The Oxford Single Cell Biology Consortium

Lead Research Organisation: University of Oxford
Department Name: Weatherall Inst of Molecular Medicine

Abstract

Limitations in our ability to study the biology of individual cells has historically been a major obstacle, inhibiting our understanding of some fundamental problems in biomedical research such as the onset of cancer, the immunological determination of 'self', and the ability to purify tissue-specific stem cells. Recent developments in the field of single cell genomics is now opening up unprecedented opportunities to uncover individual cell differences within such complex tissues. The objective of the proposed research is to establish a Centre of Single Cell Biology (CSCB) in Oxford that will take advantage of this pioneering technology in order to improve the diagnosis, stratification and treatment of a wide variety of human diseases. The CSCB will be coordinated by the Weatherall Institute of Molecular Medicine (WIMM) which has a long-standing technical and strategic expertise in single cell research. The capital development will be used to enhance single-cell research capabilities across the campus in a number of key areas:

Data analysis: Single cell genomics studies generate an enormous amount of data, with consequent challenges for the analysis and correct interpretation of these complex data sets. We propose to establish an entirely new research group devoted to the development of novel approaches for the statistical and computational analysis of single cell biology data and its application to medicine. This group will be located in new space to be developed at the WIMM, but jointly led by leading scientists across the campus. This new initiative will provide a clear pathway to integrate multidisciplinary, scientific and technical innovation in single cell biology research across the Oxford University Campus and to provide ground-breaking applications of this approach to medicine in the UK.

State of the art facilities: We will develop single cell biology research laboratories to allow practical access for research groups conducting these studies across the campus. These facilities will house cutting edge technology platforms and, importantly, will create "ultra clean" environments to carry out single cell experiments. This is necessary as very low levels of background "contamination" make the interpretation of single cell experiments challenging.

Projects: As a specific example of how this technology will be applied to address fundamental problems in human disease, the lead programme of research in the CSCB will be focused on inherited disorders of red blood cells. These disorders are amongst the most common of all human genetic diseases worldwide with an estimated 300,000 affected babies born each year and a total number of affected UK patients of ~16,000. Currently, severely affected individuals are treated with supportive care, including lifelong blood transfusion and treatment to prevent accumulation of iron in the body, which is costly, burdensome, and gives rise to serious, long-term clinical complications. Here we propose to "genetically repair" the damaged genes in the patient's own blood stem cells. Single cell biology will be central to this project: First, single cell genomic approaches will be used to identify the blood stem cells which are the best target for this therapy. Second, single-cell analysis will be used to assess the safety and efficiency of this approach. This programme, focussed on developing an entirely new approach to treating the haemoglobinopathies, has the potential to transform the treatment of all human genetic diseases that can be cured by stem cell transplantation. This is one example of many projects in development across the campus which will be greatly facilitated by the development of improved single cell research capabilities.

Oxford is in a very strong position to take a world-leading role in the up-and-coming area of Single Cell Biology and application of these technologies to important clinical and basic biology questions across the University and beyond.

Technical Summary

We will establish a Centre of Single Cell Biology in Oxford that will improve the diagnosis, stratification and treatment of a wide variety of human diseases. The Centre will be coordinated from the Weatherall Institute of Molecular Medicine (WIMM), which has established technical and strategic expertise in single cell research, and will share experimental and analytical best practice with two linked experimental sites, at the Wellcome Trust Centre for Human Genetics (WTCHG) and the MRC Functional Genomics Unit (FGU). The Centre's lead project will use a combination of single cell genomic analysis and functional assays at the clonal level to refine current stem/progenitor/effector cell purification strategies for transplantation with the ultimate aim of developing entirely new approaches to therapy in blood diseases. This single cell expertise and platforms in haematopoiesis will be used as a paradigm to develop parallel cutting-edge translational programmes for other inherited and acquired human diseases (such as in Immunology, Cancer Biology and Neurology).

There are considerable computational and statistical challenges involved in state-of-the-art analysis and modelling of single cell data. To address these, the experimental single cell studies at the WIMM will interlink with the activities of the internationally renowned computational and statistical biologists from FGU and WTCHG. Specifically, we will establish an entirely new research group devoted to develop and apply novel approaches to the statistical and computational analysis of single cell biology and its application to medicine. This new initiative will provide a clear pathway to integrate multidisciplinary, scientific and technical innovation in single cell biology research across the Oxford University Campus and to provide ground-breaking applications of this approach to medicine in the UK.

Planned Impact

This research will have a clear beneficial impact well beyond the immediate professional circle carrying out similar research. For example:

Academic Impact: As outlined in the academic beneficiaries statement, there is clear potential for academic impact in a number of key areas, including, but not limited to, computational analysis of complex single cell data sets, development of new techniques for single cell analysis, application of genomic engineering techniques for therapeutic use, understanding of ageing, understanding cell fate decisions and refining diagnosis and stratification of disease.

Beneficiaries in the commercial private sector: We have established a strategic partnership with Fluidigm, the world leader in microfluidic devices for single cell analysis. This partnership will include access to novel technology platforms and a dynamic and mutually beneficial sharing of information. Fluidigm will also co-sponsor our planned single-cell annual data analysis workshop, again, with clear potential for mutual benefit. This partnership will help to secure further inward investment and gain access to cutting-edge technologies.

