High Resolution High Throughput Mass Spectrometry to Characterise Materials, Chemicals, and BioCatalysts

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

This proposal will equip UoM new equipment that will enable high throughput high resolution ion mobility mass spectrometry analysis. This bid will increase capacity for analysis and extend our capacity to measure a wide range of analytes. Specialist equipment will be used to measure the mass and the shape of a large number of newly synthesised chemicals. In the simplest terms possible, mass spectrometry measures the movement of ions in a vacuum to give mass and ion mobility mass spectrometry measures the movement of ions in a gas to give shape. If we measure mass very accurately we can work out what atoms a molecule is made of and if we measure the shape very accurately we can work out how the atoms are arranged. So for a large range of different molecules we will be able to tell what we have made and how much we have made.

The PI has been making ion mobility mass spectrometers and using ion mobility mass spectrometry for over 20 years. She has pioneered its use in many areas of chemistry and in this proposal we plan to do it even faster and with more accuracy.

This equipment will be located with the Manchester Institute for Biotechnology in the Michael Barber Centre for Collaborative Mass Spectrometry. It will be used by research teams at the University of Manchester as well as by external users from both academia and instrument. We will use this state of the art instrumentation to underpin investments by EPRSC in the Future Biomanufacturing Research hub and the Prosperity Partnership with AstraZeneca as well as other programs in materials and catalysis. This new capability will consist of two mass spectrometers coupled to novel ionisation sources. A State-of-the-art Cyclic IMS QTof MS instrument will provide unique enhanced analytical capabilities for molecular identification and structural characterisation of complex mixtures complete with full ion mobility data. A second "work-horse" DESI interfaced Synapt XS instrument will provide broader research access and wider application, and act as an initial screening platform prior to Cyclic Structural work for rapid mass spectrometry analysis. The ionisation sources will enable analysis with minimal sample preparation both directly from surfaces via Desorption Electrospray ionisation and with microfluidic droplet dispensing to provide a unique ultra-high-throughput (uHTP) screening capability. This will provide mass and structural data for a range of chemical analytes from small molecules to polymers, supramolecular compounds to biopharmaceuticals.

Planned Impact

The high resolution high throughput mass spectrometry (HRHTP-MS) instruments and the development of unique screening capabilities will innovate HTP IM-MS research applications that will accelerate the ability to screen and accurately measure metabolites, targeted small molecule and proteins, their interactions and modifications, and hence transform our understanding of biological processes. It will accelerate the identification and understanding of bottlenecks in biocatalyst and strain engineering workflows with the benefit of rapid, accurate and direct identification of chemicals targets, and will transform screening capabilities in research areas across chemistry, advanced materials, bio manufacturing and bio catalysis, and healthcare diagnostics. The IM-MS platforms will build on existing analytical and interdisciplinary expertise to provide unparalleled access to state-of-the-art equipment infrastructure and support alongside recent EPSRC investments.
Whilst aligned closely to the UoM research strategy and Industrial Biotechnology Research Beacon, the proposed facility is also strategically aligned with the EPSRC MS roadmap (2016, https://epsrc.ukri.org/files/research/massspectrometryroadmap/) and with the future EPSRC strategy for Mass Spectrometry in the UK which demands connected national Centres with advanced analytical capabilities. It also recognizes that in order to deliver high-impact studies and set the research agenda the UK mass spectrometry community needs to be amongst the early adopters of new technologies that significantly enhance performance to provide quick contributions to the field, setting new standards pushing the research fields rapidly forwards. The HRHTP-MS platforms will provide the UK with unique innovation in HTP IM-MS, facilitating high resolution mass and structural analysis without which analytical screening will remain a major bottleneck in many key EPSRC research themes.

