Molecular mapping of SARS-CoV2 and the host response with multiomics mass spectrometry to stratify disease outcomes

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

This project forms part of an international level effort to understand the mechanisms of COVID-19 disease in the global population. Despite the considerable insight gained into the virus,SARS-CoV-2, at the genetic level, the key facets of the virus structure and its pathogenic effects remain to be determined. Equally molecular descriptors that contribute to disease progression are poorly defined, and have not yet been considered in testing strategies.
Mass spectrometry (MS) can provide rapid, precise and reproducible diagnostic information at the molecular level (multiomics) that complements genomic information. In this project we will use MS to profile patient response to COVID-19 (with samples from NHS partners). This research will be exploited by our industrial project partners for diagnostic/prognostic testing protocols and for the development of vaccines and therapeutics. Research will constitute the UK effort in an international coalition initiated by the PI, COVID-19 MS, (currently over 600 members in 28 countries) who have agreed to share experience, protocols, materials and data.
This next generation measurement approach is both transferable and accessible and through replication studies involving multiple partner labs we will overcome the accuracy, sensitivity issues of current lab- based approaches while also providing population data about individual risk to COVID-19.
Our multiomics approach allows detailed structural information of the virus and its effect on the host using an intrinsic physical property - mass - unlike the indirect lab approaches currently employed.
Outputs are multifold: we will refine testing approaches, stratify treatment options, determine isolation requirements and bring much needed speed into measurement aspects of novel therapeutic development programmes - for COVID-19 and future threats.
Through our expertise in biomarker discovery and validation to profile disease mechanisms we possess the processing pipelines to extract maximum understanding from the data. As world leaders in protein structure analysis, we will structurally characterise virus:cell interactions, informing vaccine design and therapeutic intervention. Knowledge gained will be translatable to hospital testing laboratories for targeted assays, to biopharmaceutical companies for vaccine and therapeutics development, and for the development and quality control of reagents for biomarker or serological tests.
Working with LGC Ltd. diagnostics and measurement companies (Waters, Thermo, Sciex, Bruker) and through CAMS the Community for Analytical and Measurement Science major Pharmaceutical companies (Pfizer, AstraZeneca , GSK, and Allergan) we will be able to scale up our methods and translate the outcomes to provide targeted assays to the NHS for biomarkers, to validate serological tests and for vaccine and therapeutic development embedding future resilience.
The international effort is purposefully geographically spread allowing regional NHS lab access to enable rapid implementation. Finally, we established the COVID-19 MS Coalition to share sample processing protocols and to make all curated datasets open and accessible for global effort to combat this disease.
 
Description We have established common baseline multiomics methods from which we can process and analysis blood and sebum samples from patients in both discovery and targeted approaches. Working with a cohort of samples from 280 individuals sampled in wave 1 and 2 at Frimley, we have already shown that metabolomics of sebum and serum and saliva can find diagnostic, severity and prognostic markers for COVID (see outputs below). We have also analysed the proteome and lipidome of these participants and further outputs will ensue from these analyses.
We have established metabolomic targets which can be used as severity markers and used a Biocrates panel to allow translation to clinical setting. We have also found protein markers from the same patients using plasma and a DDA analysis.
All metabolomics datasets are currently available via Metabolites. We have built and populated a REDCAP data repository for all patient data where corresponding metadata is collated and anonymised. We have linked to the Trusted research environments of PHOSP and ISARIC.
Exploitation Route Non-invasive sampling approaches are desirable in healthcare, field and home settings due to the lower burden on patients and clinical staff. In the field of metabolomics, however, most studies have utilised blood serum or plasma. As part of our work, 83 COVID-19 positive and negative hospitalised participants provided serum, saliva and sebum samples for analysis by mass spectrometry between May 2020 and July 2020. This has resulted in the first comprehensive analysis of correlations between serum metabolites, salivary metabolites and sebum lipids, allowing us to consider their relative accuracy in differentiating COVID-19 positive participants from controls. We found that sebum lipids showed clear correlations to serum metabolites, with widespread changes to the serum-sebum lipid axis in COVID-19 positive participants, evidence of multi-organ dyslipidemia. In the COVID-19 positive cohort, correlations were notably marked between sebum lipids and the immunostimulatory hormone dehydroepiandrosterone sulphate. In terms of diagnostic accuracy, serum performed best by multivariate analysis (sensitivity and specificity of 0.97), with the dominant changes seen in triglyceride and bile acid levels, concordant with other studies identifying dyslipidemia as a hallmark of COVID-19 infection. Sebum diagnostic accuracy performed well (sensitivity 0.92; specificity 0.84), with saliva offering relatively weaker diagnostic accuracy (sensitivity 0.78; specificity 0.83). These findings highlight the potential for non-invasive sampling approaches, and also provide a case study of integrated biofluid analysis providing insight into the whole-body atlas of a pathophysiological condition.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology,Other
 
