Edinburgh Super-Resolution Imaging Consortium (ESRIC) PhD Studentships

Beginning September 2013 - Two fully-funded 3 year PhD Studentships in high-resolution biological imaging: March 2013

The Edinburgh Super-Resolution Imaging Consortium represents the coming together of expertise from cell biologists to physical scientists with the aim to extend the boundaries of cellular imaging beyond diffraction limits in order to investigate normal cellular function and cell dysfunction associated with human disease. ESRIC provides a platform to image from single molecules, to sub-diffraction sized cellular structures and large-scale entities in vivo. This is possible through access to an unparalleled range of cutting-edge microscopy systems and analysis capabilities as well as experts from diverse disciplines. ESRIC formed through partnership between the Institute of Biological Chemistry, Biophysics and Bioengineering (IB3), Heriot-Watt University and the MRC Institute of Genetics and Molecular Medicine (IGMM), The University of Edinburgh. This collaboration combines the disciplines and skills required to drive the development and application of novel super-resolution optical techniques and data analysis for the study of important biological processes. 2 Studentships are available within ESRIC, shared and jointly supervised between IB3 and the IGMM. The ideal candidates will be graduates interested in working across traditional discipline boundaries to address fundamental biological questions using the most advanced techniques. Candidates should have, or expect to have, at least good 2.1 Degree in a relevant biological science or chemistry subject. Potential projects include;

Gene regulation and chromatin folding:

The 3D spatial organisation of the genome is important for gene regulation during development, and is perturbed in disease – such as cancer. Super-resolution fluorescence microscopy provides a new opportunity to uncover the three dimensional folding of mammalian chromatin in the nucleus at super- resolution (<200nm), particularly the interaction of distant regulatory elements with their target genes during development (Bob Hill and Wendy Bickmore), changes in chromatin folding induced by synthetic heterochromatin (Alexander Kagansky), and developing novel imaging probes to study chromosome packaging in living cells (Nick Gilbert). Williamson et al. (2012) Anterior-posterior differences in HoxD chromatin topology in limb development. Development. 139:3157-67

Dynamic Protein interactions in disease:

Using super-resolution optical microscopy to evaluate the dynamic protein interactions in receptor-chaperone pairs that mediate cell growth and metastasis, and developing smart biological sensors to measure multi-protein trafficking complexes in real time (Ted Hupp). Use super-resolution microscopy and novel biological reagents to image dynamic protein interactions and the assembly of supermolecular protein structures in stem cell models of Parkinson's Disease (Kathryn Ball).

Structure and function of cilia:

Cilia are vital membrane appendages which mediate cell signalling. They have a complex structure involving many hundreds of proteins – many of which are mutated in human disease. The size of cilia lies close to the resolution limit of conventional microscopy. The project will use mutant cell lines in which the cilia are affected, and antibodies against proteins in the cilial transition zone and in ciliary appendages, with super-resolution microscopy to refine the structure of cilia (Ian Jackson). Mill P, et al (2011). Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am J Hum Genet. 88:508-15.

Development of new photoactivatable fluorescent probes for super-resolution microscopy:

This project will develop new fluorescent tools to answer key questions in cellular communication and diabetes (Colin Rickman). Until recently, fluorescence microscopy in biological and pharmacological research has been limited in resolution (~ 250 nm) by the physical properties of light and diffraction. The advent of super-resolution microscopy overcomes this barrier, permitting the visualisation and quantitation of cellular processes down to single molecule level. This project will involve the design and synthesis of a new class of photoactivatable fluorescent probes (Nicola Howarth) for use in the technique of photoactivation localisation microscopy (PALM). PALM allows single protein molecules to be observed with accuracy of ~ 10 nm. However, at present, PALM can only be achieved using encodable fluorophores (e.g. Green Fluorescent Protein (GFP)) and so there is a need to develop synthetic analogues for use in this technique. A significant part of this project will involve the chemical synthesis of new photoactivatable fluorescent probes. Candidates must therefore have a strong background in organic chemistry. The ideal candidate will have a degree in chemistry or an associated chemistry subject with research laboratory experience in the design and development of synthetic strategies desirable. 1. Yang L, et al., PLoS One. 2012;7(11):e49514. doi: 10.1371/journal.pone.0049514. 2. Smyth AM, et al. J Biol Chem. 2013 Feb 15;288(7):5102-13. doi: 10.1074/jbc.M112.407585

