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2018 -
Long-Term Fellowships - LTF

Functional metagenomic discovery of host-microbiome effectors using massively parallel scRNA-seq


Laboratory of Genetically Encoded Small Molecules - Rockefeller University - New York - USA

BRADY Sean (Host supervisor)

Over a 100 years ago, Élie Metchnikoff’s visionary work laid the foundations to our understanding regarding the importance of the gut microbiota for the physiology of the host. Recently, technological breakthroughs sparked a renaissance in the research of the human microbiome. While many observational studies identify clinically relevant correlations between the structure of the microbiome and states of disease, our true aim is to uncover the molecular mechanisms and functional roles of host-microbe interactions. Here I describe an innovative sequencing-based functional metagenomic approach, termed FunMet-Seq, which utilizes transcriptional profiling of single human cells towards the discovery and characterization of microbially produced effector molecules. To this end, a library of microbiome-derived DNA, extracted from stool samples, is heterologously expressed in E. coli. Next, culture broth from the library is sampled, sterilized, and used to treat genetically barcoded HEK293-TN cells. Finally, massively parallel transcriptional profiling of single cells enables to identify culture broth samples which contain an effector molecule, and to trace its origin to a specific clone in the array of metagenomic DNA. While the realization of the FunMet-Seq pipeline is an ambitious goal, it will catapult forward our ability to understand the molecular mechanisms underlying the he complex microbial ecology in the human body. Moreover, as the role of the microbiome in human physiology becomes evident, deciphering the interkingdom crosstalk within the human body is critical to reveal the etiology of microbiota-related diseases, and is expected to produce therapeutic applications.

2018 -
Long-Term Fellowships - LTF

Characterizing circadian rhythms in red blood cells; a multi-level approach


Department of Pharmaceutical Sciences - Utrecht University - Utrecht - NETHERLANDS

HECK Albert J. R. (Host supervisor)

Circadian rhythms are present in almost all light-sensitive organisms from cyanobacteria through plants, flies, and mammals. Human hormone levels and metabolism are tied to circadian rhythms and affect sleep and wakefulness timings. Disruption of the synchronous action of circadian clocks leads to several human diseases, mainly sleep and metabolic disorders such as non-24-hour sleep wake disorder and diabetes. Most known circadian clocks stem from a transcription-translation feedback loop. Protein and mRNA levels oscillate with a 24 hour period, matching the day-night cycle. An intriguing exception is circadian oscillations in cultured red blood cells (RBCs); since RBCs are anuclear, the circadian rhythm must be non-transcriptionally controlled. RBCs are a major blood component, so their circadian rhythm might affect some of the many metabolic signals carried by the blood stream. Furthermore, the RBC circadian rhythms in individuals with hematological disorders may be out of sync or even cause the disorders’ phenotypes. I aim to use methods that complement each other (e.g., proteomics, metabolomics, and interactomics) to investigate in depth the molecular mechanism of the RBC circadian rhythms, which will advance our understanding of the rhythm’s role in metabolism signaling and hematological disorders. This strategy is suitable for resolving this question since the circadian rhythm is non-transcriptionally controlled and not much is known about it. Revealing the mechanism of the RBC clock will be the first time a eukaryotic non-transcription-translation based circadian rhythm is characterized.

2018 -
Career Development Awards

Investigating the circuit basis of adolescence impulsivity


Department of Psychology - University of Toronto - Scarborough - Toronto - CANADA

Adolescence is a unique transitional period marked by deficits in impulse control and behavioral inhibition, often leading to high-risk behaviors. It has long been believed that adolescent impulsivity is a product of a delay in the maturation of the brain circuit supporting decision-making, but due to technical limitations, this link remains elusive. While research has correlated adolescent changes in isolated brain regions with changes in decision-making, no study to date has probed how these brain regions act as functional circuits to modulate adolescence impulsivity. Here we will take advantage of recent technological advances to (1) investigate the pattern of brain circuit activity during live decision-making in adolescent and adult animals, and (2) determine the microcircuit dynamics underlying this behavior to identify the circuit basis of adolescent impulsivity. This will pave the way for future experiments in which we will manipulate circuit function in vivo to modulate adolescent impulsivity in behaving animals. Approaching behavior from the standpoint brain circuit maturation will consolidate a major conceptual and technical shift in systems neuroscience. This shift will shed light on the biological mechanisms underlying behavioral changes during early life and adolescence, but will also fuel a novel approach to the study of the etiology of mental and neurodevelopmental disorders with early onset, thereby informing novel, more effective circuit-specific therapeutic strategies.

