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2018 -
Career Development Awards

Schizogony: understanding atypical cell division mechanisms in malaria parasite

GUIZETTI Julien (FRANCE)

Centre for Infectious Diseases - Heidelberg University Hospital - Heidelberg - GERMANY

Although cell division is fundamental to malaria parasite proliferation its mechanisms are completely understudied. Plasmodium falciparum division, called schizogony, displays striking differences when compared to any model organism suggesting the presence of non-canonical division pathways. Key specificities of schizogony are the absence of classical mitotic checkpoints and asynchronous nuclear division. The number of emerging daughter cells is highly variable and plasmodial centrosomes have atypical structure and dynamics. Further, the parasite undergoes closed mitosis, which requires the nuclear membrane to be split between dividing chromosomes by a mechanism that is entirely elusive. Studying the dynamics of schizogony requires an exquisite temporal and spatial resolution, which could only be achieved in recent years. I propose a combination of cutting-edge microscopy and genome-editing to uncover molecular events underlying atypical parasite division mechanisms. Using live cell, super-resolution, and correlative imaging I want to generate a robust cell biological framework describing key division events. Proteomics and genome editing will enable me to functionally characterize the plasmodium-specific centrosome. Nuclear membrane fission will be investigated by correlative light and cryo-electron microscopy. These ambitious and novel approaches will drastically improve our understanding of malaria parasite proliferation. They will provide insights into diversity of cell division mechanisms beyond what has been studied in model organisms. Investigating schizogony will open up new intervention strategies against malaria, which remains a major public health issue.

2018 -
Cross Disciplinary Fellowships - CDF

Unraveling cellular process in guanine crystals forming cell

GUR Dvir (ISRAEL)

NICHD - NIH - Bethesda - USA

LIPPINCOTT-SCHWARTZ Jennifer (Host supervisor)

Structural colors using guanine crystals are widespread in nature and can be found in many organisms. While the physical basis for producing structural colors is well established, the cellular processes underlying the formation and regulation of these structures is poorly understood. We propose to study these intriguing, previously unexplored, cellular processes using the tunable structural colors of the zebrafish as a model. The structural colors of the zebrafish offer a unique opportunity due to the combination of tunable structural colors, vast information about the genome and access to developing larvae.

To study these cellular processes I will join the Lab of Jennifer Lippincott-Schwartz, where we will use state-of-the-art super resolution imaging techniques and molecular cell biology tools, which are well established in the Lippincott-Schwartz lab together with cryo-EM, micro-spot X-ray diffraction and crystallography, in which I have gained expertise during my Ph.D. studies.

This research will yield new insights on both the transportation and trafficking of nucleobases within the cell and will uncover new paradigms in biologically controlled organic crystal formation. Our findings will also provide new information on the interface between organic crystals and the cell cytoskeleton and may also inspire new therapeutic approaches for pathological conditions arising from uncontrolled organic crystallization such as gout and urate kidney stones.

This research represents a radical change in direction for me. It will provide me with new skills in molecular-cell-biology, biochemistry, and experience in state- of-the-art super resolution fluorescence microscopy.

2018 -
Long-Term Fellowships - LTF

Studying brain representations as distributed processes: from neural code to behavior

HAHAMY Avital (ISRAEL)

Wellcome Trust Centre for Neuroimaging - University College London - London - UK

BEHRENS Timothy (Host supervisor)

We know coffee by its taste, but also by its name and association with caffeine. Studies of brain activity indeed confirm that the brain simultaneously processes stimuli across distributed areas, each selective for a specific stimulus aspect. However, the study of stimulus-representations, which is crucial for understanding the computational principles underlying brain activity, is currently constrained to the detailed inspection of isolated brain areas. I propose a new formalism and method that may allow studying representations as a distributed neural process, by employing novel brain imaging, stimulation and computational research approaches. I first wish to understand how different stimulus-aspects are represented in distributed brain areas. In line with existing theoretical accounts, I aim to demonstrate that each brain area forms representations that reflect the natural world statistics of the information it processes, and this principle can be used for linking distributed representations of a single stimulus. Next, I will test whether parallel neural representations co-express to bind different aspects of a given stimulus. Yet, to enable adaptive interaction with the environment, behaviorally-irrelevant representations must be inhibited. I aspire to support this conjecture experimentally by showing that behaviorally-irrelevant representations emerge when inhibition is alleviated. This line of work promises insight into computations that underlie distributed cognitive processes, by suggesting a principle for understanding the relationships between distributed stimulus-representations, and a mechanism that regulates their expression to allow flexible behavior.