Contribution to the nation's health: Our overarching goal is to accelerate the recent advances in single cell technologies though to patient benefit. There are a number of key areas where this might be achieved. First, improved understanding of complex tissues, for example, through refined stem cell purification strategies has clear potential to improve outcome of stem cell transplantation procedures, which are still associated with considerable morbidity and mortality. Second, the application of single cell genomic approaches to help accelerate the development of techniques to "genetically repair" inherited disorders of blood cells has clear potential to transform the application of single cell genomics into a major clinical research activity, with broad cross-disciplinary applicability. The concept of correcting inherited genetic abnormalities clearly has far reaching potential to contribute to improvement in the nation's health. Third, single cell genomics approaches will help to further develop and refine diagnostic and stratification approaches in human disease and thereby personalize patient management, for example though a deeper understanding of clonal complexity of tumour propagating cancer stem cells, and monitoring of these cells throughout the disease course and impact of therapy. Finally, single cell analysis offers the potential to provide unique insights into the ageing process at the single (stem) cell level, and how this affects tissue function and contributes to age-dependent disease (tissue degeneration, cancer).

Dissemination of knowledge: As outlined in the communication plan, the lead investigators have considerable experience of disseminating scientific research findings across academic peers and more broadly with the public, including schools, and also for inspiring young potential scientists. A number of specific initiatives will be developed to help disseminate research conducted by the Centre of Single Cell Biology, including a new website and an annual single cell workshop.

New processes: Techniques in single cell technology are likely to develop rapidly over the coming years. If funded, the Oxford Centre of Single Cell Biology will place the MRC at the forefront of these developments. As an example, the WIMM introduced the first Fluidigm C1 microfluidics platform in Europe in 2012. This new technology allows capture of single primary cells and the interrogation of RNA and DNA content by multiplex PCR or through whole transcriptome/genome analysis, all at the single cell level. This technology is now being introduced across a number of centres in the UK. We would anticipate that the Oxford Centre of Single Cell Biology would lead the way with similar groundbreaking technological advances in the future.

Publications

10 25 50
 
Description CRUK Senior Cancer Research Fellowship
Amount £2,426,011 (GBP)
Organisation Hub at the MRC/CRUK/BHF Clinical Trial Service Unit 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 05/2025
 
Description Capital Prioritisation for MRC Units and Institutes
Amount £300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 04/2019
 
Description Clinical Research Training Fellowship (Nicholas Fordham): The Role of EZH2 mutation in paediatric myelodysplasia
Amount £276,500 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2020
 
Description ELSTAR Small Scale
Amount £7,980 (GBP)
Organisation Elstar Therapeutics Inc. 
Start 01/2018 
End 12/2018
 
Description ELSTAR: Large Scale
Amount £777,818 (GBP)
Organisation Elstar Therapeutics Inc. 
Start 01/2019 
End 01/2022
 
Description Exploring mechanisms of enhancer action in erythropoiesis
Amount £250,000 (GBP)
Funding ID 209181 
Organisation Sir Henry Dale Fellowships 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2022
 
Description Genome and Transcriptome analysis of patients with rare stem and Myeloid disorders
Amount £65,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 07/2017 
End 06/2019
 
Description Identification and therapeutic targeting of the abnormal bone marrow stromal cells underlying bone marrow fibrosis in myelofibrosis
Amount £216,000 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2018 
End 10/2021
 
Description Impact of Leukaemia-Associated Loss of Function of Epigenetic Regulators on Distinct Haematopoietic Stem Cells (Co-applicant with Sten Eirik Jacobsen)
Amount £266 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2019
 
Description MRC CRI: The Oxford Single Cell Biology Consortium (co-investigator)
Amount £4,975,434 (GBP)
Funding ID MR/M00919X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2015 
End 04/2016
 
Description MRC Discovery Award (co-investigator)
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2016 
End 04/2019
 
Description MRC Discovery Award - Identification and characterisation of cellular targets for genome editing of foetal haematopoietic stem/progenitor cells
Amount £56,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2016 
End 08/2017
 
Description MRC Proximity to discovery Industry Engagement Fund
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 07/2016
 
Description Measuring DNA damage in Single Cells Using a Novel High Throughput Genomic Assay
Amount £15,000 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2018
 
Description Proximity to Discovery Industry Engagement
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 07/2016
 
Description Rosetrees Trust
Amount £40,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 01/2017
 
Description The Oxford Single Cell Biology Consortium
Amount £399,179 (GBP)
Funding ID MR/M00919X/1 
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 05/2016 
End 03/2019
 
Description The Oxford Single Cell Biology Consortium
Amount £4,975,434 (GBP)
Funding ID MR/M00919X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2015 
End 09/2016
 
Description The single cell immunological landscape of Juvenile Myelomonocytic Leukaemia
Amount £12,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 07/2019
 
Description The single cell immunological landscape of Juvenile Myelomonocytic Leukaemia
Amount £36,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 07/2019
 
Description Tracking the origins of post-transplant myelofibrosis relapse at single cell level
Amount £240,000 (GBP)
Organisation Hub at the MRC/CRUK/BHF Clinical Trial Service Unit 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description Unravelling signatures of clonal response, resistance and evolution of high-risk essential thrombocythaemia at single-cell resolution
Amount £261,848 (GBP)
Funding ID MR/S001190/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2018 
End 08/2021
 
Description Wellcome Trust Postdoctoral Research Training Fellowship for Clinician
Amount £248,107 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 08/2016 
End 07/2019
 
Description Molecular Haematology Unit seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact A talk regarding the work on single-cell systems biology carried out by the company to date. This sparked a good debate between the presenter and the audience.
Year(s) Of Engagement Activity 2016,2017,2018,2019
 
Description Science Career Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact A career talk to students and post-docs involving working in the USA
Year(s) Of Engagement Activity 2016