MODERNISING MEDICAL MICROBIOLOGY: ESTABLISHING HOW NEW TECHNOLOGIES CAN BE OPTIMALLY INTEGRATED INTO MICROBIOLOGY

Lead Research Organisation: University of Oxford
Department Name: Clinical Medicine

Abstract

Successful control of infectious diseases depends on completely understanding how they are transmitted. The major challenges posed by tuberculosis, MRSA and hospital acquired diarrhoeas (C. Difficile and norovirus) would be easier to tackle if we could recognise individual outbreaks of infection with different strains. However, current typing schemes, which try to classify how different bugs are related to each other, are too slow and inadequate to reliably do this.

High-throughput sequencing of the human genome has revolutionised scientific research. We intend to exploit these advances to improve infectious diseases clinical practice. We will systematically collect strains of four pathogens from major UK hospitals and the clinical details of each case. The genomic techniques will allow us to precisely type large numbers of isolates so that we can track individual local outbreaks even if the bugs are very closely related. Better descriptions of routes of transmission will identify where guidelines for infection control can be improved. We will then develop rapid typing techniques so that infection outbreaks can be recognised and followed in real-time, and then successfully interrupted in a rational way. We will develop a web-based computer database so that a single system can be used across the country.

Technical Summary

Three areas continue to challenge medical microbiology: detecting and managing outbreaks, identifying microbial pathogenic factors causing specific disease manifestations, and understanding the contribution of human host susceptibility. Ongoing advances in sequencing, bioinformatics and web-based technologies have now reached a stage where their potential for revolutionising the way we characterise microbes and investigate human disease can be envisaged. The real challenge is to harness and translate this potential into clinical practice and public health.

The goal of this Consortium is therefore to transfer new and established sequencing technologies into effective everyday public health and clinical microbiology practice.

Specific primary objectives are (i) at a national level, to rapidly detect and track the spread of new epidemic strains (ii) at a local level, to identify hitherto unrecognised outbreaks within an endemic setting, by coupling more discriminatory sequence typing with carefully defined sampling frames (iii) at an individual patient level, to recognise and follow outbreaks early enough to intervene effectively (iv) to develop attractive, easy-to-use web-accessible bioinformatics tools enabling local practitioners to direct routine infection control practices efficiently. Our secondary objective is to enable future population-based studies of microbial pathogenic factors and host genetically-determined susceptibility by assembling isolate collections and matched human DNA.

Our strategy focuses on four major pathogens providing diverse challenges and varying potential for successful application. We will use ultra-fast whole genomic sequencing to identify regions of informative diversity to augment established and lower resolution typing schemes, and to achieve sufficient power to detect transmission even of highly prevalent pathogenic strains. Rigorous population-based sampling frames appropriate for each organism will be defined, relevant clinical/epidemiological data collected, and infecting organisms and host DNA archived. Improved typing schemes will be implemented using established sequencing platforms, and outputs integrated in a single web-based environment for reporting and analysis. This should deliver near-real-time data-driven national surveillance and local clinical decision making, and could be integrated into the HPA Regional Microbiology Network (RMN).

To realise our scientific goal we will draw together the breadth of the HPA RMN, research strengths of the University of Oxford, and the sequencing/informatic resources of the Wellcome Trust Sanger Institute, enhancing training opportunities and leadership development in cutting-edge technologies for a large pool of microbiologists. UK capacity will be strengthened by creating a novel partnership with national reach, nurturing research trainees, developing practical software and analytical tools and assembling large well-defined sample archives.

Publications

10 25 50
 
Description Blackett Review
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Chapter within Part II of CMO's Annual Report on Healthcare Associated Infections
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description HPA Bioinformatics Committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Artist in Residence Scheme, Leverhulme Trust
Amount £12,500 (GBP)
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start  
 
Description EPSRC studentship
Amount £45,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description Gates (CRyPTIC)
Amount $2,257,632 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2015 
End 10/2017
 
Description HPA Fellowship (2 people)
Amount £450,000 (GBP)
Organisation Public Health England 
Sector Public
Country United Kingdom
Start 09/2009 
End 08/2013
 
Description Health Innovation Challenge Fund
Amount £2,845,822 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2016
 
Description Health Protection Research Unit
Amount £3,691,617 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2014 
End 03/2019
 
Description Institut Biomerieux
Amount € 200,000 (EUR)
Organisation Merieux Institute 
Sector Private
Country France
Start 04/2013 
End 03/2015
 
Description MRC Clinical Fellowship
Amount £181,530 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description MRC Clinical Training Fellowship
Amount £147,340 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2013 
End 10/2015
 
Description MRC Research Training Fellowship
Amount £196,069 (GBP)
Funding ID MR/J011398/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description NIHR Fellowship
Amount £355,425 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description NIHR Flexibility and Sustainability Fund (FSF)
Amount £165,764 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2009 
End 08/2011
 
Description NIHR Oxford Biomedical Research Centre
Amount £5,500,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description NIHR PGfAR (ARK)
Amount £2,649,834 (GBP)
Funding ID RP-PG-0514-20015 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2016 
End 02/2021
 
