About the Project
Recent advances in nanosensing technology are promising to revolutionise medicine, the management of healthcare, food supply chains and environmental safety through sensitive measurement and digital tracking of specific biomarkers or small molecule pollutants. One such cutting-edge technology, nanopore sensors, relies on the characteristic changes in electrical signalling that arise from single molecules as they pass through- or interact with- tiny channels, or ’nanopores’ ~ < 5 nm in diameter, supported in a barrier membrane. Bioinspired protein nanopores are extremely sensitive and can be engineered to detect specific markers from complex mixtures such as biological fluids or environmental water samples, and to sequence DNA/RNA or peptides. However, development and application of this technology is limited by the availability of different types of protein nanopores that are robust, and easy to engineer and produce.
Portal proteins from large dsDNA viruses, such as bacteriophages as well as human and animal herpes viruses, are natural biological nanopores containing a channel through which the DNA genome is translocated into the preformed viral capsid during virus particle assembly [1]. The portal protein also serves as a central component of an ATP-driven DNA packaging machine, which is the most powerful biological motor found on our planet: it can work against a huge pressure (up to 10 x that contained in a champagne bottle) that builds up inside the capsid when DNA is packaged at crystalline density. Portal proteins from bacteriophages found at extreme environments, such as deep-sea vents or thermal springs, are intrinsically robust and resistant to the high temperature and pressures of the natural environment. These stable and tractable proteins are promising to significantly expand the variety of protein nanopores available, to create a toolbox of nanopore scaffolds with varying properties that can be ’tuned’ for different biotechnological applications [2,3].
This project provides a unique opportunity for an international interdisciplinary collaboration spanning molecular biology, protein biochemistry, structural biology and single molecule biophysics, at the interface of academic research (University of York, UK) and industrial biotechnology research and development (Dreampore, Paris, France). Portal proteins from thermophillic viruses will be structurally (X-ray and Cryo-EM) and biophysically (NanoDSF, NanoDLS) characterised at York to identify those that are stable and assemble with defined geometries. The geometric and physiochemical properties of the internal channel will be engineered for different sensing applications before characterisation as single molecule nanopore sensors, using sensitive, high band-width electronic detection equipment during an 8-month placement with Dreampore, a world leader in the development of peptide and protein biosensors. Due to the nature of unique collaboration, the project will provide opportunities for the student to work at the interface of highly competitive areas of research: structural biology including Cryo-EM, experiments at the single molecule level using nanopores, protein sequencing and detection of biomarkers.
You will work in a dynamic environment, with internationally recognized academics and entrepreneurs. Dreampore offers opportunities to learn to valorize the industrial potential of your research and to participate in cross-disciplinary collaboration from bench to bedside. At York, you will participate in a world class academic research program. You would gain invaluable experience for a research and development career in academia, industry or with a start-up company.
This prestigious Doctoral Training Partnership (DTP) brings together the very best molecular, chemical and cellular bioscience research across the White Rose Consortium of Universities (Leeds, Sheffield and York), which maps on to the research themes of the BBSRC. Students benefit from a regional PhD training programme that has interdisciplinary collaboration at its core. Students develop a range of research skills in biological and biochemical areas and are equiped with core mathematical, data analysis and generic professional skills that are necessary for bioscience research in the coming decades.
Dreampore S.A.S, created in 2017 is a spinoff company of Excilone (www.excilone.com, a well-established French company with EUR2.3m in sales in 2017), together with researchers of Cergy-Pontoise and Evry-Val d’Essonne universities and Paris Lariboisière hospital (AP-HP), offering services for micro- and nanogenomics, e.g., sample preparation for cytogenetics, microdissection, imaging, digital solutions. It benefits from world-class and state-of-the-art resources. Headed by entrepreneur, inventor, Luc Lenglet and various insights, from protein modelling to access to patient samples through local hospitals. As a licensee from Excilone, Paris universities and AP-HP, Dreampore benefits from privileged access to their combined resources, expertise & equipment, in addition to its own proprietary resources.
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).
Funding Notes
The studentship is fully funded by BBSRC and covers: (i) a tax-free annual stipend at the Research Council rate (£14,777 for 2018/19, to be confirmed for 2019/20), (ii) research costs, and (iii) tuition fees. Additional funding from Dreampore includes: (i) a £600 pa supplement to the stipend, (ii) Research and training costs during the placement, and (iii) travel and accommodation costs during the placement.
Eligibility: The studentships are available to UK and EU students who meet the UK residency requirements. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award.
References
References:
1. Simpson AA et al. Structure of the bacteriophage phi29 DNA packaging motor. Nature 2000;408:745-750; Lebedev A, et al. Structural framework for DNA translocation via the viral portal protein. EMBO J 2007;26:1984-1994.
2. Cressiot B et al. Porphyrin-Assisted Docking of a Thermophage Portal Protein into Lipid Bilayers: Nanopore Engineering and Characterization. ACS Nano 11, 11931–11945 (2017);
3. Cressiot, B. and Greive, S. et al. Thermostable virus portal proteins as reprogrammable adapters for solid-state nanopore sensors. Accepted in Nature Communications, (2018).
• Applicants should submit an application for a PhD in Biological Chemistry by 14 January 2019
• Supervisors will contact their preferred candidates either by email, telephone, web-chat or in person
• Formal interviews will take place on 6 February at the University of York
• Candidates may be interviewed by external partners as well as the academic supervisors
• Supervisors will select their preferred candidate from those that meet the University’s entry requirements
• Candidates will be notified of the outcome of the panel’s decision by email