2018 -
Long-Term Fellowships - LTF

Characterizing the activity of neural assemblies in the hippocampus during rapid-eye movement sleep


Developmental Backbone for the Organization of Cortical Networks - Institut de Neurobiologie de la Méditerranée - Marseille - FRANCE

COSSART Rosa (Host supervisor)

Sequences of place cells, hippocampal neurons active when a subject enters a particular location, encode spatial trajectories while navigating a given environment. During periods of restful wakefulness and non-REM sleep, condensed sequences corresponding to prior navigation recur during sharp-wave-ripple events in the hippocampus, the disruption of which disturbs memory. Enabled by the use of large-scale neural imaging, recent work has revealed that these sequences are in fact composed of multiple discrete neural assemblies connected together. Understanding such assembly activity during various behaviors is critical as they may represent the basic unit upon which memories are encoded. However, the functional organization of the microcircuits, including assembly activity, recruited during REM sleep (REMs) remains unknown despite the recently confirmed role for REMs in the formation of spatial memory. The goal of the research outlined in this proposal is to address this issue using large-scale neural imaging in the hippocampus of fully habituated head-fixed mice. Specifically, this research aims to investigate the occurrence and characteristics of neural assemblies during REMs under baseline conditions as well as following learning of a spatial task. As a final step, local microcircuits within the hippocampus will be manipulated optogenetically during REMs following spatial learning in order to probe for a direct relationship between place cell (assembly) activity during REMs and subsequent memory performance. Cumulatively, these experiments will provide a novel characterization of the recruitment and mechanistic role of neural assemblies in the hippocampus during REMs.

2018 -
Cross Disciplinary Fellowships - CDF

Non-invasive deep brain stimulation and imaging using near-infrared upconversion nanocrystals


Helen Wills Neuroscience Institute - University of California, Berkeley - Berkeley - USA

FOSTER David (Host supervisor)
JI Na (Host supervisor)

Non-invasive transcranial stimulation and imaging of targeted neurons deep in brain are a central goal of neurobiology and related engineering science. Optical techniques, such as imaging and optogenetics, have revolutionized experimental neuroscience but are limited by the inability of visible light to penetrate deep into brain tissue. Here I propose an approach for transcranial near-infrared (NIR) deep brain stimulation and imaging by taking advantage of upconversion nanoparticles (UCNPs). UCNPs are lanthanide-doped nanocrystals unique in their ability to absorb tissue-penetrating NIR light and convert into emission in both visible and NIR spectral ranges. First, I will demonstrate UCNP-mediated optogenetics for deep brain stimulation, where UCNPs will be employed to convert transcranial NIR irradiation into visible emission to stimulate rhodopsin-expressing neurons in mouse brain. Second, I will develop blood-brain barrier-crossing UCNPs for targeted imaging of molecular markers in deep brain. For proof of concept, UCNPs will be conjugated to curcumin, a specific binder to beta amyloid - a molecular marker of Alzheimer’s disease, therefore allowing transcranial imaging of amyloids by UCNPs’ NIR emission. Finally, I will integrate the dual functions of UCNPs in deep brain imaging and stimulation, by taking advantage of their simultaneous NIR and visible emission, to achieve transcranial diagnostic imaging and optogenetic treatment of neurological diseases in model mice. The new techniques developed here will allow for non-invasive brain stimulation and imaging without the need for implants, and hold potential for next-generation remote neural therapeutics.