2018 -
Grant Awardees - Program Grants

From molecular stochasticity to robust cell divisions

HAMANT Olivier (FRANCE)

Laboratoire Reproduction et Développement des Plantes - INRA, CNRS, UCBL1, ENS de Lyon - Lyon - FRANCE

DUMAIS Jacques (CANADA)

Facultad de Ingeniería y Ciencias - Universidad Adolfo Ibáñez - Viña del Mar - CHILE

MJOLSNESS Eric (USA)

Dept. of Computer Science - University of California - Irvine - USA

SCHNITTGER Arp (GERMANY)

Dept. of Developmental Biology - University of Hamburg - Hamburg - GERMANY

Cells achieve reproducible outputs while relying on intrinsically stochastic molecular processes. In plants, cell division orientation is accurately predicted before mitosis by a microtubular ring, the preprophase band (PPB), through an unknown mechanism. Using high-throughput microscopy, quantitative image analysis, biomechanics and stochastic modeling, we will investigate how the stochasticity of microtubule (MT) self-organization is used, or filtered out, during PPB formation to sense temporal, geometric and mechanical cues in order to generate a robust placement of cell division planes. In short, we will test whether the PPB acts as a macromolecular mechanosensor. Using statistical mechanics such as Monte Carlo, event-based modeling and mean-field theory, we will assess how stochasticity leads to distinct dynamical states for MT arrays. We will develop biophysical models of dynamic MTs in 3D cells to explore how stochastic MTs self-organize into PPBs and how spatiotemporal cues modulate that process. Using the Arabidopsis shoot apical meristem, we will identify correlations between MT array dynamics, PPB behavior, cell shape, growth and mechanics, cell cycle progression, and cell division plane from statistically representative sample involving hundreds of dividing cells. To challenge the robustness of PPB and cell division in vivo and in silico, we will globally and locally increase variability in these cell parameters with mutants (MT dynamics, wall mechanics, cell cycle, mechanotransduction), inducible lines, mosaics, and micromechanical perturbations. Last, we will unravel the molecular mechanism processing molecular stochasticity to channel cell divisions: we will investigate how the TTP (TON1-TRM-PP2A) complex, a key regulator of PPB formation in connection with the cell cycle, contributes to generate reproducible divisions by monitoring MT self-organization, integrating geometric, mechanical and temporal cues. Implications of this project go beyond cell division robustness: while many cellular pathways are adapted to respond to rapid and discontinuous changes, we expect here to unravel mechanisms managing slow and continuous signals, like shape, growth or tissue-stress. We will also gain insight into the mathematical properties of stochastic extended objects like microtubules, and we will propose a mechanism for cells to perceive directional cues.

2018 -
Grant Awardees - Program Grants

New letters to the DNA alphabet

HANSEN Lars Hestbjerg (DENMARK)

Section of Microbial Ecology and Biotechnology - Dept. of Plant and Environmental Sciences - Copenhagen - DENMARK

DE CRECY-LAGARD Valerie (USA)

Dept. of Microbiology and Cell Science - University of Florida - Gainesville - USA

MOINEAU Sylvain (CANADA)

Dept. of Biochemistry, Microbiology, and Bioinformatics - Laval University - Québec - CANADA

The recent discovery of 7-deazapurine bases in bacterial and bacteriophage DNA revealed an unexpected interplay between RNA and DNA modification pathways. In phages, these hypermodified bases could play major roles in pathogen-host interactions, DNA replication, DNA-packaging into capsids, gene expression and bacteriophage evolution. Using a combination of genetic, biochemical and sequencing approaches, our objectives are to discover i) how widespread is this phenomenon, ii) the exact pathway(s) leading to the incorporation of these alternative bases into DNA, iii) the “raison d’être” for these modified bases, and iv) if this phenomenon arose as an offensive or as a defensive tool.
To characterize the distribution of 7-deazapurine bases in bacteriophages DNA, we will use several approaches including comparative genomics, mass-spectrometry analysis of modified bases, high-throughput sequencing of restriction endonuclease resistant environmental virome samples, and genome sequencing of phages infecting a wide range of bacterial hosts. This will generate a collection of diverse, sequenced and partially characterized phages that will be made publicly available via deposition in the Félix d’Hérelle Reference Center for Bacterial Viruses. Biochemical, molecular biology and genetic studies will be performed on phages harboring a variety 7-deazapurine variants to elucidate these novel DNA modification pathways. We will also study the role(s) played by the DNA modifications in phage biology, with a particular emphasis on understanding their potential role in overcoming host defences or in facilitating phage-mediated destruction of unmodified host DNA. In addition to classical biochemical, genetic and omics methods, third generation sequencing (PacBio and Nanopore) technologies will be exploited. These can already detect simple DNA modifications, like methylation, but we will combine machine learning with the sequencing of phage DNA molecules containing specific 7-deazapurines to expand the range of detectable DNA modifications. Although the scope of this project is limited to deciphering the role of 7-deazapurines in bacteriophage DNA, our results could spark developments of new genome editing tools and increased knowledge on gene regulation and epigenetics that may some day change paradigms in human health.