Description Impact of the COVID-19 MS Coalition The coalition has already produced more than 200 papers that use mass spectrometry to study coronavirus and there have been numerous studies exploring prognostic markers. Early COVID-19 MS Coalition studies that took place when disease rates and hospital admissions were high have contributed to a greater awareness of how to treat the virus and an understanding of how people that meet a specific criteria, such as cardiovascular problems or obesity, are affected. "Coalition members are working together to find solutions to coronavirus so it's important that we use the same methods, as we want those methods to be adopted by hospital labs," says Professor Barran. "I hope this coalition will lead to more collaborative science and that this pandemic allows us to develop public health that is less competitive. I also hope that any new resource being purchased for coronavirus, certainly through mass spectrometry, will benefit the diagnosis and treatment of other diseases." "The global data being collected now will be a great future resource as it allows scientists to have knowledge about people's health and illnesses. The way we're accelerating rapid diagnostic tests to a point of having them validated and being used by clinicians is a real celebration."
First Year Of Impact 2020
Sector Healthcare
Impact Types Cultural,Societal,Economic
 
Description COVID-19 MS coalition 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution When faced with limited access to coronavirus tests at the height of the pandemic, Perdita Barran, Professor of Mass Spectrometry at The University, was inspired to repurpose her laboratory to assist with national testing. She was not able to do that at that time. Similarly, colleagues across the UK and Europe were facing similar issues and joined forces to determine the best use of their skills and resources to support the crisis. They decided that the best use for mass spectrometry - the method of separating and weighing molecules - was to focus on prognosis, rather than diagnosis, of patients. As a result, mass spectrometry scientists looked for risk factor biomarkers to determine whether people would have a moderate or severe response to COVID-19 and the long-term effects it might have on patients. The new COVID-19 MS Coalition involves more than 800 scientists from 18 countries, including members from the Human Proteome Organisation (HUPO), an international collection of researchers who are identifying and quantifying human proteins with mass spectrometry.
Collaborator Contribution Mass spectrometry and virus detection Mass spectrometry helps scientists understand how the virus interacts with the host by investigating the nature of the viral protein and the proteins found at the back of people's throats - this practice is normally an important step when developing vaccines or therapeutics. Perdita leads the COVID-19 MS Coalition team at Manchester leading a £1.8 M grant funded by UKRI which involves five other Universities and combines the mass spectrometry capabilities of the Michael Barber Centre and the Stoller Biomarker Discovery Centre. This project is using mass spectrometry to find prognostic biomarkers to guide clinical decisions and also catalogues all mass spectrometry research data into a single web catalogue. Data scientists around the world can then access the information to see how people are affected by the disease. Perdita is also is acting as an advisor to the Department of Health and Social Care, assisting the NHS on using mass spectrometry as an alternative testing method to RT-PCR. Here the aim is to develop capacity capability for diagnostics and prognostics.
Impact We have the grant. I have been acting as the Chief scientific advisor to the DHSC for the use of Mass Spectrometry for diagnostics and prognostics.
Start Year 2020
 