Description NIHR Programme Development Grant
Amount £81,995 (GBP)
Funding ID RP-DG-1108-10125 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 07/2010 
End 12/2011
 
Description Nuffield Department of Clinical Medicine, University of Oxford, Scientific Leadership Fellowship
Amount £300,000 (GBP)
Organisation University of Oxford 
Department Nuffield Department of Medicine
Sector Academic/University
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description OXBRC NIHR Fellowship
Amount £120,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 09/2011 
End 12/2013
 
Description Oxford Infection Theme, NIHR Biomedical Research Centre Programme
Amount £9,138,170 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2007 
End 03/2017
 
Description The Environmental REsistome: confluence of Human and Animal Biota in antibiotic resistance spread (REHAB)
Amount £1,009,083 (GBP)
Funding ID NE/N019989/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Wellcome Trust Clinical Fellowship
Amount £235,032 (GBP)
Funding ID 099423/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description Wellcome Trust Collaborative Award (CRyPTIC)
Amount £3,999,868 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2016 
End 03/2020
 
Description Wellcome Trust Value in People Award
Amount £53,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Improved Multilocus Sequence Typing (MLST) scheme for C. difficile 
Description An existing Multilocus Sequence Typing (MLST) scheme for C. difficile, that was critically limited in its typing resolution by its choice of relatively non-variable and difficult-to sequence target genes, has recently been modified in Oxford. This novel extended scheme currently achieves resolution at least equal to ribotyping and can be further refined using additional loci to achieve greater resolution. A paper describing this scheme has been recently been published by the Journal of Clinical Microbiology (see details below). The revised MLST scheme is now hosted on www.pubmlst.org. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, Golubchik T, Harding RM, Jeffery KJM, Jolley KA, Kirton R, Peto TE, Ress G, Stoesser N, Vaughan A, Walker SA, Young BC, Wilcox M, Dingle KE. Multilocus Sequence Typing of Clostridium difficile. Journal of Clinical Microbiology; 2010 Mar;48(3):770-8. Epub 2009 Dec 30. 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact We have used this technology to track C. difficile around hospitals in Oxfordshire (Plos Med 2012) 
URL http://pubmlst.org
 
Description Birmingham Regional Centre for Mycobacteriology 
Organisation University of Birmingham
Department Regional Centre for Mycobacteriology
Country United Kingdom 
Sector Public 
PI Contribution Sequencing samples, analysis and interpretation of results
Collaborator Contribution Large retrospective sample collection of M. tuberculosis. Substantial intellectual contribution to the project.
Impact Peer-reviewed publications.
Start Year 2009
 
Description Brighton and Sussex University Hospitals NHS Trust 
Organisation Brighton and Sussex University Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Sequencing samples, analysis and interpretation of results
Collaborator Contribution Have conducted a large observational study of S. aureus transmission in the Intensive Care Unit. Substantial intellectual contributions to the project.
Impact Publications submitted to peer-reviewed journals on study findings.
Start Year 2009
 
Description Leeds Teaching Hospitals NHS Trust 
Organisation Leeds Teaching Hospitals NHS Trust
Department Microbiology Department
Country United Kingdom 
Sector Hospitals 
PI Contribution Access to sequencing, analysis and interpretation of results
Collaborator Contribution Have contributed samples, have conducted a large retrospective study of C. difficile transmission, and a prospective study of Norovirus transmission. Have made a substantial intellectual contribution to the project.
Impact Publications in peer-reviewed journals.
Start Year 2009
 
Description Public Health England (PHE) 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution Access to sequencing data and research results.
Collaborator Contribution Access to S. aureus, Norovirus, C. difficile and TB samples and related epidemiological data. Staff to collect the samples and data and to ship this to Oxford and the Wellcome Trust Sanger Institute for sequencing. As well as intellectual input into the research. Member of REHAB Steering Committee
Impact Successful translation of next generation sequencing into public health microbiology
Start Year 2009
 
Description University of Virginia 
Organisation University of Virginia (UVa)
Department Department of Infectious Diseases and International Health
Country United States 
Sector Academic/University 
PI Contribution Undertook sequencing of over 400 carbapenamase-producing Enterebactereaciae and trained a clinical academic on sabbatical in bioinformatic and other analysis technique.
Collaborator Contribution Provided the most comprehensive consecutive sequential isolates representing transmission of multidrug resistant organisms in an intensive care unit
Impact None as yet. Partnership is multidisciplinary: including bioinformatics, statistical genetics, microbiology, infectious diseases and epidemiology
Start Year 2013
 
Description Wellcome Trust Sanger Institute 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Access to TB samples and epidemiological data
Collaborator Contribution Access to sequencing machines, staff to process TB samples on these machines and advice
Impact Whole genome sequencing of TB samples and advice. Successful translation of next generation sequencing into public health microbiology.
Start Year 2009
 
Title Pathogen whole genome sequencing for transmission and resistotyping 
Description Pathogen whole genome sequencing is under evaluation in S. aureus, C. difficile, Norovirus, M. tuberculosis and E. coli as a tool to enable tracking transmission of pathogens at a local, regional and national level. The main product is single nucleotide variant thresholds to rule in and rule transmission. The main source of funding is the ongoing MMM award. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact The project has demonstrated the feasibility of using whole genome sequencing to track infectious pathogens. It is now being evaluated in large scale studies. 
 