2018 -
Grant Awardees - Program Grants

The architecture of the postsynaptic density

HOELZ André (GERMANY)

Division of Chemistry and Chemical Engineering - California Institute of Technology - Pasadena, CA - USA

CLARIDGE-CHANG Adam (AUSTRALIA)

Dept. of Neuroscience and Behavioral Disorders - Duke-NUS Medical School - Singapore - SINGAPORE

COPLEY Richard (FRANCE)

Laboratoire Biologie du Développement de Villefranche-sur-mer - UMR7009 CNRS UPMC - Villefranche-sur-Mer - FRANCE

ROBINSON Robert (UK)

Structural Biology Laboratory - Research Institute for Interdisciplinary Science - Okayama - JAPAN

The human brain gains much of its computational abilities from the trillions of connections made between cells by synapses. Molecular changes in synapses (a process called synaptic plasticity) are considered to underlie learning and memory. An important component of the synapse is the postsynaptic density (PSD). This specialized structure has been studied extensively to understand its function, in particular because >100 neurologic disorders (such as autism spectrum disorder and schizophrenia) have been associated with PSD dysfunction. Information regarding the overall molecular architecture of the PSD, however, is largely incomplete, in part because the PSD is extremely complex, containing hundreds of individual components connected in a dense network. The PSD is also highly dynamic and asymmetrical—two properties that render protein structural analyses challenging. While solving the structure of the entire PSD seems insurmountable, half of the PSD’s mass is composed of only ten classes of linker proteins. We hypothesize that these highly-abundant proteins form a molecular scaffold, a network we term the ‘postsynaptic scaffold’ (PSS). We aim to develop an approach we call the ‘Thermophile-Assisted Postsynaptic Architecture Strategy’ (TAPAS) to solve the PSS structure. Given the delicate nature of proteins, structural biologists like to work with resilient, temperature-resistant proteins that can be obtained from thermophilic organisms. For brain-derived proteins, there is one animal known to be comfortable at temperatures >50 °C: a worm that lives on hydrothermal vents in the Pacific Ocean. We plan to sequence this worm’s genome (Alvinella pompejana) to find the PSS proteins that it shares with humans. We will determine the structures of the thermophilic proteins by X-ray crystallography. As much of the PSS architecture consists of filamentous structures that do not crystallize, we will use cryo-electron microscopy to define these larger structures. Finally, we will integrate several other methods (biochemical, proteomic, bioinformatic and advanced electron tomography methods) to build a model of the overall PSS. Achieving this ambitious goal will inform studies into learning and memory, lead to new treatments for devastating brain disorders, and help explain how the synapse contributes to human cognition.

2018 -
Cross Disciplinary Fellowships - CDF

Quantitative implementation of causality in dynamic molecular pathways

HUH Jaewon (KOREA, REPUBLIC OF (SOUTH KOREA))

Department of Bioinformatics - University of Texas Southwestern Medical Center - Dallas - USA

DANUSER Gaudenz (Host supervisor)

Biology has become a data science. The vastness of data acquired in life science require advanced analysis methods and the demand for computation and mathematical modeling is higher than ever before. In this circumstance, I am proposing a new framework in deciphering the information flow within molecular pathways utilizing the financial market analysis skills I acquired during my PhD.
The current approach to studying complex molecular pathways in cell biology is to perturb pathway components and then classify the effect as a phenotype. This approach has enabled cell biologist to discover the molecular players of pathways and even to infer hierarchical interaction cascades in pathways. However, under conditions of nonlinearity and high redundancy, the interpretation of these phenotypes can become exceedingly complicated.
The proposed research will focus on the following 2 aims. Establish the mechanisms of information flow within the GEF, GTPase network. Establish the mechanisms of detecting the transient topology with protrusion events.
The Significance of the proposed research derives from; 1) the project challenges the experimental paradigm of molecular cell biology in that it seeks to circumvent the limitations of molecular perturbation in deciphering pathways with nonlinearity and redundancy; 2) the project introduce to the field of molecular cell biology a theoretical foundation for the definition of causality; and 3) the unique data sets available between the Danuser and Hahn labs will allow me to develop this framework on the example of GEF-GTPase interaction networks, in which the current tools fail to address the redundancy and non-linearity.