Description COVID-19 MS coalition 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution When faced with limited access to coronavirus tests at the height of the pandemic, Perdita Barran, Professor of Mass Spectrometry at The University, was inspired to repurpose her laboratory to assist with national testing. She was not able to do that at that time. Similarly, colleagues across the UK and Europe were facing similar issues and joined forces to determine the best use of their skills and resources to support the crisis. They decided that the best use for mass spectrometry - the method of separating and weighing molecules - was to focus on prognosis, rather than diagnosis, of patients. As a result, mass spectrometry scientists looked for risk factor biomarkers to determine whether people would have a moderate or severe response to COVID-19 and the long-term effects it might have on patients. The new COVID-19 MS Coalition involves more than 800 scientists from 18 countries, including members from the Human Proteome Organisation (HUPO), an international collection of researchers who are identifying and quantifying human proteins with mass spectrometry.
Collaborator Contribution Mass spectrometry and virus detection Mass spectrometry helps scientists understand how the virus interacts with the host by investigating the nature of the viral protein and the proteins found at the back of people's throats - this practice is normally an important step when developing vaccines or therapeutics. Perdita leads the COVID-19 MS Coalition team at Manchester leading a £1.8 M grant funded by UKRI which involves five other Universities and combines the mass spectrometry capabilities of the Michael Barber Centre and the Stoller Biomarker Discovery Centre. This project is using mass spectrometry to find prognostic biomarkers to guide clinical decisions and also catalogues all mass spectrometry research data into a single web catalogue. Data scientists around the world can then access the information to see how people are affected by the disease. Perdita is also is acting as an advisor to the Department of Health and Social Care, assisting the NHS on using mass spectrometry as an alternative testing method to RT-PCR. Here the aim is to develop capacity capability for diagnostics and prognostics.
Impact We have the grant. I have been acting as the Chief scientific advisor to the DHSC for the use of Mass Spectrometry for diagnostics and prognostics.
Start Year 2020
 
Description COVID-19 MS coalition 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution When faced with limited access to coronavirus tests at the height of the pandemic, Perdita Barran, Professor of Mass Spectrometry at The University, was inspired to repurpose her laboratory to assist with national testing. She was not able to do that at that time. Similarly, colleagues across the UK and Europe were facing similar issues and joined forces to determine the best use of their skills and resources to support the crisis. They decided that the best use for mass spectrometry - the method of separating and weighing molecules - was to focus on prognosis, rather than diagnosis, of patients. As a result, mass spectrometry scientists looked for risk factor biomarkers to determine whether people would have a moderate or severe response to COVID-19 and the long-term effects it might have on patients. The new COVID-19 MS Coalition involves more than 800 scientists from 18 countries, including members from the Human Proteome Organisation (HUPO), an international collection of researchers who are identifying and quantifying human proteins with mass spectrometry.
Collaborator Contribution Mass spectrometry and virus detection Mass spectrometry helps scientists understand how the virus interacts with the host by investigating the nature of the viral protein and the proteins found at the back of people's throats - this practice is normally an important step when developing vaccines or therapeutics. Perdita leads the COVID-19 MS Coalition team at Manchester leading a £1.8 M grant funded by UKRI which involves five other Universities and combines the mass spectrometry capabilities of the Michael Barber Centre and the Stoller Biomarker Discovery Centre. This project is using mass spectrometry to find prognostic biomarkers to guide clinical decisions and also catalogues all mass spectrometry research data into a single web catalogue. Data scientists around the world can then access the information to see how people are affected by the disease. Perdita is also is acting as an advisor to the Department of Health and Social Care, assisting the NHS on using mass spectrometry as an alternative testing method to RT-PCR. Here the aim is to develop capacity capability for diagnostics and prognostics.
Impact We have the grant. I have been acting as the Chief scientific advisor to the DHSC for the use of Mass Spectrometry for diagnostics and prognostics.
Start Year 2020
 
