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- Professor Buzz Baum
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Type of attachment: Satellite
Group size: 2
Start date: December 2016
Duration: 2 years
Research to be undertaken at the Crick:
The shape and internal organisation of each cell is determined by a combination of physics, biochemistry and information processing, so our work at the Crick will involve using a wide range of techniques to address the problem (including molecular biology, genetics, high-content RNA interference (RNAi) screening, live cell imaging, microfabrication, biophysical techniques and computational modeling).
The wider aims of our research are to better understand the evolution of eukaryotic cell shape, to determine how cells regulate their form, and to determine how these processes contribute to normal tissue development and homeostasis and, when they go awry, to the evolution of metastatic cancer.
- Professor David Jones
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Type of attachment: Group secondment
Group size: 8
Start date: October 2016
Duration: 3 years
Research to be undertaken at the Crick:
The aim of our work at the Crick will be to explore some new ideas for linking diseases to human genes by applying so-called "big data" bioinformatics techniques. Over the past 5 years, we have collected a very large amount of both experimental and predicted functional data (calculated using the Legion Supercomputer) for every human gene e.g. sequence similarity, gene co-expression, predicted gene fusions and so on.
So far we have used this data to predict the biological functions of functionally uncharacterised genes with a lot of success e.g. topping the rankings in the international Critical Assessment of protein Function Annotation (CAFA) algorithms challenge in 2011, and this work has led to new developments, including a project funded by Elsevier via the UCL Big Data Institute. The exciting possibility that we would like to explore whilst at the Crick is whether we can go beyond gene function prediction and to extend these same ideas to predicting novel disease-gene associations.
At the Crick we will have immediate and easy access to potential biomedical collaborators working on molecular genetics, cell biology and disease will be invaluable to provide the expert knowledge needed to ensure that the results of this project will be meaningful and focussed on the right questions. More generally, we are very keen to try to use our expertise in applying state-of-the-art machine learning techniques to difficult biological problems to tackle other interesting problems that may be posed by the experimentalists working at the Crick.
- Professor Jernej Ule
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Type of attachment: Group secondment
Group size: 9
Start date: August 2016
Duration: 3 years
Research to be undertaken at the Crick:
During our time at the Crick, we will study the structure of protein-RNA using new methods, crossing the boundaries of genomics, biophysics and computational biology to ask the following questions:
- What is the structure of regulatory protein-RNA complexes in neurons, and how does the structure instruct their function?
- How do the non-coding regulatory elements contribute to the processing and regulation of neuronal RNAs? Can mutations in these elements cause disease?
- Mutations that change the sequence of RNA-binding proteins can cause motor neuron disease. Do these mutations disrupt the dynamics of protein-RNA complexes, and what treatments could ameliorate this?
- How do protein-RNA complexes respond to cellular signals? In particular, how do they coordinate local translation in neuronal dendrites to regulate synaptic plasticity?
- Dr Isabel Llorente-Garcia
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Type of attachment: Sabbatical
Duration: 1 year
Work to be undertaken at the Crick:
Physical forces, mechanical properties and binding affinities play a crucial role in the processes involved in the immune response of white blood cells to infection by pathogens. Crucial to this, is the specific recognition of pathogen-derived molecules by specialised molecular complexes on the surface of immune cells.
In my sabbatical at the Crick, I will collaborate with Dr Pavel Tolar to investigate the role of physical forces in controlling these recognition mechanisms in B lymphocytes (a type of white blood cell in our immune system). We will carry out magnetic-tweezer experiments in live cells which will ultimately inform the development of new methods for generating protective antibodies by vaccination.
Being a physicist, this sabbatical will give me the opportunity to work in close collaboration with life scientists and benefit from hands-on experience in live-cell handling protocols and force-sensing experiments on living cells. These techniques will be invaluable for my current and future research programs and collaborations.
- Professor Gyorgy Szabadkai
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Type of attachment: Satellite
Group size: 2
Start date: May 2017
Duration: 1 year
Research to be undertaken at the Crick:
The overarching aim of our research at the Crick is to understand how mitochondria provide adaptation during the development of heterogeneous and chemoresistant tumours. We study the transcriptional program underlying adaptation and how this is translated into the metabolic phenotype of cancer cells.
This knowledge will be converted into clinical approaches to stratify breast cancer by mitochondrial subtypes and to predict chemoresistance in ovarian tumours. We are part of the Consortium for Mitochondrial Research and use advanced imaging approaches at the UCL campus and will perform metabolomic profiling of in vivo tumour models at the Crick institute.