2018 -
Long-Term Fellowships - LTF

The role of bacterial symbionts in development and homeostasis of the immune system


Microenvironment and Immunity - Institut Pasteur - Paris - FRANCE

EBERL Gerard (Host supervisor)

Pattern recognition receptors (PRRs) of the innate immune system recognize structures that are shared by a large group of microbes. Originally posited as the initiators of immunity recognizing pathogen-associated molecular patterns (PAMPs), it was realized that PRRs also detect structures on symbionts which were therefore termed microbe-associated molecular patterns (MAMPs). In addition to initiating inflammation, MAMPs are also involved in the maintenance of symbiosis and in the development and regulation of the immune system. Given the very large microbiota resident in the intestine, a significant amount of intestinal MAMPs penetrates the circulation and modulate diverse aspects of immunity and physiology. For this project, we have developed a transgenic mouse system to control the expression and delivery of a MAMP into the host and assess its impact on immunity and physiology. We will assess the molecular mechanisms governing MAMP detection in the host and impact on development of immunity both basally to maintain homeostasis and during disease. As early life exposure of MAMPs likely modulates effects later in life, we will determine if fetal and neonatal exposure to MAMPs imprints the host. Moreover, as the penetration of MAMPs into the host is normally controlled by the innate immune system, we will use transgenic mice lacking this compartment to assess how innate immunity modulates physiology through the control of MAMPs. We thereby aim to determine the impact of MAMPs on the host, and the threshold levels of MAMPs beyond which immunity and physiology cross into pathology. This study will open the way for the use of MAMPs as modifiers of human physiology.

2018 -
Long-Term Fellowships - LTF

Unraveling co-evolution of multiple pathogens in humans using genomics and “big data”

DATTA Manoshi (USA)

Department of Biology - Technion, Israel Institute of Technology - Haifa - ISRAEL

KISHONY Roy (Host supervisor)

While microbial pathogens evolve during infection to adapt to the human environment and overcome antibiotic treatments, little is known about how adaptation is affected by other co-infecting species. Recent advances in whole-genome sequencing and phenotyping of microbial pathogens derived from human hosts during infection reveal that bacterial pathogens can diversify quite rapidly within a single patient, accumulating mutations that allow them to adapt to challenges presented by the human environment, as well as to overcome antimicrobial treatments. Yet, pathogens within the human body often do not evolve alone. Indeed, many complex infections, especially long-term chronic infections, involve multiple co-infecting pathogenic species within the same patient. In such polymicrobial infections, interactions between pathogens can determine virulence and alter the nature of evolutionary adaptation for each species. As an HFSP Fellow, I will investigate how interspecies interactions influence pathogen evolution in patients. First, I will focus on the cystic fibrosis lung, a canonical site of polymicrobial infections. Second, I will expand to a wide range of infections, leveraging clinical data from >2 million patients. This research will improve our ability to predict how pathogens will evolve in the human body and to design new strategies to thwart their evolution.

2018 -
Cross Disciplinary Fellowships - CDF

Protein liquid-liquid phase separation as a mechanism of peroxisome matrix membrane transport


Dept. of Biochemistry - Université de Montréal - Montreal - CANADA

MICHNICK Stephen W. (Host supervisor)

Proteins in the cell can undergo liquid-liquid phase separation (LLPS), forming liquid droplets - the so-called “non-membranous organelles”. The Michnick group has shown that protein liquid droplets generate work to drive membrane invagination in clathrin-mediated endocytosis. I propose an entirely new role for protein liquid droplets in membrane biology: protein transmembrane transport. My studies will focus on exploring a molecular-level mechanism of protein import from the cytosol to the peroxisome lumen, a mysterious process that occurs without the need of proteins being unfolded. Although this process is crucial to peroxisome biogenesis, its mechanisms remain unknown, due to lack of evidence of detectible transmembrane channels in these organelles. The Michnick group has evidence that two of the proteins involved in peroxisome protein translocation (Pex5 and Pex13) have both transmembrane domains and sequences that favor LLPS. My hypothesis is that these proteins form liquid droplets inside the peroxisome membrane (i.e. between the lipid bilayer leaflets), which would act as a conduit for transmembrane protein transport. After being recognized by a C-terminal peroxisome-targeting sequence, the cargo proteins could then dissolve in the droplet and emerge on the other side of the membrane. My studies will employ the budding yeast S. cerevisiae and will mainly use genetic manipulation with super-resolution and electron micrographic methods to characterize liquid droplets. Further spectroscopic and biophysical methods (e.g. fluorescence recovery after photobleaching, FRAP) will be used to assess protein dynamics inside the droplets and transmembrane protein transport.

