-
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.
Awardees
2022
-
Cross Disciplinary Fellowships - CDF
Tumour homing immune cells for cavitation therapy
SMITH Cameron (.)
. - California Institute of Technology - Pasadena - United States
SHAPIRO Mikhail (Host supervisor)
One of the great difficulties in the treatment of cancer is the inaccessibility of the tumour core. Due to poor vascularity, hypoxia, and high interstitial pressure, many conventional cancer therapeutics are unable to treat this significant portion of the target tumour, leading to less successful therapies. In this project we will address these limitations by utilising recent developments in synthetic biology and ultrasound. Our approach will take advantage of the Shapiro laboratory’s work on genetically encoded air-filled proteins called gas vesicles (GVs), which we will express in engineered tumour-infiltrating macrophages and T-cells in response to tumour-specific biomarkers such as VEGF, Her2, or claudin-6. The resulting GVs will act as seeds for highly selective and localised therapy when combined with focused ultrasound. We hypothesise that high energy inertial cavitation – the formation and violent collapse of bubbles – will be seeded by GVs to damage surrounding tumour cells. This would both allow for selective killing of tumour cells as well as the potential release of antigens which would make the tumour more susceptible to attack by the immune system, while additionally having the potential to allow the immune system to recognise and attack metastases. Successful completion of this project will produce a new class of local and targeted anti-tumour therapy and create a scientific and technological foundation for future developments and therapies utilising the combination of engineered cells and ultrasound.
2022
-
Long-Term Fellowships - LTF
Enhancing receptor signaling by liquid condensate formation
SONG Daesun (.)
. - The Board of Trustees of the Leland Stanford Junior University - Redwood City - United States
LIN Michael (Host supervisor)
Transmembrane receptors activate intracellular signaling pathways mediating growth, survival, or differentiation. Liquid condensate formation by T cell receptors enhances downstream signaling, but whether condensation can generally enhance receptor function is unknown. I propose to study the ability of condensation to generally enhance receptor function using the epidermal growth factor receptor (EGFR) as a model, with the following aims:
1. Design inducible EGFR condensates. Fusions of cryptochrome 2 (CRY2) and the Fused-in-Sarcoma intrinsically disordered region (IDR) form droplets in response to blue light, while cryptochrome variants CRY2olig and GFP-CRY2high without IDR create visible accumulations of unknown liquidity. I will fuse EGFR-GFP to CRY2-IDR, CRY2olig, or CRY2high and assess liquidity of light-induced accumulations by time-lapse morphology and FRAP.
2. Compare signaling –/+ EGFR condensation. I will activate the above proteins –/+ light –/+ EGF, comparing to EGFR-GFP, while measuring amplitude and kinetics of EGFR/Akt/ERK phosphorylation, Shc-RFP recruitment, and receptor internalization. This will determine if condensation enhances signaling, and if so at what step and in what manner.
3. Determine if any observed signaling enhancement also augments function by assessing proliferation of keratinocytes expressing EGFR-EGFP or the above fusions –/+ light –/+ EGF.
This project will combine my existing expertise with liquid condensates from my Ph.D. training with the expertise of the Lin Lab at Stanford in CRY2 biochemistry and EGFR signaling to obtain insights into the role of condensation in organizing and amplifying biological signals.
2022
-
Long-Term Fellowships - LTF
Functional cell atlas of neural crest cell contribution to newt development and regeneration
SUZUKI Miyuki (.)
. - California Institute of Technology - Pasadena - United States
BRONNER Marianne (Host supervisor)
During development, neural crest stem cells arise within the forming central nervous system but then migrate into and throughout the periphery where they differentiate into diverse cell types. In addition to their importance in development, neural crest cells have recently been implicated in organ regeneration (e.g. heart regeneration in adult zebrafish) raising the intriguing possibility that they may be required in multiple regenerating structures. Salamanders have the remarkable regenerative ability and represent an excellent model for exploring the role of neural crest cells in both organogenesis and organ regeneration. To identify neural crest-derived cells that potentially re-express a neural crest gene regulatory program during organ regeneration, I have established Sox10::EGFP and Cre/loxP transgenic newts, Pleurodeles waltl, that genetically label and enable visualization of Sox10-expressing cells in vivo. With this in hand, I will explore two pressing questions: 1. Do neural crest-derived cells contribute to adult limb and heart regeneration in the newt? 2. If so, what are the underlying molecular mechanisms? To address these questions, in Aim 1, I will generate an atlas of cell types formed by neural crest-derived cells using Cre/loxP technique; in Aim 2, I will evaluate the involvement of neural crest-derived cells in organogenesis and organ regeneration using in vivo cell ablation technique. Aim 3 will generate a single-cell RNA-seq transcriptome profile during the regenerative process. This comprehensive atlas of cellular fates and functions of neural crest in newts promises to deepen understanding of development and regeneration in vertebrates.
