A 3-year full-time PhD studentship is available in the Analytical and Biological Sciencies Team within the Science, Research and Innovation operational group (SR&I) of the Medicines and Healthcare Products Regulatory Agency (MHRA), in collaboration with the department of Biochemical Engineering at University College London. The project will be supervised by Drs Tim Rudd, Paul Matejtschuk and Gail Whiting at MHRA and Professor Paul Dalby at UCL. The studentship is anticipated to commence on October 1st 2023 with a student stipend of £19800pa
About the Project
A molecular understanding of the basis of biological function is a key area for research, both in the delivery of biotherapeutics and in the preparation of suitable reference materials and powerful activity indicating biological assays. Recent advances in the use of high-end molecular characterisation, Hydrogen deuterium exchange mass spectrometry (HDX-MS) and heteronuclear isotope-labelled nuclear magnetic resonance (NMR) spectroscopy, have allowed greater understanding of the interaction between protein molecules, their stability, interaction with target molecules and control of function. Complementary to experiment, the increased use of molecular dynamics (MD), facilitated by high performance computing, have also contributed useful insight into these areas.
The hypothesis for the PhD project is that MD coupled with high-end NMR spectroscopy and mass spectrometry (MS) can help us to elucidate the molecular basis of differences in biological activity in glycosylated and non-glycosylated biomolecules and help bio-design more effective biological medicines. An ideal model system to start the investigation is G-CSF, which has pharmaceutical variants which are non-glycosylated, glycosylated and pegylated.
Furthermore, once the glycosylated protein system is understood the effect of formulation excipients can be investigated. The basis of the project is to combine 1H-15N HSQC NMR experiments measured over a temperature gradient, with detailed MD studies, allowing amino acids/regions of the protein that are less stable to be identified, providing in depth structural information. Direct comparison of non-glycosylated/glycosylated forms of the protein of interest will allow the effect of glycosylation on the structure, dynamics and stability of the protein to be identified and this can be correlated with biological properties.
In addition, MS will be used to identify atomistic information, pertaining to structural degradation and the effects glycosylation have on the molecules, for example glyco-peptide analysis and the identification of solvent accessible amino acids. Comparing the glycosylated and non-glycosylated forms, and also different formulations, will relate their impact on structural dynamics to the stability of the protein itself, enabling improved formulation as an ideal protein drug product.
The successful candidate will have access to high-end analytical techniques, including, Thermofisher Eclipse Tribrid high-resolution orbitrap MS system, 700 MHz Bruker NEO Avance NMR spectrometer, fitted with a QCI-F Cryoprobe and High Performance Computing capabilities.
About MHRA
The Medicines and Healthcare products Regulatory Agency enhances and improves the health of millions of people every day through the effective regulation of medicines and medical devices, underpinned by science and research.
About SR&I
Based at a state-of-the-art scientific facility in South Mimms Hertfordshire, SR&I is an operational group of the MHRA. We are a global leader in the characterisation, standardisation and control of biological medicines with the objective to deliver public health impact via world-leading science, research and innovation. The successful candidate will have the unique experience of undertaking the PhD research at a government facility.
About the Team
The Formulation Science and Laboratory of Molecular Analysis teams, within the Analytical and Biological Sciences Division of SR&I, are leaders in the formulation and analysis of biological medicines, studying their structure, stability and other physicochemical properties. This underpins the development of many WHO international standards and supports of the R&D and Control Testing functions of the MHRA.
Awarding Institution
The successful candidate will be registered with the Department of Biochemical Engineering at University College London, one of the UK's top research Universities, and a global leader in bioprocessing research for the manufacturing and formulation of biological therapies, including monoclonal antibodies.
About You
As a candidate you will be a motivated individual with a passion for wanting to improve patient outcomes. You will have a keen interest in undertaking research in the field of molecular immunology with a focus on antibody engineering and protein structure and function analysis.
Your key responsibilities will be:
· To undertake the research projects in line with the project aims.
· To communicate effectively, orally and through written media, undertake presentations at scientific meetings and maintain excellent records.
· To interact regularly and effectively with your supervisors and interact appropriately and effectively with other staff.
· To meet the expectations of the study for a PhD by the awarding body (University).
The studentship is only available for students eligible for home UK fees. You will have or expect to achieve a 1st or 2:1 (or international equivalents) in a relevant degree subject (Immunology, Biochemistry, Molecular Biology, Bio/chemical Engineering, Chemistry, Physic, for example); or a 2:2 (or international equivalent) and a masters’ degree (or substantial experience), both in a relevant degree subject. UCL actively supports equality, diversity and inclusion and encourages applications from all sections of society. We strongly encourage applications from those who are currently under-represented within our research student community: BAME British applicants, applicants with disabilities and older applicants.
How to Apply
You should submit a covering letter, with your application and cv, detailing what you can bring to the project and what you would anticipate achieving from the studentship to [Email Address Removed]. Please quote the relevant reference number, 278737 in your letter. Informal enquiries can be directed to [Email Address Removed]
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