2018 -
Long-Term Fellowships - LTF

Defining the key regulators of cell fate decisions by single cell co-assays


Department of Genome Sciences - University of Washington - Seattle - USA

SHENDURE Jay (Host supervisor)

In mammalian development, a zygote gives rise to three germ layers and ultimately hundreds of cell types. How a single genome drives the cell fate decisions underlying development remains one of the most intriguing questions in biology. Extensive work over recent decades has identified some 'master regulator' transcription factors (TFs) that specify certain lineages upon expression, e.g. MYOD for muscles. However, for many lineages the TFs and regulatory regions governing cell type specification remain in the dark. In addition, the sequence of events that leads to open and TF-bound chromatin at developmental enhancers is unknown. These cell fate decisions inherently occur in heterogeneous cell populations, making them difficult to study with bulk techniques. The ability to simultaneously measure changes in chromatin accessibility and gene expression in each of many single cells, coupled to cell lineage information, would provide unprecedented insights into mammalian development. Here I propose to develop and apply such single-cell ‘co-assays’ using mouse embryoid bodies (EBs) as a model system. This will allow me to identify the TFs and regulatory regions involved in early mammalian lineage specification. I will then genetically perturb candidate genes and characterize the effects on lineage establishment. In addition I propose a systematic screen to identify lineage-specifying TFs that serve as ‘pioneer factors’, capable of accessing binding sites in previously closed chromatin. The approach developed in this easily accessible and perturbable system will provide unique insights into intricate biological processes in the future, from in vivo mouse development to disease.

2018 -
Career Development Awards

A new epitranscriptome mark - deciphering function and mechanism of N1-methyladenosine (m1A) in mRNA


Cancer Research Center - Sheba Medical Center / Tel-Aviv University - Tel-Aviv - ISRAEL

The primary sequence of mRNA transcripts contains essential regulatory information in the form of internal chemical adducts, coined the epitranscriptome. Groundbreaking studies of N6-methyladenosine (m6A), by us and others, revealed that this abundant mRNA modification participates in many aspects of the mRNA life cycle to affect cellular, developmental and disease processes. It does so primarily through recruitment of specific binding proteins that channel modified transcripts to various processing pathways and fates. I recently identified a new mRNA modification, N1-methyladenosine (m1A), which occurs on thousands of human and mouse transcripts. It is strongly enriched at the 5’UTR and positively correlates with translation. These distinct features, together with its evolutionary conservation and dynamic nature, suggest a fundamental role in gene expression. The objective of this proposal is to establish the function of m1A in mRNA metabolism, focusing on 5’UTR and translation, and delineate the mechanisms through which it is executed. Aim 1 will systematically identify m1A-binding proteins that will be characterized to expose pathways controlling methylated transcripts. Aim 2 will functionally interrogate the effect of individual 5’UTR m1A sites on translational output in vitro and in vivo (now made possible by method advancement in my lab allowing robust mapping of m1A with single-base precision). Aim 3 will combine results of Aim 1 and 2 to mechanistically dissect the combination of factors and sequence features required for translation initiation. This study is expected to expose a new and central player in translation regulation affecting thousands of genes.

2018 -
Long-Term Fellowships - LTF

Mechanisms of radiation resistance in neural stem cells


Physiology and Metabolism Laboratory - The Francis Crick Institute - London - UK

GOULD Alex (Host supervisor)

Protecting genome integrity from environmental stresses is essential for the stable propagation of genetic information from stem cells to their daughters. The most important significance of this work is to add to our basic knowledge of how some cell types, especially neural stem cells, are able to cope with ionising radiation damage better than other cells. The two main aims of this project are to identify the cell-autonomous mechanism of radiation resistance in neuroblasts and to determine the non-cell autonomous role of the stem cell niche in neuroblast resistance. To pursue both aims, I will use a combination of confocal microscopy with molecular markers, cell-type specific genetic manipulations, genetic screens and in vitro stem cell cultures. Using the power of fruit fly genetics to get at some of the underlying mechanisms for neural stem cell radiation resistance may also help to provide us with tools for manipulating the resistance process in many different cell types. The findings of this project will have long-term implications for improving our understanding of how stem cells react to challenging environments and the inputs they receive from their niche.

2018 -
Long-Term Fellowships - LTF

How are genes born de novo and integrated into cellular systems?