2022
-
Long-Term Fellowships - LTF
Investigating the regulomic basis of major evolutionary transitions
TAYLOR Benjamin (.)
. - Purdue University - West Lafayette - United States
HARPUR Brock (Host supervisor)
The evolution of life on Earth has been extensively shaped by major transitions in biological complexity. The evolution of insect eusociality is one such transition and has occurred multiple times independently in recent evolutionary history. Unfortunately, the mechanistic basis of this transition is poorly understood. One major hypothesis proposes that eusociality is associated with substantial increases in gene regulatory complexity, but no study to date has provided a robust empirical test of this possibility. I propose to provide such a test. Using a novel meta-analytic machine learning approach, I will integrate new and existing multi-omic datasets from eusocial, subsocial, and solitary hymenopteran species to identify phylogenetically-robust signatures of the transition to eusociality. I predict that eusocial species will exhibit substantial expansions in regulatory complexity compared to related solitary taxa, in the form of increases in the proportion of the genome that is subject to alternative splicing or epigenetic regulation. Additionally, I will combine population genomic data and lab-based transgenic experiments to validate the functional role of regulatory loci, thereby corroborating the causal role of the regulome in generating complex social phenotypes. This project will integrate my experience in machine learning and gene expression analysis with expertise in alternative splicing and functional genomics provided by Dr Harpur’s group. Doing so will allow us to greatly advance our understanding of how social life evolves and diversifies by answering a fundamental biological question: how can biological complexity evolve without increases in gene content?
2022
-
Long-Term Fellowships - LTF
Templated polypeptide synthesis inside a nanopore cavity
TOPARLAK Omer duhan (.)
. - University of Oxford - Oxford - United Kingdom
BAYLEY Hagan (Host supervisor)
Genetically-coded protein synthesis is the universal hallmark of cellular life, where the ribosome is the central figure, linking nucleic acids to protein catalysts. Yet, our understanding of templated polypeptide synthesis is restricted to the extant ribosome and its engineered derivatives, with its limited chemistry. In order to facilitate the design of artificial ribosomes by simplifying the complex nature of the task, we propose to study peptide bond formation and the DNA-templated polymerization of amino acids within a nanotube cavity. Recent developments in nanopore technologies have unlocked the potential of single molecule chemistry with angstrom-level precision. To this end, we will utilize phi29 DNA packaging motor nanopores, which will allow the base pairing between template DNA and aminoacylated polynucleotides as activated substrates. Inspired by non-ribosomal peptide synthesis and prebiotic reactions on the early Earth, we will explore thiol-thioester, thiol-disulfide and S-to-N acyl transfer reactions. We will make use of thioester-activated (e.g. acetyl-CoA) and aminoacylated trinucleotides as transfer RNA mimics to drive polymerization. Modified or unnatural amino acid side chains on the nanopore wall can enable otherwise uphill condensation reactions. The newly synthesized polymers will not be restricted to the inclusion of natural amino acid side chains or conventional polypeptide backbones. The synthesis will take place continuously, at a useful rate and without the need for an external fuel. The ultimate chemistry we propose will enable (bio)chemists to produce efficient protein synthesis devices that will serve as a foundation for synthetic cells.
2022
-
Cross Disciplinary Fellowships - CDF
A multi-scale all-optical platform for the investigation of membrane potential dynamics
TORTAROLO Giorgio (.)