2018 -
Long-Term Fellowships - LTF

High-speed 3D-nanoscopy to study the role of adhesion during 3D cell migration

JAHR Wiebke (GERMANY)

- Institute of Science and Technology Austria - Klosterneuburg - AUSTRIA

DANZL Johann Georg (Host supervisor)

Directed cell migration is at the core of vital processes in immune response or development. We know key mechanisms of 2D migration, especially how remodeling the actin cytoskeleton forms leading/trailing edges. 3D migration deviates considerably from 2D behavior, is physiologically more relevant and barely understood, mainly since available imaging fails to provide sufficient spatial and temporal resolution but affects living specimen adversely.
I propose a novel microscope to provide 3D subdiffraction resolution at several frames per second, while being “gentle” due to low intensities. I strive to combine benefits of light sheet microscopy and coordinate-targeted nanoscopy with protected STED: A secondary off-state protects emitters from state-cycling and photobleaching during depletion. Selective illumination of the focus-plane and widefield detection limit phototoxicity at high imaging speeds, while two superimposed depletion patterns achieve axial and highly parallelized lateral superresolution.
It is unclear to which extend amoeboid cells rely on adhesion receptors vs remodeling of actin cytoskeleton during 3D migration. I will label membrane, actin and adhesion-associated proteins of both wildtype and talin knockout leukocytes and image migration in a 3D collagen matrix to study: 1) what are the characteristics of actin flow, 2) do cells form adhesions and 3) what forces are transmitted onto the substrate?
The proposed project advances both state-of-the-art imaging and understanding of 3D cell migration substantially. My microscope will enable further study of diverse live systems well beyond current methods, including development, cell biology and neuroscience.

2018 -
Grant Awardees - Young Investigator Grants

Tracing AID/APOBEC- and MSI-mediated hyper-mutagenesis in the clonal evolution of gastric cancer

JU Young Seok (KOREA, REPUBLIC OF (SOUTH KOREA))

Graduate School of Medical Science and Engineering/Lab. of Cancer Genomics - Korea Advanced Institute of Science and Technology - Daejeon - KOREA, REPUBLIC OF (SOUTH KOREA)

KOO Bon-Kyoung (KOREA, REPUBLIC OF (SOUTH KOREA))

Institute of Molecular Biotechnology (IMBA) - Austrian Academy of Sciences - Vienna - AUSTRIA

SNIPPERT Hugo (NETHERLANDS)

Dept. of Molecular Cancer Research - University Medical Center Utrecht - Utrecht - NETHERLANDS

Cancer evolves through the continuous acquisition of DNA mutations. As a result, multiple diverse tumor subclones can arise during the course or tumor progression from benign to malignant carcinoma. These diverse cancer subclones have different traits, such as different levels of therapy resistance or metastatic potential. Intriguingly, cancers can obtain a hypermutator phenotype that leads to accelerated acquisition of DNA mutations. In gastric cancers, a medical burden especially in East Asia, multiple types of mutations are observed, suggestive of pronounced impact of hypermutator phenotypes on the development of these cancers. However, how hypermutator action facilitates the evolutionary trajectory of cancers is not fully understood.
In this HFSP project, we intend to use organoid technology to study the impact of diverse hypermutator phenotypes in gastric cancers. Organoid technology is a state-of-the-art culture technique for human mini-organs in a dish from both normal tissues as well as cancers, and mimics the in vivo scenario to great extent.
To understand the role of hypermutator action in human gastric cancer, three research teams integrate their expertise into a novel experimental pipeline: 1) the establishment and analysis of patient-derived tumor organoids with natural occurring hypermutator phenotypes, in parallel with engineered tumor organoids with introduced hypermutator phenotypes. 2) Monitoring mutational accumulation within these tumor organoids using DNA sequencing at every intermediate step along their progression towards malignant carcinoma and 3) filming the diverging cellular behaviors between different tumor subclones using advanced microscopy. Ultimately, we aim to map the dynamic mutation landscape during the evolutionary trajectory of diverging tumor subclones in comparison to the phenotype of the changing tumor cells.
This project will provide a unique opportunity to obtain a comprehensive understanding on the role of hypermutator phenotypes in cancer evolution. Moreover, we expect that our improved insights on the emergence of genetic subclones in gastric cancer can guide us to understand to other cancer subtypes and will help us to fight against chemo resistance and metastasis of cancer.