Determining the nano-scale location of large cohorts of single calcium channel proteins:

Calcium ion channels are key to normal cellular function and physiology. Most of the available information describing ion channel function and location in cells comes from electrophysiology approaches that inherently provide poor spatial resolution. The new approaches developed in ESRIC provide the opportunity to determine the nano-localisation of many 1000s of single molecules in living cells. This project will employ STED- and single molecule-microscopy to provide the highest possible resolution information about ion channel location, function, interactions and dynamic behaviours in living neurons during neurotransmission. 1. Rickman C, et al. J Biol Chem. 2010 Apr 30;285(18):13535-41. 2. Yang L, et al., PLoS One. 2012;7(11):e49514. doi: 10.1371/journal.pone.0049514. 3. Smyth AM, et al. J Biol Chem. 2013 Feb 15;288(7):5102-13. doi: 10.1074/jbc.M112.407585

Protein interactions in diabetes, cancer and neurotransmission:

This project will work at the interface of biology, physics and engineering to push the boundaries of existing fluorescence lifetime imaging microscopy (FLIM) technologies towards live cell imaging, notably through the incorporation of novel single photon detectors from our collaborators at the University of Edinburgh. By combining these new technologies with our existing state-of-the art commercial FLIM system, and working with other pioneering techniques, including super-resolution PALM, STORM and STED, the project will deliver a significant step-forward in cutting edge cellular imaging technologies. This will be applied to address specific biological challenges including; quantifying protein-protein interactions that underlie cell membrane biology, secretion and the regulation of cancer pathways. This project is an ideal opportunity to work at the scientific interface, with biologists, physicists and engineers to develop a skill base in cellular and protein biology, optics and microscopy, photonic detection systems and image processing. The multi-disciplinary nature of this project welcomes candidates with a background in biology who are keen to developed skills in microscopy and biophysics or a candidate with a physics/engineering background keen to develop skills in cellular and protein biology. 1. Rickman C, Duncan RR. J Biol Chem. 2010 Feb 5;285(6):3965-72. 2. 2. Rickman C, et al. J Biol Chem. 2007 Apr 20;282(16):12097-103.

About the host institutes:

The Institute of Biological Chemistry, Biophysics and Bioengineering (IB3) is part of Heriot-Watt University and is focused on applying advances in the chemical, physical, and engineering sciences to enable and enhance life science research. The interdisciplinary research interests of the members and the state-of-the-art facilities provide a unique environment for integrative research. Key biological interests include; ion channel biology, membrane trafficking, diabetes, neurotransmission and cancer. Approximately 100 PhD students in training in our Graduate School who benefit from core skills courses, post-graduate society activities and an inter-disciplinary environment in a beautiful campus.

The Institute of Genetics and Molecular Medicine (IGMM) is a part of the University of Edinburgh and is a large, research institute composed of the Molecular Medicine Centre, the Medical Research Council Human Genetics Unit, and the Edinburgh Cancer Research Centre. The IGMM’s priorities are basic biomedical research through to clinical research across a range of themes including: the genetics of common and complex human diseases, epigenetics, developmental biology and pediatrics, brain biology and disease, cancer biology and biomedical systems analysis. There are currently around 100 PhD students in training across the IGMM, with a thriving postgraduate society.

How to apply

Applicants should submit a covering letter stating clearly why you are interested in applying for an ESRIC studentship. Applications (electronic or hard copy) should include a full up-to-date C.V. (include vacation address), and names and addresses of two academic referees, sent by 5th April 2013 to: Mrs Maureen Franks, IB3 Administrator, David Brewster Building, Heriot-Watt University, Edinburgh, EH14 4AS (email: m.h.franks@hw.ac.uk)

PLEASE NOTE that there are eligibility criteria for these studentships relating to nationality, and period and purpose of residency in the UK. Only EU nationals are eligible, but there are further restrictions for non-UK nationals.