. - Swiss Federal Institute of Technology Lausanne (École Polytechnique Fédérale de Lausanne, (EPFL)) - Lausanne - SWITZERLAND
MANLEY Suliana (Host supervisor)
Membrane potential is a ubiquitous cellular feature, underlying important functions including the release of neurotransmitters upon arrival of an action potential, and calcium signaling related to cell proliferation control. Voltage imaging is becoming the standard to investigate membrane potentials, offering significant advantages over electrophysiology: it is less invasive, scalable, and suited to examine intracellular organelles. Although recent imaging implementations capture fast action potentials, they rely on averaging multiple events over a reduced field of view and are limited in temporal resolution. Hence, they can detect the single action potential but miss its propagation dynamics and, significantly, its modulation of synaptic transmission. Furthermore, intracellular propagation of membrane potentials remains unstudied. To overcome these limitations, I propose an all-optical optogenetic approach that leverages “smart” controlling architectures and state-of-the-art detectors to realize a paradigm change: from voltage imaging to on-demand voltage tracking. Upon further developing hardware in the host laboratory, I will investigate the propagation of organellar and plasma membrane potential signals, spontaneous or evoked, in non-excitable cells and neurons. I anticipate that this approach will uncover unprecedented insights into the intra- and inter-cellular signaling mechanisms and their modulation during activity. Indeed, these signatures are hypothesized to be altered by multiple sclerosis and other neurodegenerative diseases, and have so far proved elusive to measure.
2022
-
Long-Term Fellowships - LTF
Chemical and optogenetic approaches to identify and quantify the membrane sources of autophagosomes
UEMATSU Masaaki (.)
. - Cornell University - Ithaca - United States
BASKIN Jeremy (Host supervisor)
Autophagy is one of the main systems for the degradation of intracellular components. In this dynamic process, an ad hoc membranous structure called an autophagosome is transiently created to engulf cytoplasmic cargo to be degraded. Previous studies have identified many proteins essential for autophagy. However, the membrane sources of autophagosomes are still under debate, in large part due to the lack of direct methods to measure inter-organelle lipid transport with high spatiotemporal resolution.
I propose to develop a method to locally label lipids on donor organelle membranes and detect them on the destination organelle (autophagosome) after lipid transfer. I will use a unique system, developed by my host laboratory and termed optoPLD, a light-controlled enzymatic tool that can produce labeled lipids from phosphatidylcholine (PC) on specific organelle membranes. For the labeling, I will engineer optoPLD to produce deuterated PCs on the donor membrane. For detection, I will generate a second optoPLD with an orthogonal optogenetic tool that can be activated with different wavelength of light to release the deuterated portion of PCs on the destination membrane via hydrolysis. I will measure the deuterated fraction of the released moiety to quantify the amount of transferred lipid.
Combining this method with the acute knockdown of autophagy-related proteins to accumulate autophagosomes will determine the fractional contribution of organelles to the membrane sources of autophagosomes. Beyond autophagy, I envision that this method will be applicable to investigate any inter-organelle lipid transport, providing a much-needed tool to understand lipid homeostasis.
2022
-
Long-Term Fellowships - LTF
Haemogenic gastruloids: a novel approach to generate and study blood stem cells in vitro
VAN DEN BRINK Susanne carina (.)
. - Institut Hospital del Mar d'Investigacions Mèdiques (Hospital del Mar Medical Research Institute, IMIM) - Barcelona - SPAIN
BIGAS Anna (Host supervisor)
Bone marrow haematopoietic stem cell (HSC) transplants are life-saving treatments in a plethora of haematological and non-haematological malignancies. The availability of HSC transplants is limited, and there has been little success in producing or expanding HSCs in vitro. Rare instances of in vitro production of HSCs are of low efficiency and require ectopic expression of multiple genes, limiting their clinical applicability. During embryonic development, HSCs are formed in a specific niche which is key to HSC production. The study of the cellular and molecular contributions of the niche to mammalian HSC production remains restricted to in vivo mouse embryos, which are onerous to manipulate and not amenable to high-throughput screenings. Here, I propose to reconstruct the HSC generating niche in vitro using gastruloids; stem cell aggregates that self-organize into embryo-like structures with spatial and temporal precision. By modifying the original mouse gastruloids protocol, we have been able to recapitulate the emergence of haematopoietic clusters in the wall of vascular structures, with coordinated successive production of haemogenic endothelial and HSC-like cells. By systematically comparing haemogenic gastruloids with embryos I will build on these observations to: 1) obtain a tractable model system that can be used to study the embryonic HSC-forming niche in vitro 2) use this model to study how niche signals regulate HSC formation 3) achieve robust in vitro production of transgene-free, engraftable HSCs. Altogether, I will generate a model that will a) increase our understanding of the HSC niche and b) allow scalable in vitro production of tissue compatible HSCs.