2018 -
Long-Term Fellowships - LTF

Revealing the principles of biogenesis and regulation of the Eukaryotic CO2-concentrating organelle

KAFRI Moshe (ISRAEL)

Department of Molecular Biology - Princeton University - Princeton - USA

JONIKAS Martin (Host supervisor)

Biological carbon fixation is a key step in the global carbon cycle that produces our food and fuels, and regulates the atmosphere’s composition. Approximately 30-40 percent of global carbon fixation occurs in an overlooked algal organelle called the pyrenoid.
In this work, I will utilize the single-celled green alga C. reinhardtii to explore how the pyrenoid, a non-membrane bound organelle, is separated from its environment in order to carry out its fundamental function. Specifically, I will apply biophysical methods to experimentally test whether the pyrenoid forms by liquid-liquid phase separation. I will discover the necessary and sufficient molecular components for pyrenoid formation, and will explore their ability to form droplets in-vitro, a hallmark of liquid-liquid phase separation proteins.
Next, I will characterize the regulatory mechanisms of the pyrenoid dynamic assembly and disassembly. I will explore the mechanisms governing pyrenoid phase switching by mass-spectrometry PTMs (post-translational modification) mapping. To identify regulators, I will use the novel method of proximity proteomic mapping in living cells by the engineered peroxidase (APEX2).
By revealing the underlying mechanism for pyrenoid biogenesis and regulation, I will improve our understanding of its activity, a key step towards a systematic understanding of the global regulation of photosynthesis. Additionally, this work will enhance our understanding of formation and function of non-membrane bound organelles, and will expend this field into the photosynthetic kingdom.

2018 -
Cross Disciplinary Fellowships - CDF

De novo computational design of functional metalloproteins

KALVET Indrek (ESTONIA)

Institute of Protein Design - University of Washington - Seattle - USA

BAKER David (Host supervisor)

De novo design of proteins enables access to the vast regions of sequence space previously unexplored by nature. These proteins are computationally designed based on physicals principles of protein structure and folding, and are tailor-made with a specific function in mind. As a result, it would be possible to design customized proteins that can give insights into the fundamentals of protein biochemistry as well as tackle practical challenges in medicine and materials sciences. To further push the boundaries of de novo protein design, its concepts will be combined with the world of metal-catalysis. As a result, novel functional metalloproteins will be developed with the protein structure designed to support an active site that is most optimal for high reactivity and selectivity. The design efforts will be directed towards both known biochemical transformations as well as those natively not catalyzed by enzymes. To achieve this goal, quantum chemical methods will be used to develop precise active site models for the transition states of the catalyzed reactions. Rosetta protein design algorithms will then be employed to identify sequences that would best support the atomic arrangements of these theoretical enzyme models. Further rounds of sequence optimization will be performed to ensure high stability and predictability of the active site as well as the entire protein structure. Finally best designs will be expressed and experimentally tested for their activity. In general, the knowledge gained in the process will be beneficial for establishing the general underlying principles behind de novo metalloprotein design.

2018 -
Career Development Awards

Genomic conflict and stability during germline development

KARAM TEIXEIRA Felipe (BRAZIL)

Department of Genetics - Cambridge University - Cambridge - UK

A large fraction of our genome consists of selfish DNA modules known as transposable elements (TEs) – mobile units that aim to increase in copy number by jumping from one location to the other. Since their discovery, TEs have been involved in the organization, functioning, and evolution of genomes, but their uncontrolled activity is detrimental to the host and must therefore be tightly regulated. This is especially true in the germline, the grounds where host and TE mechanisms compete for maximizing their influence over the genetic information that will be passed to the following generations. A classic example of disruptive TE activity is provided by hybrid dysgenesis in Drosophila, a syndrome that specifically affects germline development and that is triggered by the P-element DNA transposon. Using this textbook model of genomic conflict, we have recently uncovered the existence of a novel mechanism by which an evolutionary conserved small RNA system controls TE expression by regulating chromatin states and alternative splicing. Building on this foundation, the proposal first aims to dissect the emerging and exciting relationship between chromatin states, transcription, and splicing regulation in vivo. In parallel, I will use this system in combination with developmental, genetics, and high-throughput molecular approaches to understand, at the single-cell level, how host-mechanisms access and control genome integrity during catastrophic germline damage. Dissecting such mechanisms will not only provide unique insight into our comprehension of germline development, but will help us understand one of the major forces that shape the evolution of eukaryotic genomes.