- Professor Lucia Sivilotti
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Type of attachment: Sabbatical
Duration: 1 year
Research to be undertaken at the Crick:
My core research expertise is in recording the activity of synaptic ion channels at single molecule level and in interpreting the data (single channel electrical currents) by computational fitting of stochastic Markov models to reconstruct the free energy landscape of channel activation.
We have optimised this technique over the years and it has allowed my group to look at the fundamental principles of the effect of agonist drugs on these proteins and establish the steps in receptor activation that determine the efficacy of agonists in the nicotinic superfamily of ligand gated ion channels (Lape, Colquhoun and Sivilotti, Nature, 454,722-727, 2008).
We have started to develop a new technique to record ion fluxes through channels as optical signals. The novelty lies in the fact that we will record from single ion channels at a time resolution sufficient to provide information that can be combined with the electrophysiological data. Achieving this will allow our analysis to be extended to channels and specific questions that have resisted current electrophysiological techniques.
The work requires single molecule total internal reflection fluorescence (TIRF), together with loading cells with microinjection of poorly diffusible dyes. We are collaborating with Dr Justin Molloy (NIMR, Crick) who is a specialist in the single-molecule optical techniques required and my sabbatical at the Crick will give me the ideal opportunity to bring the new technique to fruition.
Initial work on the project at NIMR has allowed to do a feasibility study of the various stages of the protocol that we need. We already have encouraging pilot data that show that we can express channel molecules at an appropriate density, without too much aggregation, and that the diffusion of the single channel molecules in the membrane is sufficiently slow to allow us to record single channel signals long enough to obtain useful data.
- Dr Ricardo Henriques
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Type of attachment: Satellite
Group size: 3
Start date: June 2017
Duration: 3 years
Work to be undertaken at the Crick:
Our aim within the Crick Institute is to apply and further develop some of our experimental SR methods and technologies, such as SRRF.
Our laboratory was established in 2013 at UCL to undertake research combining cell biology, optical physics and biochemistry. We focus on biological problems that cannot be addressed with current imaging technology, and thus we tailor and develop novel analytical, optical and biochemical approaches to address these questions, particularly through the use of super-resolution microscopy.
In cell biology we aim to understand how pathogens enter and replicate within cells, remodelling membranes and the cytoskeleton. We have particularly focused on cell entry and the mechanisms needed to cross the actin-myosin cortex. To do so, we are developing new classes of fluorescent probes, high-speed cell friendly Super-Resolution (SR) methods and computational modelling approaches that, although designed to answer questions of interest in the lab, will have broad applications in cell biology research.
Recently we have established collaborations with groups in the host-pathogen interactions field at the Francis Crick Institute - Maximiliano Gutierrez, Eva Frickel and Moritz Treeck.
At the core of these collaborations we will join our expertise in cell biology, optical physics, photobiochemistry and applied mathematics, to collaborative studies on host-pathogen interactions during the intracellular infectious life cycle of M. tuberculosis, P, falciparum and T. gondii. Particularly on the modulation of host-factors such as the cytoskeletal framework. The inherent dynamic nature of these processes requires novel live-cell friendly and robust super-resolution imaging modalities.
- Dr Paola Bonfanti
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Type of attachment: Group secondment
Group size: 7
Start date: January 2017
Duration: 4 years
Research to be undertaken at the Crick:
The main goal of our research is to understand and manipulate the function of human thymus, which is the primary lymphoid organ essential for the establishment of immune T cell competence and induction of self-tolerance.
Our work brings a multidisciplinary approach by combining epithelial cell biology, novel tissue engineering technologies, and molecular analysis of T cell development. The outcome of this work will set the basis for novel clinical protocols for organ transplantation and immunodeficiency disorders.
Because of a broader interest in epithelial stem cell biology our group is also studying self-renewal and differentiation potency of human epithelial oesophageal cells with the aim of providing a functional and growing epithelium for a tissue engineering approach for neonatal atresia.
Finally, we are studying human pancreas development and building in vitro model systems to dissect fate and potency of pancreatic progenitors.
- Professor Judith Breuer
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Type of attachment: Sabbatical
Duration: 1 year
Research to be undertaken at the Crick:
To answer questions about the pathogenesis of Varicella zoster virus, the virus I focussed on until recently, which has no animal model of natural infection, I developed methods for using whole genome sequencing from low copy number low volume clinical material allowing recovery of high quality whole genome sequences from degraded material not possible in other ways. I am now beginning to apply this technology to a variety of other pathogens.I am a clinical virologist with a longstanding interest in molecular epidemiology and viral evolution, including, HIV-2.