2022
-
Cross Disciplinary Fellowships - CDF
Targeted protein degradation and electrophysiology to study the function of the proteasome
WHITTAKER Joanna (.)
. - University of Groningen - Groningen - NETHERLANDS
MAGLIA Giovanni (Host supervisor)
TYCH Katarzyna (Host supervisor)
The proteasome, a large protein complex capable of proteolysis, is the primary means by which misfolded or unnecessary proteins are degraded in eukaryotes and archaea. Due to its size and complexity, the mechanisms underlying its function, including the way in which it processes substrates with different primary and secondary structure content, are poorly understood. Accordingly, experimental methods must be used that enable the spatio-temporal measurement of these functions.
Biological nanopores are created when a transmembrane protein forms a nanometre-scale hole in a membrane. Building on their effective use in a broad range of applications, planned developments using nanopores include their integration into biosensors for the detection of analytes from blood. Recently, the group of Prof. Maglia developed a proteasome nanopore, paving the way to protein sequencing using nanopores. This significant development also provides an excellent platform for this proposed fundamental study into the function of the proteasome.
In this work, PROTACs (proteolysis-targeting chimeras) will be used to target proteins with different primary and secondary structure content for polyubiquitination by the E3 ubiquitin ligase. Electrochemical measurements will be used to observe the impact of physico-chemical properties and structure on unfolding and degradation by the proteasome in real time. PROTACs enable selected proteins to be targeted for degradation from mixtures or biological samples. This project is expected to have a significant impact on our understanding of the function of the proteasome, as well as in the areas of peptide sequencing and biosensors for tailored medicine.
2022
-
Long-Term Fellowships - LTF
Defining mechanisms of metabolic-epigenetic crosstalk that drive cancer initiation
XIAO Yi (.)
. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
MCBRAYER Samuel (Host supervisor)
Recent discoveries of recurrent mutations in metabolic genes across human cancers have revealed a central role of altered metabolism in cancer initiation. Pathogenic metabolic gene mutations trigger accumulation of a class of biomolecules called “oncometabolites”, which impair the activities of enzymes that catalyze the demethylation of histones and DNA. Despite these advances, the specific chromosomal regions and genes that represent the functional effectors linking oncometabolites with cancer initiation are poorly understood. This knowledge gap persists in part due to the difficulty of using primary tumor specimens to retrospectively identify mechanisms of malignant transformation. To circumvent this challenge, the host lab has created the first genetically engineered mouse (GEM) model of lower grade glioma driven by the isocitrate dehydrogenase 1 (IDH1) R132H mutant oncoprotein, which produces the oncometabolite R-2-hydroxyglutarate (R-2HG). I propose to use this model together with isogenic, IDH1 wild-type companion GEM models to elucidate the dynamics of changes in chromatin structure, gene expression, and cell populations induced by R-2HG in vivo. I will conduct ATAC-seq, bulk RNA-seq, and single-cell RNA-seq analyses of engineered neural cells isolated throughout the process of metabolism-dependent malignant transformation. My studies will provide a conceptual framework for understanding the deterministic and stochastic functions of oncometabolite signaling to chromatin. My studies will also identify specific oncogenic mechanisms that operate at the interface of metabolome and epigenome to drive malignancy, which could nominate new therapeutic targets in glioma.
2022
-
Cross Disciplinary Fellowships - CDF
Revealing the fundamental regulators of cell mechanical properties by single cell microfluidics
XU Catherine (.)