2018 -
Long-Term Fellowships - LTF

A biophysical study on the role of mechanical feedback in learning and the emergence of locomotion

KARZBRUN Eyal (ISRAEL)

Kavli Institute for Theoretical Physics and Dept. of Physics - University of California, Santa Barbara - Santa Barbara - USA

SHRAIMAN Boris (Host supervisor)
STREICHAN Sebastian (Host supervisor)

Animals move by coordinated muscle activity, which they have to learn during early development. The motor learning period involves spontaneous muscle and neuronal activity, neuromuscular coupling, and experience-dependent network plasticity. Through these processes, the brain ‘discovers’ physical constraints of the body, to generate motion. How does the interplay between neuronal dynamics and body mechanics leads to coordinated motion during development remains unclear. Here, I propose to study the role of mechanical feedback during motor learning of the D. melanogaster embryo. I will explore how physical parameters such as muscle force and elasticity are encoded into neural activity during development, and how non-linear tissue mechanics and spontaneous myogenic contractions enrich neural dynamics and drive the emergence of coordinated motion. To test these ideas, I will assemble a novel light-sheet/light-field microscope, which will enable high-frequency 10-50hz in toto imaging of neuronal and muscle activity in the developing embryo. In addition, I will apply optogenetic tools to directly manipulate muscle contraction activity, and study their effect on the learning dynamics. This comprehensive data set will allow me to develop a physical model of motor learning. The model will combine biological parameters such as spontaneous neural activity and network plasticity, together with physical parameters such as muscle force response, tissue elasticity and substrate friction. This research will reveal novel aspects of motor learning, with implications to developmental biology and medical research.

2018 -
Grant Awardees - Young Investigator Grants

Behavior-dependent optimization of the brain’s metrics for space and time

KITAMURA Takashi (JAPAN)

Dept. of Psychiatry - University of Texas Southwestern Medical Center - Dallas - USA

ITO Hiroshi (JAPAN)

Memory and Navigation Circuits Group - Max Planck Institute for Brain Research - Frankfurt am Main - GERMANY

KROPFF Emilio (ARGENTINA)

Neural Plasticity Lab - Fundacion Instituto Leloir - IIBBA, CONICET - Buenos Aires - ARGENTINA

Is our perception of time and distance the same when we walk in the park, travel in a high speed train, or wait for the starting gun in a field race? Over a century ago, Einstein opened the way into considering space and time as relative variables. New evidence now suggests that areas of our brain might have been doing so all along. In this case, however, rather than resulting from the gravitational pull of a massive star, the effect would be the natural consequence of a simple principle of economy. Not all dimensions need to be represented all the time; one could possibly do better with simplified schemas adapted to every situation in an information compressed manner.
The entorhinal cortex is an area of the brain where a rodent or human represents its own position in space and time. Recent evidence suggests that spatio-temporal dimensions can actually be represented in a flexible way, depending on behavioral demands. We lack, however, all knowledge about the repertoire of possible schemas that it can choose from, on how these schemas are formed and stored, and on the neural mechanisms behind the selection process. We here propose to study the neural basis of this “brain relativity” in rodents by means of a variety of tools that include behavioral experiments, recordings of neural activity, manipulation of specific neural circuits and computational modeling. We will challenge animals by making them explore artificial environments with geometries that require a switch between representations, as would happen when touring through an Escher scene. A room will be slowly morphed into a corridor, or distance estimation into time. We hope that this will allow us to understand the shape that these representations have in the brain, their number, and the mechanism that controls which one is applied at any given time. We also plan to identify specific circuits of the rodent entorhinal cortex that encode information about space and time using state-of-the art genetic tools, which will allow us to gain on-line control over the selection of schemas and its behavioral consequences. Along the process, results will be compared with computational models to understand the logic underlying each observation. All this will help us to get a deeper insight into how we perceive and interact with space and time in our daily experience.