The HRHTP-MS platforms will provide an open and shared facility in the interdisciplinary MIB (Faculty of Science and Engineering at UoM) and will benefit from being part of the MBCCMS, which is a national flagship research hub of MS with a well-established network of academic and industrial collaborations. The facility also will benefit from UoM strategic industrial partnerships including Waters Corp and AZ, and major new EPSRC funded initiatives including the Future Biomanufacturing Research Hub, Catalysis Hub and Prosperity Partnership with academic and industrial partners. The specialist instruments will be housed close to biological research laboratories (bacterial/mammalian cell growth and automation) and supported and managed by expert technical and data analysis/management support. This will allow the delivery of novel capabilities to a broad range of cross-disciplinary expert and non-expert users. The expert technical support will ensure that the full breadth of research applications are provided and novel methods developed in collaboration with both academic and industrial users. Forming part of a wider core facility infrastructure within the MIB (including NMR, EPR, In silico computational modelling and synthetic biology and directed evolution pipelines) and connected across UoM, the instruments will be managed as fully open access resources with full training and technical support provided. The instrumentation will support a very strong research portfolio of national and international research grants led by MIB PIs that will ensure early delivery of research impact.

Central to the growth of this facility and to National importance will be the involvement of external users. The Future BRH has 20 core industrial partners (Allergan, Almac, Arcinova, Biocatalysts, Biopropane consortium, BP, Britest, Calysta, CoEBio3 consortium (8 companies), Croda, GSK, Ingenza, Johnson Matthey, Prozomix, Quorn, Shell, Singer, Sphere Fluidics, Unilever, Victrex) as well as 9 associate partners who will have access to this.

Publications

10 25 50

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Bell DJ (2023) Hexanuclear Ln6 L6 Complex Formation by Using an Unsymmetric Ligand. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Bennett T (2024) Studying Cation Exchange in {Cr7Co} Pseudorotaxanes: Preparatory Studies for Hybrid Molecular Machines. in Chemistry (Weinheim an der Bergstrasse, Germany)

 
Description All of the papers cited are advancements in mass spectrometry that were assisted by this award.
Highlights are:
1. Our research program uses mass spectrometry (MS) to find biomarkers for Parkinson's disease to enable diagnosis . We do this from endogenous compounds excreted with sebum and obtained from skin swabs. In lab, using this instrument we showed we can determine if an individual has PD with >95% accuracy . Our statistical model shows that this will provide sensitivity of 0.95 and selectivity of 0.96 if applied to the target population of patients referred to secondary care with suspect PD. We showed that we can do this with by rubbing sebum onto a piece of paper using instruments supported by this grant.

2. We used instruments funded by this grant for a systematic investigation which discerns the structure and stability of a series of polymetallic inorganic complexes where we vary the metal present. We have used high resolution tandem ion mobility coupled with tandem mass spectrometry, supported by DFT calculations. Our investigation provides an experimental and theoretical framework by which it is possible to determine the influence of the metal composition on the stability and disassembly of the entire polymetallic complex. This is useful in the design of molecules that might be used as catalysts and batteries as well as use in quantum computing.

3. We have used this instrument to look at the separation of chiral molecules that are being developed as drugs. We are developing methods to separate large oligonucleotides with these instruments.

4. We have used the instrument to look at very very large molecules called AAVs that are used as drug delivery vehicles.

5. We have developed methods that can screen chemical reactions with these instruments on the fly. We look at the starting material and the end product all in the crude reaction mixture. This is being used by Astra Zenca because of what we did.

6. We have used these instruments to discover lipids that are markers of COVID infection and COVID recovery.
Exploitation Route We are hoping to translate the discovered biomarkers into a first in class diagnostic test for Parkinson's Disease. We are hoping to translate this to the NHS.

Our screening of biocatalysts is being adopted by others including project partners AZ.