. - Max Planck Institute for the Science of Light (Max-Planck-Institut für die Physik des Lichts) - Erlangen - GERMANY
GUCK Jochen (Host supervisor)
Changes in mechanical properties of cells are key in a range of processes, including cell migration and development, and are frequently altered in disease states such as cancers. Yet, despite their key role, the gene regulatory networks underlying these processes are currently largely unresolved. Thus, the central aim of my proposed project is to gain a detailed understanding of how cellular mechanical properties are controlled, by developing microfluidic technology to simultaneously measure the mechanical phenotype and transcriptome of single cells in high throughput. The advent of single cell sequencing methods has been transformational for our understanding of biology, and multimodal approaches such as those combining genome and transcriptome measurements of the same cell, are likely to be even more so. The physical dimension, however, remains largely unexplored, and its exploitation offers the prospect of revealing how the biochemical composition of cells relates to their physical properties. I will thus apply my PhD experience to develop a microfluidic platform that combines physical and biochemical cell analysis, using real-time deformability cytometry and droplet-based single cell RNA sequencing. By matching the transcriptomic profile of each cell with its brightfield image, which yields their mechanical and morphological features, I will identify genes involved in the regulation of mechanical properties and their generality across cell types. In addition to elucidating fundamental regulators of cell mechanics, this technology will allow the investigation of their interplay with gene expression during both physiological and pathological cell state changes.
2022
-
Long-Term Fellowships - LTF
Molecular and material design principles for meiotic microtubule-organizing centers
YAGUCHI Kan (.)
. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
WOODRUFF Jeffrey (Host supervisor)
Formation of viable oocytes requires meiotic microtubule-organizing centers (MMOCs) lacking centrosomes. Multiple MMOCs assemble in oocyte cytoplasm and coalesce at two opposite spindle poles. While much is known about centrosomes, how MMOCs assemble and resist microtubule-mediated stresses is largely unexplored. I hypothesize that MMOC scaffolds begin as liquid droplets formed through demixing of proteins from the cytoplasm (phase separation model). In this case, these scaffold droplets could then fuse with each other and resist forces through regulated material hardening. Alternatively, MMOCs might assemble via diffusion-limited accretion (network percolation model) that require no hardening to resist forces. To test these hypotheses, this proposal aims to quantify the material properties of MMOCs and define the compositions for functional MMOC assembly. First, I will measure the liquidity and strength of MMOCs over time in living C. elegans oocytes. This can be accomplished using an optical technique pioneered in my host lab to induce nano-scale shear force (FLUCS). Second, I will use in vitro reconstitution system combined with FLUCS to determine the minimal protein motifs sufficient for MMOC assembly and material property. The host lab’s unique FlexiBAC expression system allows me to purify truncated candidate proteins known to localize at MMOCs. Finally, I will assess the fidelity of meiotic chromosome segregation when the material properties or components of MMOCs are altered in living oocytes. I expect these results to identify molecular and material designs for MMOC function. They will also represent a key first step toward creating a fully synthetic oocyte.
2022
-
Long-Term Fellowships - LTF
Physiological functions and molecular mechanisms of neuronal ER-phagy
YPERMAN Klaas (.)
. - Leibniz-Forschungsinstitut für Molekulare Pharmakologie - Berlin - GERMANY
HAUCKE Volker (Host supervisor)
Neurons are highly polarized cells with a complex architecture that underlies their function in information processing in the brain. The fact that neurons are long-lived post-mitotic cells poses special challenges for the pathways that preserve the integrity of their functional proteome. How neuronal proteostasis is maintained over the lifetime of an organism is a major unanswered question in neuroscience. The proposed project combines and extends my prior expertise in molecular cell biology in plants with recent findings from the host lab to dissect the physiological functions and molecular mechanisms of the turnover of the endoplasmic reticulum (ER), the largest neuronal organelle, via autophagy. Work in the host lab has shown that loss of the essential autophagy protein ATG5 causes the selective accumulation of tubular ER in axons and a concomitant increase in excitatory neurotransmission as a consequence of elevated calcium release from ER stores. Major questions regarding the physiological triggers for neuronal ER-phagy and the machinery involved remain unsolved. In the proposed project, I will use an unbiased proteomic approach utilizing novel proximity labeling strategies to identify the factors that control neuronal ER-phagy in the central nervous system. Moreover, I will develop live correlative light and electron microscopy approaches in genome-engineered mouse hippocampal and stem cell-derived human neurons to unravel the physiological stimuli that trigger axonal ER-phagy. The results obtained will provide fundamental new insights into the role of ER-phagy in maintaining brain function and aid the development of therapies to combat neurodegeneration.
