Advancing therapeutics by exploiting single cell functional analysis
Lead Research Organisation:
University of Manchester
Department Name: Life Sciences
Abstract
The human body contains trillions of cells of many different lineages and functions, yet all are descended from the same fertilised embryo. Understanding their similarities and differences (cell 'heterogeneity') is a huge barrier to the design of all therapies that need to target particular rare cells within the body. There is an increasing need to analyse the basis of how varying groups of cells arise, as well as the set of characteristics (biomarkers) that mark them out as being different. This may be due to stable changes, or dynamic changes in these cells that lead to repeatedly fluctuating cell characteristics. It is important to understand when and whether each of these possible situations applies. This requires new technical advances that can better analyse these cells to show the basis of this variation and to identify, characterise and manipulate important groups of cells that underly disease processes.
We focus on characterising a group of rare cells (called circulating tumour cells, or CTCs) that give rise to drug-resistant cancers such as certain lung cancers and lead to relapse, and specific stem cells (cells with the potential to self-renew or differentiate) that can enable the regeneration of damaged tissues such as muscle, joints, skin and blood vessels.
To achieve a 'step-advance' in our ability to design therapies that can specifically target such specific 'progenitor' cell populations, we will establish a ground-breaking Single Cell Research Centre (SCRC) at the University of Manchester. Exploiting and innovating in the very latest single cell technologies, it will comprise a common integrated pipeline from receipt of clinical samples, to identification and characterisation of single target cells within each sample, to the design of treatments that target these specific cells. In this way, it will expedite progress to cell-based and 'personalised' treatments for some of the most challenging diseases and degenerative conditions of man.
Our vision for SCRC is that, within the first 3-5 years, the cellular 'signatures' will have been obtained and verified that will form the basis for potent new 'precision' therapies. The establishment of SCRC is thus particularly timely, given the rapidly growing numbers of people with degenerative conditions and untreatable cancers.
We focus on characterising a group of rare cells (called circulating tumour cells, or CTCs) that give rise to drug-resistant cancers such as certain lung cancers and lead to relapse, and specific stem cells (cells with the potential to self-renew or differentiate) that can enable the regeneration of damaged tissues such as muscle, joints, skin and blood vessels.
To achieve a 'step-advance' in our ability to design therapies that can specifically target such specific 'progenitor' cell populations, we will establish a ground-breaking Single Cell Research Centre (SCRC) at the University of Manchester. Exploiting and innovating in the very latest single cell technologies, it will comprise a common integrated pipeline from receipt of clinical samples, to identification and characterisation of single target cells within each sample, to the design of treatments that target these specific cells. In this way, it will expedite progress to cell-based and 'personalised' treatments for some of the most challenging diseases and degenerative conditions of man.
Our vision for SCRC is that, within the first 3-5 years, the cellular 'signatures' will have been obtained and verified that will form the basis for potent new 'precision' therapies. The establishment of SCRC is thus particularly timely, given the rapidly growing numbers of people with degenerative conditions and untreatable cancers.
Technical Summary
We will establish a Single Cell Research Centre (SCRC) to enable targeted cancer and regenerative medicine therapies. It will deliver a unified track from clinical tissue to cell selection, 'omics and imaging analysis, bioinformatics and e-Health.
Lab 1 will handle and store clinical tissues and cells. Laser capture microscopy will enable identification and isolation of single cells from tissues. Innovative microfluidics will enable live single cell selection, delivery and imaging (with Zeiss). Labs 2 and 3 will support multi-parameter flow cytometry. Lab 2 will house an ImageStreamX flow cytometer to image, quantify and select cells in suspension; Lab 3 will house a time of Flight Mass Cytometry (cyTOF) for single cell high speed flow cytometry with targeted mass spectrometry. We will innovate in imaging cyTOF for high spatial resolution of multiple proteins in cells within clinical tissues. Lab 4 will undertake single cell genomic/transcriptomic analysis using a Fluidigm C1 and Fluidigm IFC Controller HX, building on existing platforms. The SCRC - CRUK Manchester Institute oncology lab, fully integrated in 'omics technologies and informatics, is defining circulating tumour cells. it will use NextSeq 500 and Nanostring in on-site GCLP facilities for RNA/DNA analyses of patient CTCs, to enable transition to CTC-based diagnostics. Lab 5 will innovate in imaging single cells from clinical tissues, using confocal microscopy with multiphoton laser, 4D light sheet and luminescence imaging. Fluorescence correlation spectroscopy will enable dynamic quantification of molecules in cells. Lab 6 will integrate bioinformatics with network analysis and co-varying signals, infer regulatory interactions underlying differentiation, model gene expression dynamics, and develop models of cell processes from clinical samples. All data will be integrated with our Health e-Research Centre (HeRC), part of MRC-funded Farr Institute for Health Informatics.