Description Art shows 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Anna Dumitriu is currently a Leverhulme Artist in Residence for the UKCRC (MMM) Modernising Medical Microbiology Consortium. Anna has created "The MRSA Quilt" that tells the story of MRSA (Methicillin Resistant Staphylococcus aureus) research and diagnosis through a textile work stained with MRSA bacteria (grown on chromogenic agar) as it undergoes a number of commonly used tests. The final work has been autoclaved and made safe. It has been made in collaboration with Dr John Paul, Dr James Price and has been shown in numerous exhibitions worldwide.

In 2014 Anna's exhibition "The Romantic Disease: An Artistic Investigation of Tuberculosis" has been shown in the UK and the Netherlands.

Relayed the research to the public by art.
Year(s) Of Engagement Activity 2011,2012,2013,2014
 
Description BRC Infection Theme talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact General talks to the public, health care professionals and researchers, on the BRC Infection Theme research, have been undertaken by Prof Derrick Crook in the John Radcliffe Hospital on S. aureus and C. difficile as part of the BRC Open Day (see separate output). About 50-100 people attend the talks.

n/a
Year(s) Of Engagement Activity 2010,2011
 
Description BRC open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 100-500 members of the public attend an annual BRC open day at the John Radcliffe Hospital. Every year we have a stand and activities to engage the public, as well as posters, video and a talk. Interactive exhibitions allow visitors to get hands on with technology and techniques, tackle experiments and even try their hand at investigating genetic relationships using Lego. Researchers from MMM were on hand throughout the day to answer questions on everything from microbiology techniques and infection control in hospitals, to how genetic sequencing is improving treatment. The open day and the research was reported by the BBC Oxford news.

n/a
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description Horton Foundation Trust 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Gave a named lecture titled 'Infection control: understanding how we can beat the bugs' to the Horton Foundation Trust staff

n/a
Year(s) Of Engagement Activity 2009
 
Description IORD 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presented information about our C. difficile research to the IORD group at the John Radcliffe Hopsital. This group includes patient and public representatives.

n/a
Year(s) Of Engagement Activity 2009,2010,2011
 
Description Infection detectives - mapping outbreaks in the 21st century 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public engagement lecture as part of the Oxford BRC series.

n/a
Year(s) Of Engagement Activity 2014
 
Description Mutamorphosis, Prague 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Just occurring so too early to have results yet

Stimulated a lot of interest from attendees
Year(s) Of Engagement Activity 2012
 
Description Newspaper article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This was titled 'cientists turn DNA detectives to track spread of hospital superbugs Oxford', 4th January 2010

n/a
Year(s) Of Engagement Activity 2010
 
Description Oxford London Lecture series, talk titled 'Gene Revolution' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Professor Peter Donnelly referred to the BRC Genomic research in his talk 'The Gene Revolution', Oxford London Lecture series, February 2011.

n/a
Year(s) Of Engagement Activity 2011
 
Description Response to requests from press for opinions 
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 Public/other audiences
Results and Impact Talked to 4 journalists on different occasions about genomics and infectious disease epidemiology

Coverage in Reuters, The Economist and local newspaper media
Year(s) Of Engagement Activity 2012,2017
 
Description S. aureus carriage study open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact All participants of the 'S. aureus Carriage Study', were invited to attend this day at the JR hospital

Explaining the research to the participants in the study
Year(s) Of Engagement Activity 2010
 
Description S. aureus research day in London 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact A S. aureus research day was held in London, with over a 100 attendees to discuss research options

n/a
Year(s) Of Engagement Activity 2011
 
Description Set up patient panels 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We circulated an advert inviting members of the public to join patient panels to inform all aspects of the groups' work. Over 100 individuals responded, and we held two open meetings where different aspects of the work were presented. Following this smaller groups have been set up to review and advise on different projects.

Members of the public have really valued the opportunity to get involved.
Year(s) Of Engagement Activity 2014,2016
 
Description UKCRC MMM workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact In 2009/10/11/12/13/14 we have run a UKCRC MMM workshop in Oxford to showcase the work arising from the UKCRC MMM consortium. Between 90-140 attendees attend each year, with diverse backgrounds who engage in discussions about how to translate whole genomic sequencing of pathogens for infection control and public health management.


Participants report gaining scientific knowledge and further ideas about how to translate genomics into clinical medicine
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Websites 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Contributed and prepared information for websites about the UK CRC Modernising Medical Microbiology Consortium and related research for the public. These websites are;
o UK CRC Modernising Medical Microbiology Consortium www.modmedmicro.ac.uk
o BRC Infection Theme http://oxfordbrc.nihr.ac.uk/infection/introduction-infection/


n/a
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013