2022
-
Long-Term Fellowships - LTF
Development of neural circuits for cooperative behavior in schooling fish
ZADA David (.)
. - The Regents of the University of California, San Diego - La Jolla - United States
LOVETT-BARRON Matthew (Host supervisor)
Throughout the natural world, many species behave in cooperation with their social groups. For example, individuals in a school of fish sense the actions of their neighbors to coordinate their actions. These complex sensory-motor behaviors emerge at the transition to adulthood, but it is unknown how the maturation of an individual’s neural circuits produces the capacity for social coordination. Here we propose a novel approach to study the functional development of neural circuits underlying social attention in schooling fish, using large-scale cellular-level calcium imaging and immersive virtual reality. We will apply these technologies to the micro Danionella translucida; glassfish remain small and transparent throughout their lifespan, allowing for whole-brain neural activity imaging in socially-mature animals. We will engage Danionella in a head-tethered virtual reality environment, where we can image neurons across the brain as fish move their tail to navigate a panoramic visual environment with an interactive group of computer-simulated schooling fish. We will record cellular-level calcium activity from across the visual-motor circuits of transgenic Danionella expressing a genetically-encoded calcium indicator in all neurons, and identify cells that encode the actions of others in the social group. By imaging from early development to mature adult, we will identify the developmental onset of socially-encoding neural circuits and schooling behavior. Overall, this new research direction will provide foundational insights into the function and evolution of the social brain, and identify how these abilities emerge from neural circuit development and maturation.
2021
-
Cross Disciplinary Fellowships - CDF
Cell migration in complex environments as a crucial step in the immune response
JAKUSZEIT Theresa (GERMANY)
Cell Biology and Cancer Department - Institut Curie - Paris - FRANCE
PIEL Matthieu (Host supervisor)
Cell migration has a crucial function in a variety of processes in the human body, e.g. dendritic cells explore tissues in search of pathogens, while cancer metastasis significantly decreases survival chances. Research over the last decade has shown that different migratory modes may be adaptations to changing extracellular conditions as experienced by immune cells migrating between tissues with different physicochemical properties. However, it remains unclear how cells integrate potentially competing physical and chemical cues to choose a path in complex environments such as dense tissue. To identify key cellular and extracellular factors that limit migration, we need to understand the underlying physical principles of migration under defined physical and chemical conditions. To this end, I will study dendritic cell migration in microfluidic channels with a high control over the microenvironment such as its porosity or gradients of chemokine. Collaborating with Prof. Voituriez, I will develop a mechanical understanding of the cytoskeleton dynamics in complex environments using active hydrodynamic models to study the interaction of cells with physical barriers. I will combine this cellular level of understanding with random walk models to analyse the large-scale dynamics of cell migration. To elucidate the physiological relevance, I will apply the theoretical framework to cells with migratory defects that display a primary immune deficiency. Thus, the interplay of experiment and theory will develop a quantitative understanding of how immune cells integrate physical and chemical cues to navigate complex environments, which is essential for an effective immune response.
2021
-
Long-Term Fellowships - LTF
Estimating male mutation bias across vertebrates
DE MANUEL MONTERO Marc (SPAIN)
Department of Biological Sciences - Columbia University - New York - USA
PRZEWORSKI Molly (Host supervisor)
In many species, the germline mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This observation is widely interpreted as resulting from the higher number of cell divisions that lead to male gametes compared to female gametes, and thus support the textbook view that germline point mutations stem mostly from errors in DNA replication. Recently, several lines of evidence call into question this interpretation: notably, the male bias has been reported to be stable with parental ages in humans and across a handful of mammals. In this proposal, we aim to fill in an important piece of the puzzle by estimating the extent of male mutation bias across a large number of vertebrates. To do so, we will employ a comparative genomics approach to infer neutral substitution rates in sex chromosomes and autosomes for different types of mutations. Importantly, we will use recent modelling that translates sex-to-autosome substitution rates into male-to-female mutation ratios taking into account sex-specific life histories. With this research design in mind, we thus aim to deepen our understanding of the genesis of germline mutations through the study of how male mutation bias arises and varies across species.