Department of Biology - Massachusetts Institute of Technology - Cambridge - USA

LAUB Michael T. (Host supervisor)

Organisms must innovate to survive. While adaptation often occurs via mutations in existing proteins or through protein domain shuffling, evolution sometimes must invent functional proteins de novo. Such proteins can arise when organisms acquire the ability to express a short open reading frame encoding a peptide of benefit. Although nearly a third of the genes in many genomes are predicted to have emerged de novo, the mechanisms and constraints governing gene birth remain mostly elusive. During my post-doctoral studies, I will use the molecular, biochemical, and next-generation sequencing-based approaches that are fully accessible in the Laub lab to study how genes emerge during evolution and become integrated into cellular processes. I will develop an approach that explores the link between environmental challenges, existing cellular systems, and de novo gene birth – a largely uncharted area. Specifically, I will (i) screen for beneficial and deleterious randomized protein sequences under various conditions, (ii) characterize those sequences to reveal the molecular mechanisms behind their cellular effects, and (iii) generate models that identify and predict the potential functions of natural de novo genes. This project will provide insight into how cellular innovation arises and how the existing complexities of the cell shape such innovation.

2018 -
Cross Disciplinary Fellowships - CDF

In vivo voltage imaging of cortical circuits


Chemistry and Chemical Biology - Harvard University - Cambridge - USA

COHEN Adam E. (Host supervisor)

Neuronal activity consists of electrical transients on the millisecond timescale. Recently developed genetically encoded voltage indicators (GEVIs) have potential to record optically those transients in thousands of neurons simultaneously. Despite great efforts and improvements on the GEVIs, many technical challenges must be overcome for GEVIs to being used in large-scale recordings in live animals.
Here, we propose to develop and implement new imaging modalities to enable recordings of voltage dynamics from neuronal networks in layer 2/3 of the mouse cerebral cortex in vivo. As a voltage indicator, we will use a recently developed Archaerhodopsin mutant, called 'NovArch', offering optical sectioning by nonlinear activation. We will use protein engineering to further improve trafficking of NovArch to minimize background fluorescence, and we will co-express it with an actuator to allow for simultaneous optical stimulation.
We also plan to develop a microscope specifically optimized for voltage imaging in vivo. It will contain adaptive optical elements to direct optical excitation to the two-dimensional cell membranes where the GEVIs reside, thereby minimizing illumination of non-signal-bearing regions of the sample. This approach will provide high signal levels, while minimizing light scattering and photodamage. We will use this novel microscope to map neural activity in cortical sensory circuits under conditions of sensory stimulation in vivo. The recordings will probe the precise activity levels, sub-threshold voltage dynamics, and intercellular correlations in activity of genetically defined neurons. These data will aid in constraining models of cortical function.

2018 -
Cross Disciplinary Fellowships - CDF

Quantitative in situ liquid cell transmission electron microscopy of microtubules


Department of Chemistry - Northwestern University - EVANSTON - USA

GIANNESCHI Nathan (Host supervisor)

Microtubules form the basic structure, and transport systems in cells, responsible for fundamental processes including cell division, and hence are important drug targets for diseases including cancer, with common taxane-based drugs having them as their biological target of action. Broadly, one of the mysteries of cell biology is the basic set of properties involved in the seed and growth of microtubules and the processes underlying how these systems are initiated. New avenues for controlling cell development and division, possibly related to anticancer treatments will come with a fundamental understanding of the basic mechanisms that lead to unusual switching behavior – dynamic instability. After decades of studies, both in cells and in reconstituted systems there are many open questions about this fascinating behavior. The major bottleneck in exploring microtubules is that the process of seeding is short-lived and the molecular species are structurally very small making standard microscopy observations very difficult, especially for capturing dynamics. In situ liquid cell transmission electron microscopy (LCTEM) has the potential to solve this crucial problem. To enable these kinds of experiments, the microtubule growth, and concentration need to be optimized for confinement within the liquid-cell. Imaging conditions need to be optimized to maximize contrast (as biological systems produce very low contrast under electron beam). We contend that LCTEM experiments replicating naturally occurring nucleation, growth, shrinkage, and re-growth process of microtubules and quantitative image analysis would offer us unique insights into their formation and reorganization.

