Underpinning UK Biomolecular Research with Next-Generation High Resolution Mass Spectrometry at the University of Edinburgh

Mass spectrometry (MS) is a mature analytical technique that impacts all areas of the biological sciences. Over the last three decades MS has developed from a technique for routine molecular mass measurement of small molecules to become a powerful tool for the analysis of very large biological molecules (such as proteins or DNA) or for the characterisation of very complex biological mixtures. One reason for this advancement is the ability of modern mass spectrometers to separate (resolve) the many signals which derive from molecules which are close in molecular mass. Modern MS instruments can also measure mass with extremely high accuracy. If this mass accuracy is high enough, the measured mass can be used to directly determine a molecule's elemental composition.

Fourier transform ion cyclotron resonance (FT-ICR) instruments are the highest performance mass spectrometers available today - offering unsurpassed mass resolution and mass accuracy. Recent technological improvements in commercial FT-ICR mass spectrometers have resulted in transformative increases in mass resolution, mass accuracy, and speed. The aim of this proposal is to make this 'next-generation' instrumentation available to the scientific communities in the University of Edinburgh, other academic institutions throughout the UK, and our partners in the industry.

The new instrument will underpin scientific research in several key strategic priorities for BBSRC for the next decade (technology development for the biosciences; healthy ageing across the lifecourse; new strategic approaches to industrial biotechnology; combatting antimicrobial resistance; synthetic biology; the replacement, refinement and reduction (3Rs) in research using animals; and bioenergy, food, nutrition and health).

This proposal brings together a broad range of researchers who will exploit this new instrument in three main areas of bioscience research: (i) for detailed analysis of biologically important proteins; (ii) for imaging the distribution of biomolecules in tissues and tissue models; and (iii) for profiling and chemical characterisation of small molecules in very complex biological mixtures.

The aim of this proposal is to purchase a SolariX 2XR Fourier-transform ion cyclotron resonance mass spectrometer, which will be used with our existing 12 tesla high-field magnet. This state-of-the-art commercial instrument is built around the new ParaCell ICR technology and the 2XR frequency doubling preamplifier and detection system, which offers a step change increase in performance over previous designs. The new system will offer a maximum mass resolving power of 20 million at 400 m/z, routine mass resolving power of two million at 400 m/z with 1Hz duty cycle, and mass accuracy of less than 200 ppb. The instrument will be equipped with electrospray (ESI) and matrix assisted laser desorption (MALDI) ionisation sources.

The SIRCAMS facility in the School of Chemistry provides high resolution mass spectrometry capability to research groups across the University of Edinburgh, as well as other users in UK academia and industry. The increased performance of the SolariX 2XR will be truly transformative and be a huge benefit to all its users, enabling researchers from across the biological sciences to gain greater chemical insight into complex biological systems. Specifically, the instrumentation will facilitate:

(i) Detailed characterisation of the posttranslational (and chemical) modifications in proteins and allow high mass resolution analysis of native protein complexes.
(ii) Untargeted molecular imaging of metabolites and drugs in tissues and 3D cell culture models using MALDI mass spectrometry imaging techniques.
(iii) Untargeted metabolite profiling from complex mixtures without prior separation.

The research underpinned by the investment in this equipment will have far reaching impacts for a variety of sectors and the wider public. As well the production of academic impacts at the University of Edinburgh, this work will have the following wider impacts:
Commercial Entities. The increased equipment base will allow our researchers to build on existing high-quality partnerships with industry partners. We will also be able to forge new links with other organisations by leveraging the new capabilities of the SolariX 2XR. The research outputs from these collaborations will allow the development of new products and processes for market, including new drugs, biocatalysts, and bio-industrial routes for manufacture. Similarly, provision of research expertise and equipment access through various programmes to UK SMEs allows them to maintain their market position, stabilize or increases their employee numbers in the current uncertain economic times.
Research Students and PDRAs: Training Highly Skilled Researchers. The School of Chemistry has a strongly research driven approach to teaching and the new high resolution MS capabilities will be used in teaching and outreach activities with direct benefit to the quality of national and international students.
Hands-on access to the instrument will be encouraged for research staff and research students in the School, and appropriate training will be provided by skilled technical staff (Mackay/Taylor). The skills gained by our researchers (in particular BBSRC-funded PhD students in the EASTBio DTP) will include training in cutting edge MS technology, advanced data analysis tools as well as transferable skills such as the ability to solve complex problems independently.
Government and Policy Makers.University of Edinburgh scientists have in the past provided expert testimony to national parliamentary panels (Holyrood and Westminster, for example on geothermal energy), and lead international (NIH, NASA) as well as national research council projects, and expect our capacity to deliver such impacts to continue through support of an enhanced equipment base.
Broader National Academic Impact. The specialist mass spectrometry facilities will be made available to the wider UK academic community through our user program. In this way, the user base of the instrument will be strengthened, the science underpinned by the instrument will be broadened, and the impact derived from this investment will be increased.