During my sabbatical at the Crick, I would seek to:
(i) develop and extend my collaborations with Drs Jonathan Stoye and Kate Bishop, two leading figures in retrovirus research and with Professor John McCauley, head of the World Influenza laboratory
(ii) secure funding to support the creation of a future satellite lab in the Crick to answer fundamental questions about how host and virus interact to drive rapid clinical deterioration in HIV-1 while in HIV-2 a large number of untreated individuals have normal life expectancy.
(iii) obtain further funding for the public health aspects of utilising our sequencing technologies for studying hard to culture pathogens. Because of previous difficulties in obtaining full genome sequences from these pathogens, little is known about their evolution and how this contributes to pathogenesis. As a result of our ability to generate large numbers of high quality genomes directly from clinical and degraded material, we have uncovered hitherto unrecognised biological questions. In addition to the HIV and influenza related questions, the sabbatical period will allow me to write and develop follow up proposals to address aspects of pathogenesis in Varicella zoster virus, Cytomegalovirus Epstein Barr virus and Norovirus (shortlisted for a WT collaborator award). In all cases, the biological questions have major clinical application.
- Dr Rickie Patani & Dr Sonia Gandhi
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Type of attachment: Group secondment
Group size: 7
Start date: September 2017
Duration: 2 years
Research to be undertaken at the Crick:
Eukaryotic cells possess myriad strategies to mitigate diverse stressful stimuli. Upon stress, ribonucleoprotein (RNP) granules assemble into stress granules due to prion-like polymerization of RNA binding proteins (RBPs) together with RNAs.
Hyperformation and persistence of such granules is likely pivotal in neurodegenerative disease (NDD) pathogenesis either through altered RNA regulation, or through protein misfolding/toxicity. The investigation of RNP granules in NDD thus forms a strong conceptual bridge between protein misfolding and RNA regulation.
Prototypic neurodegenerative conditions are frequently designated as RNA regulation diseases (ALS) or protein aggregation disorders (AD and PD), although the overlap between these processes through RNP granules is a common molecular denominator.
Against this background, our core experimental questions are:
1) What is the role of perturbed RNA regulation in NDD?
2) What is the role of RNA binding protein misfolding and aggregation in NDD?
3) How do these processes conspire to deregulate homeostasis of RNA granules?
- Professor Paul Fish
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Type of attachment: Satellite
Group size: 2
Start date: February 2018
Duration: 3 years
Research to be undertaken at the Crick:
At the Crick, we will aim to investigate the contribution of Notum in neurodegeneration and propose to pursue genetic and chemical approaches in parallel.
Our work will be divided in four specific aims:
Aim 1: To achieve a detailed survey of all the cells that express Notum in adult mice. This will inform on organs or tissues, besides the brain, where Notum activity may be required (J.P. Vincent). Assess expression of Notum in human diseased & healthy brain (P.Whiting).
Aim 2: Demonstrate functional role that Notum modulates Wnt signalling in brain (P. Salinas/P.Whiting).
Aim 3: To assess the effect of global genetic deletion of Notum in adult mice using a conditional knockout allele. We will focus on neurogenesis in the hippocampus but will also assess general health as the mice age (J.P.Vincent).
Aim 4: To design, synthesise and validate brain penetrant small molecule inhibitors of Notum (P.V.Fish), using our structural information as a guide (Y.Jones).These inhibitors will be developed from hits from a successful fragment screen and/or by optimisation of a published flawed lead. Once identified, an in vivo ready tool compound will be dosed in adult mice to assess whether the genetic deletion phenotype is reproduced. Successful outcome of the above would underwrite preclinical validation of Notum as a target to treat neurodegeneration.
- Professor Joerg Albert
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Type of attachment: Satellite
Group size: 3
Start date: February 2018
Duration: 2 years
Research to be undertaken at the Crick:
Mosquitoes mate within swarms, where they use their complex ears to recognize the wing beats of mating partners. Despite the importance of this behaviour and its implications for mosquito control, the molecular and mechanical processes involved in mosquito partner recognition are poorly understood.
At the Crick, we would like to shed some light on this significant topic by using the antennal ears of disease transmitting mosquitoes (primary focus on Anopheles, with Culex and Aedes as additional controls) to study mosquito hearing and acoustic communication.
The work will focus on three key aspects:
(i) the physiological roles (and mechanistic origins) of distortion products (DPs);
(ii) the sensory ecology and neurobiology of biogenic amine (BA) signalling in the mosquito ear and
(iii) the interrelation between mosquito auditory sensitivity and the circadian clock.
Current Attachments
2018 Call
Apply for a sabbatical at the Francis Crick Institute. This will enable Principal Investigators to spend up to 12 months working in an existing Crick research group.