2021
-
Long-Term Fellowships - LTF
Programmable protease circuits to control vaccine immunogenicity
VLAHOS Alex (CANADA)
Department of Chemical Engineering - Stanford University - Stanford - USA
GAO Xiaojing (Host supervisor)
The development of vaccines to prevent morbidities from infectious diseases remains one of medicine’s greatest achievements. However, many successful vaccines have been developed empirically and vaccine efficacy is highly variable. Rationally differentiating immune cells to specific fates such as memory T cells to improve long-term vaccine efficacy is limited by current methods for controlling differentiation, in part due to inadequate quantitative and temporal control of cytokines. In this work, we propose to overcome these limitations by using engineered cells to function as programmable tools that can respond to combinatorial environmental inputs and produce controlled responses for interrogating basic biology of memory formation and its application in vaccination in an entirely human-derived system. I propose to construct a generalized platform (CHOMP-sec) to detect and secrete proteins using synthetic protein circuits. This platform will be used to systematically scan the effect of IL-2 expression and dynamics on driving the differentiation of memory CD8+ T cells using patient-derived tonsil organoids. The proposed work will provide the field of Immunology with tools to quantitatively control cytokine secretion and a new framework for exploring immune cell differentiation for additional applications, such as inducing tolerance by biasing regulatory T cell responses to engineered tissues.
2021
-
Grant Awardees - Program
Maintenance, homeostasis and heredity of mitochondria and their genomes
MANLEY Suliana (USA)
Dept. of Institute of Physics - Ecole Polytechnique Federale de Lausanne (EPFL) - Lausanne - SWITZERLAND
BADRINARAYANAN Anjana (INDIA)
National Centre for Biological Sciences - TIFR - Bangalore - INDIA
PAULSSON Johan (SWEDEN)
Dept. of Systems Biology, HMS - Harvard University - Boston - USA
MARSHALL Wallace (USA)
Dept. of Biochemistry and Biophysics - University of California San Francisco - San Francisco - USA
Mitochondria are central to modern eukaryotic life. As self-reproducing organelles with their own DNA, they must prevent damage and fluctuations in copy number from accumulating, while their network is locally sculpted through fission and fusion. Yet, even the most basic mechanisms of control are largely unknown, leaving many key questions unanswered. What mechanisms exist to ensure inheritance of genetic material between mitochondria, and mitochondria between cells in the face of segregation errors and noise? Self-replication is dynamically unstable in the absence of feedback control, and multilevel segregation requires multilevel control. How does the mitochondrial genome maintain its integrity? Genotypic selection of a heteroplasmic population of mitochondria post-mutation reflects a process similar to the neutrally stable dynamics behind mutual exclusion in ecological systems. How do mitochondria within a single cell maintain or modulate their size distribution or overall network size? Local decisions to divide or fuse must propagate up to the scale of the network. These decisions should adapt in response to damage, to protect the viability of the network.
At present, these questions remain open, in part because they transcend standard sub-disciplines of biology. Finding answers thus requires a quantitative interdisciplinary approach, combining molecular biology, theoretical and quantitative analysis, modeling, and precision microscopy measurements. With our research team, we will develop novel molecular tools to specifically induce mtDNA damage, follow single nucleoids and count single copies (AB), image hundreds of cells to resolve their mitochondria and mtDNA at resolutions of 10-100 nm (SM), use microfluidics devices to follow 10^5 - 10^6 mutants and interpret fluctuations in copy number using stochastic theory (JP), and perturb, characterize and synthesize our observations into geometric models of cellular architecture (WM).
On a fundamental level, we wonder why mitochondria form dynamic networks. Many have asked how mitochondrial dynamics or network morphologies contribute to cellular health through optimized energy production, ion buffering, or myriad other important roles. We hypothesize that the mitochondrial network, and the dynamic processes that produce it, exist largely to support the life cycle of the mitochondria as an endosymbiont, allowing its genome to be stably propagated in an intact form.