2018 -
Long-Term Fellowships - LTF

Quantitative analysis of single-cell regeneration dynamics in living planarians


Morgridge Institute for Research - University of Wisconsin - Madison - USA

HUISKEN Jan (Host supervisor)

Unlike humans, some multicellular organisms are able to regenerate their organs after severe injuries. Understanding how regeneration properties emerge from fundamental biological processes such as gene expression and stem cell differentiation is of utmost importance for basic science and regenerative medicine. Nevertheless, little is known on the mechanisms underlying the initiation, maintenance and control of regeneration. Therefore, many fundamental biological questions remain unanswered, i.e.: (i) how do stem cells migrate, divide and differentiate? and (ii) how do regenerating organs control their size and orientation?
Thanks to their astonishing regenerative properties and simple body plan, planarians form an ideal model system for the study of regeneration. However, due to their opaque tissues, time-lapse microscopy of living planarians has so far been impossible and a comprehensive understanding of the mechanisms underlying their regeneration is still lacking. In the proposed research, I aim to use an interdisciplinary approach to characterize, for the first time, the single-cell dynamics of planarian regeneration. I will use light sheet microscopy, an ideal technique for live imaging of large specimens, and design microfluidic devices to keep the organism at physiological conditions. Fluorescently labelled animals will be used to follow the regeneration dynamics at the single-cell level. Together with complementary genetic and molecular biology techniques, this approach will give us new insights on single stem cells and gene expression dynamics during regeneration.

2018 -
Cross Disciplinary Fellowships - CDF

In vitro control of cell collective flows and tissue folding by means of surface patterns


Department of Biochemistry - University of Geneva - Geneva - SWITZERLAND

ROUX Aurélien (Host supervisor)

In nature, cellular tissues efficiently remodel to attain crucial biological processes, both in health (organogenesis and development) and disease (cancer invasion and metastasis). Such reshaping events require collective cell migration, by means of which tissues can generate forces at large length scales. Although studies in vivo have evidenced the essential role of collective migration modes and flows within reshaping tissues, in vitro studies are necessary to explore these processes in simpler and better controlled microenvironments. In particular, this project aims at inducing reshaping events within confluent monolayers of cells by controlling cell flows through patterns of differential adhesiveness. First, we will explore the effects of geometrical confinement in the steady state positioning of topological defects in cellular nematics as a tool for localizing stress singularities of different strengths within cell tissues. Second, we will gain control over cellular active flows in order to induce unidirectional collective migration patterns. To this purpose, we will use gradients of surface-bound cues to control cell migration (haptotaxis) that, together with geometrical constraints, will provide with the tools for controlling flow and force fields within tissues. Finally, we will design patterns combining geometrical confinement and adhesion gradients to locally frustrate active flows and induce the creation of folds in preassigned regions within proliferative cell monolayers. Our work not only will provide experimental verification of the link between tissue mechanodynamics and reshaping, but also envisions the development of living 3D tissue structures in vitro.

2018 -
Long-Term Fellowships - LTF

Block-Seq, an innovative strategy to decipher cell-cell signaling in root meristems


Department of Biology - New York University - New York - USA

BIRNBAUM Kenneth (Host supervisor)

The indeterminate growth of plant meristems is mediated by the long-term maintenance of stem cells. While patterns like the placement of stem cells are highly dependent on cell-cell communication in plants, there is incomplete understanding of the sources of signals that pattern the meristem. In addition, there is even less knowledge about how stem cells form during organogenesis and regeneration. In plant roots and other organs, patterning processes have been shown to be highly dependent on symplastic signaling through plasmodesmata -- membrane lined channels that connect every plant cells and allow trans-cellular movements of proteins (including transcription factors), miRNAs, RNAs, sugars and ions.
To study cell-cell signaling on a broad scale, the host institute has developed a novel system to monitor complex communication from one cell to another during development. The system relies on recently developed tools to inducibly block plasmodesmata combined with single-cell RNA-seq profiling in plants. Here I propose to use this new set of techniques to sequentially block different cell identities and assess the consequent transcriptional changes using single-cell RNA-seq – a strategy we call “Block-Seq.” In particular, single-cell resolution offers the advantage of detecting responses in a subset of cells rather than expecting a tissue to respond uniformly. For the first time, these approaches will allow me to map communication from one cell type to another in the root meristem.

2018 -
Career Development Awards

Schizogony: understanding atypical cell division mechanisms in malaria parasite


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


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


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.