2019 Crick PhD Student Recruitment 2019 Crick PhD Positions This document provides information on the PhD positions available to start on the Crick PhD Programme in September 2019. Positions are listed alphabetically by supervisor’s surname. Positions by supervisor, in same order as this document: Alex Gould | Investigating neural stem cell metabolism with subcellular resolution Andreas Schaefer | The neural circuits underlying spatial information processing Andreas Wack & Charlotte Odendall | Functions of type III IFNs in immunity against the enteric bacteria salmonella and shigella Anne Schreiber | Understanding the structural and mechanistic basis of autophagosomal membrane formation Axel Behrens | Targeting pancreatic cancer stem cells using patient-derived tumour organoids Caetano Reis e Sousa | Innate immunity and dendritic cells Dominique Bonnet & Pierre Degond | Mathematical and In- silico modelisation of normal and malignant HSC in their niche and of their interactions with stromal cells Florencia Iacaruso | Functional organization of neuronal circuits for target selection Folkert van Werven & Vahid Shahrezaei | Dissecting and modelling of a cell fate decision in yeast Francesca Ciccarelli | Quantification of tumour heterogeneity during cancer evolution and in response to therapy François Guillemot & Rita Sousa-Nunes | Regulation of neural stem cell quiescence Frank Uhlmann & Maxim Molodtsov | Biophysics of genome structure and function Frank Uhlmann | The temporal order of cell cycle phosphorylation George Kassiotis | Determining patterns of T cell receptor reactivity with self and foreign antigens Hasan Yardimci | Single-molecule studies of eukaryotic DNA replication Ian Taylor | DARPINS for the study of retroviral restriction Ilaria Malanchi & Molly Stevens | Nanoanalytical characterization of tumour/host cell interactions James Briscoe | Developmental dynamics of spinal cord formation James Turner | How meiotic checkpoints prevent mutations and aneuploidy in offspring James Turner, Sian Ware & James Ware | Exploring sex differences in cardiovascular health and disease 1 2019 Crick PhD Student Recruitment Jean-Paul Vincent | Coordination of patterning and growth during development Johannes Kohl | State-dependent neural processing Kate Bishop | Investigating the role of the viral capsid protein in HIV-1 early replication Katie Bentley & Steffen Zschaler | A software engineering solution to better integrate computer simulations with biological experiments: removing the coding language barrier Katrin Rittinger | Structural determinants of TRIM family E3 ligase function during host immune responses Louise Walport | Probing the role of protein-protein interactions in citrullination using DNA encoded cyclic peptide libraries Maximiliano Gutierrez | Spatiotemporal regulation of the interactions between mycobacterium tuberculosis and macrophages Nathan Goehring | Design principles of intracellular pattern formation by cell polarity networks Nic Tapon | Tissue growth control during development and regeneration Paul Nurse | Global cellular controls in eukaryotic cells Peter Van Loo | Molecular archaeology of cancer: deciphering cancer’s evolutionary history from its genome sequence Radoslav Enchev | Time-resolved analysis by cryo-electron microscopy of regulators of ubiquitin signalling Richard Treisman | RPEL proteins, cytoskeletal regulation, and cancer Rupert Beale | Disentangling influenza, inflammation and autophagy Sila Ultanir | Role of NDR kinases NDR1/2 in neuronal autophagy Stephen West | Assembly of macromolecular complexes for DNA Repair Thomas Surrey | Building complexity: engineering a bipolar spindle Venizelos Papayannopoulos| Novel mechanisms of pathogenic fungal clearance Victor Tybulewicz & Jeremy Green | Analysis of the cellular basis of heart septation and how this is perturbed in down syndrome 2 2019 Crick PhD Student Recruitment Alex Gould Investigating neural stem cell metabolism with subcellular resolution The overarching goal of our research is to harness the advanced genetics available in the fruit fly Drosophila (http://flybase.org) to identify conserved aspects of metabolism that are relevant to human health and disease. The developing mammalian brain is known to be more highly protected than other organs against environmental stresses such as nutrition deprivation or hypoxia. This brain sparing process is an important survival adaptation that is clinically relevant for human intrauterine growth restriction (IUGR). Work in our laboratory has shown that brain sparing also occurs in Drosophila, opening up the possibility of using flies to identify the conserved underlying mechanisms. Very little, however, is currently known in Drosophila or mammals