We have developed a new method to analyse AAVS - we are seeking protection for this invention.
Sectors Chemicals

Healthcare

Pharmaceuticals and Medical Biotechnology

Other

URL https://pubs.acs.org/doi/10.1021/jacsau.2c00300
 
Description Our work in PD diagnostics has had tremendous public impact. Due to the unusual origin of this project, it has already attracted a lot of attention. Joy Milne receives mail addressed to 'The woman that can smell Parkinson's, Perth, Scotland'. Barran and Milne have each given a TedX talk on this work (Barran PaloAlto 2019, Milne Manchester, 2023). They have appeared in four major documentaries/films (Paxman: Putting up with Parkinson's ITV 2022, The Woman who can Smell Parkinson's BBC 2017, Operation Ouch 2021, Natures Weirdest Events 2020) and numerous other media appearance have focused interest on this remarkable start to a scientific program. The PI and Joy receive on average 10 communications per week from people who thing they or someone they know has Parkinson's based on what they have heard from our work about the odour and also increased awareness of prodromal symptoms. We anticipate this public interest will continue and where appropriate will use it to inform people with PD about this study and its outputs. We will continue to use our connections to PD groups worldwide to engage with and communicate about, our research findings. These groups include national and regional patient and career research interest groups set up by Parkinson's UK, the Young Onset PD (YOPD) interest group, PD Avengers which addresses PPI and research required for People with PD, the Women's Group in PD - Joy Milne is founder member for the promotion of the 'Unmet Needs' of Women with Parkinson's Disease.
First Year Of Impact 2019
Sector Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural

Societal

 
Description Antibiotic K16: Elucidation and Engineering Pathways to New Anti-infective Agents.
Amount £486,550 (GBP)
Funding ID BB/V008552/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 04/2025
 
Description Generalised Photocatalysis by Enzymes (GENPENZ)
Amount £3,178,051 (GBP)
Funding ID BB/X003027/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2023 
End 01/2028
 
Description Methods for bioengineering NRPS/PKS assembly lines delivering peptide natural products with electrophilic warheads.
Amount £470,912 (GBP)
Funding ID BB/V016083/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2022 
End 08/2025
 
Description Prospecting for pH sensors in host and pathogen systems
Amount £435,094 (GBP)
Funding ID BB/V006592/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2024
 
Title Geue_Supplementary_Dataset_Heterocluster_Paper.zip 
Description Supplementary dataset in support of the manuscript "Formation and Characterisation of Polymetallic Rings in vacuo", including raw data of ion mobility mass spectrometry and mass spectrometry measurements. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
URL https://figshare.com/articles/dataset/Geue_Supplementary_Dataset_Heterocluster_Paper_zip/21751442
 
Title Supplementary Dataset in support of Adduct Ions as Diagnostic Probes of Metallosupramolecular Complexes using Ion Mobility Mass Spectrometry 
Description Raw data of ion mobility mass spectrometry and mass spectrometry measurements as well as the outputs from DFT calculations. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
URL https://figshare.com/articles/dataset/Supplementary_Dataset_in_support_of_Adduct_Ions_as_Diagnostic_...
 
Description Collaboration with PHOSP https://www.phosp.org/ 
Organisation University of Leicester
Department Leicester Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We have obtained samples from 760 participants in the P-HOSP study. We have performed multiomics investigations on serum from these participants. We have performed metabolomics in two labs, (Manchester untargeted and Surrey semi targeted) untargeted proteomics in two labs (Manchester and Liverpool) and lipidomics in Manchester.
Collaborator Contribution They have collected samples and the clinical data. All is stored in the P-HOSP TRE.
Impact Pending
Start Year 2021
 
Title BIOMARKERS AND USES THEREOF 
Description The present invention relates to methods for detecting the presence or absence of Parkinson's disease (PD). 
IP Reference WO2021156637 
Protection Patent / Patent application
Year Protection Granted 2021
Licensed Yes
Impact We are seeking to translate this method and have also formed a spin out.
 
Title BIOMARKERS AND USES THEREOF 
Description The present invention relates to methods of assessing whether an individual has Parkinson's Disease (PD) and/or is no longer responding to treatment, the method comprising the identification of one or more volatile compounds in the sebum of the individual. The present invention also relates to methods of extracting and detecting analytes from sebum. 
IP Reference WO2020025967 
Protection Patent / Patent application
Year Protection Granted 2020
Licensed Yes
Impact As before - spinout Sebomix Ltd.
 