Description COVID-19 MS coalition 
Organisation University of Surrey
Country United Kingdom 
Sector Academic/University 
PI Contribution When faced with limited access to coronavirus tests at the height of the pandemic, Perdita Barran, Professor of Mass Spectrometry at The University, was inspired to repurpose her laboratory to assist with national testing. She was not able to do that at that time. Similarly, colleagues across the UK and Europe were facing similar issues and joined forces to determine the best use of their skills and resources to support the crisis. They decided that the best use for mass spectrometry - the method of separating and weighing molecules - was to focus on prognosis, rather than diagnosis, of patients. As a result, mass spectrometry scientists looked for risk factor biomarkers to determine whether people would have a moderate or severe response to COVID-19 and the long-term effects it might have on patients. The new COVID-19 MS Coalition involves more than 800 scientists from 18 countries, including members from the Human Proteome Organisation (HUPO), an international collection of researchers who are identifying and quantifying human proteins with mass spectrometry.
Collaborator Contribution Mass spectrometry and virus detection Mass spectrometry helps scientists understand how the virus interacts with the host by investigating the nature of the viral protein and the proteins found at the back of people's throats - this practice is normally an important step when developing vaccines or therapeutics. Perdita leads the COVID-19 MS Coalition team at Manchester leading a £1.8 M grant funded by UKRI which involves five other Universities and combines the mass spectrometry capabilities of the Michael Barber Centre and the Stoller Biomarker Discovery Centre. This project is using mass spectrometry to find prognostic biomarkers to guide clinical decisions and also catalogues all mass spectrometry research data into a single web catalogue. Data scientists around the world can then access the information to see how people are affected by the disease. Perdita is also is acting as an advisor to the Department of Health and Social Care, assisting the NHS on using mass spectrometry as an alternative testing method to RT-PCR. Here the aim is to develop capacity capability for diagnostics and prognostics.
Impact We have the grant. I have been acting as the Chief scientific advisor to the DHSC for the use of Mass Spectrometry for diagnostics and prognostics.
Start Year 2020
 
Description COVID-19 MS coalition 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution When faced with limited access to coronavirus tests at the height of the pandemic, Perdita Barran, Professor of Mass Spectrometry at The University, was inspired to repurpose her laboratory to assist with national testing. She was not able to do that at that time. Similarly, colleagues across the UK and Europe were facing similar issues and joined forces to determine the best use of their skills and resources to support the crisis. They decided that the best use for mass spectrometry - the method of separating and weighing molecules - was to focus on prognosis, rather than diagnosis, of patients. As a result, mass spectrometry scientists looked for risk factor biomarkers to determine whether people would have a moderate or severe response to COVID-19 and the long-term effects it might have on patients. The new COVID-19 MS Coalition involves more than 800 scientists from 18 countries, including members from the Human Proteome Organisation (HUPO), an international collection of researchers who are identifying and quantifying human proteins with mass spectrometry.
Collaborator Contribution Mass spectrometry and virus detection Mass spectrometry helps scientists understand how the virus interacts with the host by investigating the nature of the viral protein and the proteins found at the back of people's throats - this practice is normally an important step when developing vaccines or therapeutics. Perdita leads the COVID-19 MS Coalition team at Manchester leading a £1.8 M grant funded by UKRI which involves five other Universities and combines the mass spectrometry capabilities of the Michael Barber Centre and the Stoller Biomarker Discovery Centre. This project is using mass spectrometry to find prognostic biomarkers to guide clinical decisions and also catalogues all mass spectrometry research data into a single web catalogue. Data scientists around the world can then access the information to see how people are affected by the disease. Perdita is also is acting as an advisor to the Department of Health and Social Care, assisting the NHS on using mass spectrometry as an alternative testing method to RT-PCR. Here the aim is to develop capacity capability for diagnostics and prognostics.
Impact We have the grant. I have been acting as the Chief scientific advisor to the DHSC for the use of Mass Spectrometry for diagnostics and prognostics.
Start Year 2020
 
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 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 LTD 
Description Sebomix LtD. is a spinout company that seeks to exploit sebum as a diagnostic biofluid. This is based on our invention that we can swab someones skin and analyse the sample and diagnose if someone has Parkinson's disease or another disease for example REM sleep disorder or COVID. 
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