2018 -
Long-Term Fellowships - LTF

Dissecting the interaction between leukemia initiating cells and their bone marrow microenvironment

KOKKALIARIS Konstantinos (GREECE)

Harvard Stem Cell Institute and Center for Regenerative Medicine - Harvard University & Massachusetts General Hospital - Boston - USA

SCADDEN David T. (Host supervisor)

Leukemia is a paradoxical cancer case, being among the most studied but still most lethal types. Current research focuses on unraveling the cell-intrinsic genome alterations leading to malignant transformation of healthy blood to leukemia initiating cells (LICs), while mostly ignoring their interaction with the bone marrow (BM) microenvironment. This is mainly due to the complexity of the hematopoietic niche itself as well as technical challenges associated with BM imaging without distorting tissue architecture. I hypothesize that distinct BM cell population(s) play a critical role in protecting LICs from cytotoxic effects of current treatments driving minimal residual disease and subsequent deadly relapses. Here, I aim to apply novel quantitative deep-tissue imaging with single-cell resolution to localize LICs and reveal the exact cellular composition of the leukemic BM niche at disease progression, remission and relapse. Identifying the relevant cell populations, I then aim to elucidate the underlying molecular players governing this interaction at the protein level. Using genetic manipulation for both LICs and their niche, I aim to block the protective role of the leukemic niche on disease progression and relapse. To recapitulate key features of human acute myeloid leukemia (AML), a novel mouse model established in the host laboratory allowing non-invasive quantitative monitoring of disease progression in living animals will be utilized. Deciphering the identity of leukemic niche cues protecting cancer stem cells, a currently largely unexplored field of research, could help shaping future therapeutic approaches against rapidly-developing lethal cancers.

2018 -
Long-Term Fellowships - LTF

Human gut microbial determinants of non-alcoholic fatty liver disease

KRAUTKRAMER Kimberly (USA)

Department of Molecular and Clinical Medicine - University of Gothenburg - Gothenburg - SWEDEN

BÄCKHED Fredrik (Host supervisor)

Non-alcoholic fatty liver disease (NAFLD) affects 25-40% of the world’s population and is associated with significant morbidity and mortality, yet definitive diagnosis requires invasive liver biopsy, and there are currently no approved pharmacologic agents or validated biomarkers. Further, the pathogenesis of the NAFLD remains unknown, precluding the development of diagnostic and therapeutic tools. Current evidence suggests that pathogenesis involves complex interactions between environmental factors, such as diet and lifestyle, with abnormalities in glucose and lipid homeostasis. The gut microbiota, which is a key mediator of environmental exposures to the host, has been shown to be altered in a mouse model of NAFLD. Gut microbial metabolites play a role as signaling molecules in the setting of metabolic disease and have also recently been shown to regulate host chromatin, ultimately affecting gene expression. Thus, NAFLD-associated changes in the microbiota and its function may play a role in disease development via signaling at the level of cellular receptors and chromatin. Here, I propose to 1) identify NAFLD-associated changes in human gut bacterial community composition and function, 2) develop microbiota-based biomarkers with utility in screening, diagnosis, and prognosis, and 3) elucidate the molecular mechanisms by which altered bacterial taxa and metabolites contribute to disease pathogenesis. Completion of this work will impact clinical management of NAFLD, pave the way for the development of microbiota-based therapies, and yield the first evidence of gut microbial control of global host chromatin states in humans.

2018 -
Career Development Awards

A prosthetic photon-based neurotransmitter system to overcome synaptic transmission barriers

KRIEG Michael (GERMANY)

Neurophotonics and Mechanical Systems Biology Research Group - The Institute of Photonic Sciences - Castelldefels - Barcelona - SPAIN

In many neurodegenerative diseases, synaptic transmission is perturbed. Optogenetics is a powerful strategy to control neuronal function in health and disease using light-activated ion channels called channelrhodopsins. Although optogenetics could be used to overcome synaptic-transmission defects in many psychiatric and neurodegenerative disorders, several factors hold back this strategy, including the need to open the skull for efficient light delivery and the need to minimize light scattering. To overcome these limitations, I propose to integrate light-generating enzymes and light-activated ion channels into a photon-based neurotransmitter system using presynaptic expression of luciferases and postsynaptic expression of channelrhodopsins, respectively. I will develop microfluidic and novel optogenetic tools to target individual neurons in freely behaving animals. I will demonstrate the feasibility of this approach with the well-characterized sensory circuits in the roundworm Caenorhabditis elegans, a powerful model for neurodegenerative diseases. Taken together, these investigations will empower researchers and ultimately clinicians to replace the “flavor” of chemical neurotransmitters by tuning the color of luciferase-emitted photons and the channels that respond to them. I anticipate that this strategy will unleash the full potential of optogenetics for controlling neuronal function during health and disease.