about how the metabolism of neural stem cells adapts during brain sparing. One project now available in our laboratory involves identifying lipids and other metabolites that regulate how conserved underlying mechanisms. Very little, however, is currently known in Drosophila neural stem cells interact with their glial niche during brain sparing (Bailey et al 2015, Cheng et al. 2011). An important technical approach here will be to use state-of-the-art mass spectrometry imaging (MSI) (Bailey et al. 2015, Steinhauser et al. 2012). A new MSI platform, 3D OrbiSIMS, now allows metabolites to be visualized in tissues such as the CNS with unprecedented spatial resolution (Gilmore et al. 2017). The main aims of this project are three-fold. First, to use MSI to image lipids and other metabolites in Drosophila neural stem cells and glia during brain sparing induced by nutrient deprivation or hypoxia. Second, to specifically target CRISPR/Cas and RNAi, either to neural stem cells or to glia, in order to identify which of the corresponding metabolic enzymes are required for CNS sparing. And Third, to use MSI to follow up in the mammalian CNS a few of the most interesting metabolites. This is just one example of a currently available project in the laboratory. The precise project will be decided on in consultation with Alex Gould. Training in genetics, molecular biology, cell biology, biochemistry, microscopy, metabolomics, and bioinformatics will be provided. Gould lab external website: https://www.agouldlab.com 1. Bailey, A. P., Koster, G., Guillermier, C., Hirst, E. M. A., MacRae, J. I., Lechene, C. P., Postle, A. D. and Gould, A. P. (2015) Antioxidant role for lipid droplets in a stem cell niche of Drosophila. Cell 163: 340-353. PubMed abstract 2. Cheng, L. Y., Bailey, A. P., Leevers, S. J., Ragan, T. J., Driscoll, P. C. and Gould, A. P. (2011) Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell 146: 435-447. PubMed abstract 3. Steinhauser, M. L., Bailey, A. P., Senyo, S. E., Guillermier, C., Perlstein, T. S., Gould, A. P., Lee, R. T. and Lechene, C. P. (2012) Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature 481: 516-520. PubMed abstract 4. Gilmore, I., West, A., Alexander, M. and Gould, A. (2017) Principles of Systems Biology, No. 24 : Sub-cellular imaging of metabolites with 3D OrbiSIMS. Cell Systems 5: 534. PubMed abstract 3 2019 Crick PhD Student Recruitment Andreas Schaefer The neural circuits underlying spatial information processing Hepatocellular carcinoma (HCC) is one of the deadliest human cancers with no available cure. HCC is The Neurophysiology of Behaviour Laboratory aims to decipher how circuits in the brain represent, encode, and process information. We use sensory systems in mice as a model system and a variety of techniques – from volume electron microscopy to identify neural circuits, in vivo imaging in behaving animals, electrophysiology in vivo and in vitro, optogenetics, molecular tools, to computational and theoretical approaches. Furthermore, we are actively involved in developing technology especially in the realm of large- scale electrophysiology. Ongoing projects include: - Functional anatomy. After 2p imaging in behaving animals we analyse the circuitry in the very same animal using microCT imaging and volume electron microscopy to identify the connectome underlying the responses observed in the intact animal. This allows us to understand how neural circuits shape neural responses. - The circuitry underlying spatial perception. We use ethological behavioural tasks and psychophysical analysis in mice to delineate the queues that are used for detecting direction or distance. As mice are crepuscular animals, we focus on the sense of smell. Combining this analysis with electrophysiology, optogenetics, and circuit analysis we aim to discern the mechanism how information about space is extracted from the dynamic, turbulent odour environment. - Large-scale electrophysiology. To overcome the limitations of traditional recording techniques we are developing scalable electrophysiological recording approaches by leveraging CMOS technology for large- scale recordings deep in the brain. Such technology will not only allow for comprehensive description of neural activity in a brain area (for example the areas processing spatial olfactory information) but also, through targeted stimulation of circuit elements, bring us closer to an understanding of the relation between individual neurons and population activity. Furthermore, it is one of the key steps towards efficient brain- machine interfaces. - Neural computation. Both within the lab and with close collaborators we use advanced data analysis techniques to allow us to interpret and comprehend the large volumes