucidate the mechanism, from subcellular to global scale, underlying the interdependence of plants and climate during Earth's current climate transition. This century, rising CO2 will force global temperatures to increase, pushing some vegetation systems into heat stress and potentially physiological collapse, irrespective of rainfall. Indeed, the most vulnerable regions are humid, high rainfall zones where 'wet-bulb' temperature (the lowest temperature that an evaporating object or organism can cool to) will rise to levels known to induce physiological stress and cellular death.
Plants crucially affect climate through stomatal regulation of transpiration, which influences partitioning of net solar radiation into heating and evaporative cooling actions at the land surface. Plant vulnerability to heat stress can diminish this role and promote further climate warming, but little is known of the physiological and molecular mechanisms of stomatal regulation under heat stress, or of the combined physiological and climatic conditions that generate lethal leaf temperatures. This limits our capacity to predict and prepare for the long-term effects of global warming. This project will unlock mechanistic information from plant molecular genetics and heat stress physiology to formulate new theory describing stomatal regulation under temperature extremes, and apply this in an Earth system modeling framework to develop tools for predicting and adapting plant-atmosphere dynamics.
Our central hypothesis is that previously unrealized breakdown of the stomatal regulation mechanism under heat stress, when expressed at the landscape scale, will add a significant and as yet unforeseen enhancing feedback to climate change this century. To test this, we will undertake the first coordinated integration and scaling of the stomatal control mechanism responding to heat under high CO2, from molecular signaling through to global fluxes, to quantify the full effects of plant heat stress on regional and global climate. Genetic and physiological methods will be used to develop and validate a new leaf-scale model of stomatal regulation at high temperature. This will be implemented in Earth system simulations to re-evaluate end of century climate scenarios in the most heat-vulnerable regions using improved surface energy partitioning calculations.