2018 -
Long-Term Fellowships - LTF

A systems-level approach to stress granule maturation in neurodegenerative diseases

KROSCHWALD Sonja (GERMANY)

Department of Biochemistry - ETH - Zurich - SWITZERLAND

PETER Matthias (Host supervisor)

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) affect motor neurons. The degeneration of these neurons is typically characterized by the abnormal cytoplasmic deposition of protein aggregates. These pathological aggregates are amyloid-like, and evidence suggests that they evolve from physiological stress granules (SGs). Thus, to understand how SGs mature into disease causing aggregates is highly important. In the proposed project, I aim to unravel these mechanisms by establishing a motor neuron-like cell line for the comprehensive analysis of SG maturation. To do so, I will take advantage of preliminary data in yeast and develop protocols for the maturation of physiological dynamic SGs into solid-like and aberrant amyloid-like states in motor neuron-like cells. This process will be characterized by fluorescent microscopy and cryo-tomography, and biochemical methods such as limited proteolysis coupled to mass-spectrometry (LiP) to visualize structural alterations. Physiological, solid-like and amyloid-like states will be purified and analysed by mass spectrometry to reveal alterations in the SG composition and in the post-translational modifications (PTMs) of SG components. For the observed changes, I will identify whether they are causative for SG maturation. Finally, applying an advanced mass-spectrometry method, the "sentinel protein assay”, will allow me to identify cellular pathways that are specifically activated during SG maturation. I believe that these results will not only provide important mechanistic insights into SG maturation but may also help to develop innovative therapeutic strategies to prevent this transition and the onset of ALS.

2018 -
Grant Awardees - Program Grants

Can evolution minimize spurious signaling crosstalk to reach optimal performance?

LANDRY Christian (CANADA)

Dépt. de biologie - Institut de biologie intégrative et des systèmes - Québec - CANADA

VILLEN Judit (SPAIN)

Dept. of Genome Sciences - University of Washington - Seattle - USA

TKACIK Gasper (SLOVENIA)

Dept. of Theoretical Biophysics / Computational Neuroscience - IST Austria - Klosterneuburg - AUSTRIA

The complexity of cellular machineries has been forged by the motors of evolution (mutation, natural selection, and genetic drift), with boundaries that are determined by the properties of biological molecules and the biophysical limits of the cell. Our goal in this project is to determine what are the relative contributions of biophysics and evolution in shaping this complexity. Our model of interest is cell signaling, which is rapidly evolving and involves highly interconnected networks of proteins that sense and process signals and make real-time decisions to satisfy cellular needs and promote survival and proliferation. Because typical cells contain from millions to billions of protein molecules, signals can reach out to unwanted proteins in an unspecific manner. How much can evolutionary forces optimize this process so that cells can reach biophysical optimality by minimizing unspecific interactions is currently unknown. This question can be answered neither from physics nor from biology alone, and thus requires a multidisciplinary team. Our international team with expertise in theoretical physics (Gasper Tkacik), evolutionary biology (Christian R Landry) and biochemistry (Judit Villen) is poised address this question. We will generate a mathematical model of signaling network evolution that includes key biophysical and evolutionary driving forces to examine how each contributes to create unspecific signaling interactions in organisms with finite population sizes. This model will guide experiments in which we will manipulate the amount and extent of unspecific interactions and measure its biochemical impacts and its effects on fitness using experiments and bioinformatics data integration to calibrate parameters of the model. In biophysics, it is often assumed that biological systems have reached an optimum attained by natural selection and are only limited by their physical characteristics. Evolutionary biology considers that natural selection works against genetic drift and mutations to bring biological networks near their optimum, which is unknown. Our work between these two fields will reveal how close to the biophysical limits can signaling networks get and how biophysical and evolutionary forces are integrated to shape accurate signal transduction.

2018 -
Long-Term Fellowships - LTF

Real-time spectral imaging and prediction of successive state changes in model microbial communities

LANDRY Zachary (USA)

Department of Environmental Engineering - ETH - Zurich - SWITZERLAND

STOCKER Roman (Host supervisor)

In this project, we will use model microbial communities based around the degradation of polymers abundant in marine ecosystems. Raman microscopy is a hyperspectral imaging method that can be used to profile the chemical environment of live samples, and will be used to record the progression of a model microbial community within a microfluidic device. Our device contains a single polymeric primary substrate as well as a number of ports that allow for introduction of soluble substrates. By integrating this microenvironment with Raman microscopy we intend to clearly document the biochemical progression of the microbial community during primary succession and colonization of the substrate. The use of this model environment will be leveraged into a general method identify and predict state transitions in real-time as the community moves through the phases of succession, with the goal of being able to elucidate the biochemical drivers of these transitions, and subsequently demonstrate the validity of these drivers by perturbing the natural progression of these state transitions.