Title DETECTION OF LIPID MARKERS 
Description The present invention relates to methods for identifying high molecular mass lipids in samples. Such high molecular mass lipids may be useful as biomarkers for the identification of disease. 
IP Reference WO2021156638 
Protection Patent / Patent application
Year Protection Granted 2021
Licensed Yes
Impact Spin out
 
Title Use of Sebum Biomarkers 
Description Pilot studies showed odour was present in sebum from PD subjects. MS identi?ed a volatiles-associated signature of PD with 85% specificity now refined to >95% . We have since developed MS methods to identify metabolites in sebum that alter in PD and elucidated disease pathways previously identified in brain . Recent focus has translated this into a targeted approach. Direct infusion MS removes the requirement of pre-analysis and sample processing and has revealed a distinct PD lipid profile. We have demonstrated that sebum is commensurate with serum and superior to saliva as a diagnostic biofluid for COVID. [4] We are currently applying these methods to prodromal RBD cohorts. We have just submitted a full application to the MRC DPFS. We have spun out a company 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2019
Development Status Actively seeking support
Clinical Trial? Yes
Impact Due to the unusual origin of this project, it has already attracted a lot of attention. Joy Milne receives mail addressed to 'The woman that can smell Parkinson's, Perth, Scotland'. Barran and Milne have each given a TedX talk on this work (Barran PaloAlto 2019, Milne Manchester, 2023). They have appeared in four major documentaries/films (Paxman: Putting up with Parkinson's ITV 2022, The Woman who can Smell Parkinson's BBC 2017, Operation Ouch 2021, Natures Weirdest Events 2020) and numerous other media appearance have focused interest on this remarkable start to a scientific program. The PI and Joy receive on average 10 communications per week from people who thing they or someone they know has Parkinson's based on what they have heard from our work about the odour and also increased awareness of prodromal symptoms. We anticipate this public interest will continue and where appropriate will use it to inform people with PD about this study and its outputs. We will continue to use our connections to PD groups worldwide to engage with and communicate about, our research findings. These groups include national and regional patient and career research interest groups set up by Parkinson's UK, the Young Onset PD (YOPD) interest group, PD Avengers which addresses PPI and research required for People with PD, the Women's Group in PD - Joy Milne is founder member for the promotion of the 'Unmet Needs' of Women with Parkinson's Disease. 
 
Company Name SebOMIX 
Description SebOMIX develops a clinical diagnostic test for Parkinson's Disease, with the aim of commercialising its research. 
Year Established 2021 
Impact The company has only just been spun out. It owns the IP of this technology.
 
Description Numerous Media Appearances on press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Due to the unusual origin of this project, it has already attracted a lot of attention. Joy Milne receives mail addressed to 'The woman that can smell Parkinson's, Perth, Scotland'. Barran and Milne have each given a TedX talk on this work (Barran PaloAlto 2019, Milne Manchester, 2023). They have appeared in four major documentaries/films (Paxman: Putting up with Parkinson's ITV 2022, The Woman who can Smell Parkinson's BBC 2017, Operation Ouch 2021, Natures Weirdest Events 2020) and numerous other media appearance have focused interest on this remarkable start to a scientific program. The PI and Joy receive on average 10 communications per week from people who thing they or someone they know has Parkinson's based on what they have heard from our work about the odour and also increased awareness of prodromal symptoms. We anticipate this public interest will continue and where appropriate will use it to inform people with PD about this study and its outputs.
We will continue to use our connections to PD groups worldwide to engage with and communicate about, our research findings. These groups include national and regional patient and career research interest groups set up by Parkinson's UK, the Young Onset PD (YOPD) interest group, PD Avengers which addresses PPI and research required for People with PD, the Women's Group in PD - Joy Milne is founder member for the promotion of the 'Unmet Needs' of Women with Parkinson's Disease.
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019,2020,2021,2022,2023