2021
-
Grant Awardees - Early Career
The bacterial biofilm as a multicellular organism: from molecules to populations
DURHAM William (USA)
Dept. of Physics and Astronomy - University of Sheffield - Sheffield - UK
WHITNEY John (CANADA)
Dept. of Biochemistry - McMaster University - Hamilton - CANADA
TSENG Boo Shan (USA)
School of Life Sciences - University of Nevada Las Vegas - Las Vegas - USA
BERGERON Julien (FRANCE)
Randall Division of Cell and Molecular Biophysics - King's College London - London - UK
Most bacteria live in surface-attached communities called biofilms, where they play profound roles in many important processes in infection, industry, agriculture, and the natural environment. A number of different genetic pathways have been demonstrated to impact biofilm formation at the aggregate level, typically by showing that the amount of biofilm produced by mutants lacking these pathways is either reduced or abolished altogether. However, we know very little about the how these pathways contribute to biofilm architecture at the scale of single cells, nor how these pathways interact with one another during biofilm development. This is because biofilms are three-dimensional, translucent structures, which makes it difficult to visualize what is happening deep inside of them.
This project will use transformative new approaches to understand how bacteria work together to assemble biofilms. We hypothesize that multicellular biofilms undergo a series of developmental processes analogous to those observed in animals, where different pathways exhibit complex patterns of gene expression. These processes allow a single cell to transform into a multicellular biofilm, where genetically identical cells perform different roles and functions.
Because we cannot currently visualize cells deep inside a mature biofilm, we will use microfluidic devices to approximate a two-dimensional cross-section through a mature biofilm, allowing us to directly visualize the behavior of individual cells and measure the expression of multiple genetic pathways simultaneously over long time periods. We will then use cell tracking and mutants to understand how each of these pathways control the behavior of individual cells within the 2D biofilm. These results will be validated in 3D biofilms, using separate microfluidic devices formed with fluid walls, which will allow us to extract fully intact biofilms for subsequent analysis by novel electron microscopy assays and by single-cell transcriptomics. By quantifying how each pathway contributes to biofilm assembly, and how each of these pathways interact with one another, we will provide an unprecedented view of the sequence of processes that play out in space and time during biofilm development. Such insights hold the key for developing new strategies for both rationally engineering beneficial biofilms and eradicating harmful biofilms.
2021
-
Grant Awardees - Program
Decoding acoustic communication in mosquitoes: from distortion products to vector control
KAMIKOUCHI Azusa (JAPAN)
Graduate School of Science - Nagoya University - Nagoya - JAPAN
ALBERT Joerg (GERMANY)
Ear Institute - University College London - London - UK
BOZOVIC Dolores (USA)
Dept. of Physics and Astronomy - University of California Los Angeles - Los Angeles - USA
CHEN Chun-Hong (CHINA, REPUBLIC OF (TAIWAN))
Institute of infectious diseases and Vaccinology - National Health Research Institutes - Zhunan - CHINA, REPUBLIC OF (TAIWAN)
As mosquitoes become an increasingly common part of daily life for millions of people worldwide, so too do the diseases they transmit. The rapid global spread of mosquitoes is placing billions at risk of infection from dengue, malaria and Zika, with current control methods unable to control the increased threat. New control tools, with novel mechanisms of action, are necessary to prevent public health resources from being overwhelmed.
Mosquito ears are potentially the most sensitive in the insect world; this sensitivity is necessary for males to locate the faint sound of an individual female flying through the crowd of males that compromises a mosquito swarm. Although this male attraction to the noise of a female’s wing beat has been studied for decades, tools which manipulate this attraction effectively in the wild have still not been developed.
We aim to address this problem by comprehensively studying every aspect of mosquito hearing-related anatomy and behaviour. We will describe the mosquito ear itself in detail and identify the individual components which underly the hearing process. By creating new mosquito mutants, we will be able to describe exactly which components allow males to locate females within noisy environments.
We will then test which sounds specifically stimulate these components, before applying these sounds to groups of caged male mosquitoes. We will model the reaction of these groups – and their ears - to different sounds using ground-breaking mathematical models, which will feed into further experiments to identify an ‘ideal song’ to attract males. A particular focus of our project will be on the role of ‘phantom tones’, which males can generate in their own ears (and which are very similar to female flight tones) to support their hearing process. In other words, we want to understand how ‘making up’ the sound of a female can help males to find a real one.
Finally, we will test the identified optimized sounds in the field to assess their attractiveness in the real world. To this end, we will attach speakers to mosquito traps to test whether ‘making the right noises’ can indeed increase the number of captured males.
Our project aims to provide a clearer answer as to how mosquito hearing works, and whether the use of sound is a feasible path for controlling wild mosquito populations.