Lab 1 will handle and store clinical tissues and cells. Laser capture microscopy will enable identification and isolation of single cells from tissues. Innovative microfluidics will enable live single cell selection, delivery and imaging (with Zeiss). Labs 2 and 3 will support multi-parameter flow cytometry. Lab 2 will house an ImageStreamX flow cytometer to image, quantify and select cells in suspension; Lab 3 will house a time of Flight Mass Cytometry (cyTOF) for single cell high speed flow cytometry with targeted mass spectrometry. We will innovate in imaging cyTOF for high spatial resolution of multiple proteins in cells within clinical tissues. Lab 4 will undertake single cell genomic/transcriptomic analysis using a Fluidigm C1 and Fluidigm IFC Controller HX, building on existing platforms. The SCRC - CRUK Manchester Institute oncology lab, fully integrated in 'omics technologies and informatics, is defining circulating tumour cells. it will use NextSeq 500 and Nanostring in on-site GCLP facilities for RNA/DNA analyses of patient CTCs, to enable transition to CTC-based diagnostics. Lab 5 will innovate in imaging single cells from clinical tissues, using confocal microscopy with multiphoton laser, 4D light sheet and luminescence imaging. Fluorescence correlation spectroscopy will enable dynamic quantification of molecules in cells. Lab 6 will integrate bioinformatics with network analysis and co-varying signals, infer regulatory interactions underlying differentiation, model gene expression dynamics, and develop models of cell processes from clinical samples. All data will be integrated with our Health e-Research Centre (HeRC), part of MRC-funded Farr Institute for Health Informatics.
Planned Impact
We will establish a ground-breaking Single Cell Research Centre (SCRC) at the University of Manchester in order to deliver a step-advance in the design of therapies to target specific 'progenitor' cell populations. It will exploit and advance single cell technologies (genomics/transcriptomics, flow cytometry, proteomics, imaging and bioinformatics. It will be a fully integrated SCRC pipeline from receipt of clinical samples, to identification and genomic and phenotypic characterisation of target cells, to technology innovation and design of treatments that target specific cells.
Our vision for SCRC is that, within the first 3-5 years, cellular 'signatures' will have been obtained and verified that will form the basis for potent precision therapies for many challenging diseases and degenerative conditions.
Biomedical scientists
SCRC will deliver essential insights into cell heterogeneity and the very nature of multicellularity, and thus both how tissues form and can be remodelled and how mutations can cause drug-resistant cancers.
Realising the benefits: In Manchester, our research will be translated through Manchester Academic Health Science Centre (MAHSC) Experimental Medicine. Nationally, SCRC is a founding partner of (i) the Northern Single Cell Consortium (with Newcastle and Leeds) which will maximise added value by shared technology innovation and access to clinical material; (ii) the UK cyTOF user group which will work together to advance this new technology. SCRC is strongly linked with national CRUK collaborators and has UK Regenerative Medicine Platform hubs partnerships. We will share SCRC advances with regional colleagues in the Mercia Stem Cell Alliance (http://www.msca.ls.manchester.ac.uk/). Internationally, we will extend existing worldwide collaborations in cancer and regenerative medicine.
Patients
SCRC will allow characterisation of rare circulating tumour cells that give rise to drug-resistant populations, for directed early therapy to block relapse and metastasis, and the selection, expansion and characterisation of stem/progenitor cells to underpin repair and regeneration of muscle, joints, skin and vasculature.
Realising the benefits: Within its first 3-5 years, these cellular signatures will lead to targeted cell-based precision therapies.
Biopharma
Single cell research is urgently needed to inform the design and delivery of cell-based biologics. This need is highlighted by the many industrial partnerships we have established for SCRC. As an example, Zeiss is committing £428K to SCRC in order to work together in partnership to innovate in single cell imaging, and in microfluidics of single cells, on top of ~£1m for our Systems Microscopy Centre. Our SCRC capabilities will also be integrated with N8 which has >240 industrial partners.
Realising the benefits: University of Manchester Intellectual Property (UMIP) and the CRUK Manchester Institute's Drug Discovery Unit will support commercialisation of our single cell advances towards therapies targeting cells that give rise to drug-resistant cancers and stem cells for tissue regeneration. We will work towards a spin-out to market single cell discoveries.
Graduates
Graduate training of future UK leaders is a priority of the University of Manchester. Our EPSRC & MRC Centre for Doctoral Training in Regenerative Medicine (>30 industrial partners) will be linked to SCRC to ensure training in single cell technologies. Other PhD programmes that will greatly benefit from SCRC include CRUK, BBSRC DTP and Wellcome Trust and BHF 4-year programmes.
Realising the benefits: Major impact will arise by graduate training in the latest technologies to analyse and exploit cell heterogeneity.
General Public
Public engagement is a top University priority. .
Realising the benefits: SCRC will be a powerful platform to inform the public about our translational research, through NowGen and Faculty activities (see also Communications)
Our vision for SCRC is that, within the first 3-5 years, cellular 'signatures' will have been obtained and verified that will form the basis for potent precision therapies for many challenging diseases and degenerative conditions.
Biomedical scientists
SCRC will deliver essential insights into cell heterogeneity and the very nature of multicellularity, and thus both how tissues form and can be remodelled and how mutations can cause drug-resistant cancers.
Realising the benefits: In Manchester, our research will be translated through Manchester Academic Health Science Centre (MAHSC) Experimental Medicine. Nationally, SCRC is a founding partner of (i) the Northern Single Cell Consortium (with Newcastle and Leeds) which will maximise added value by shared technology innovation and access to clinical material; (ii) the UK cyTOF user group which will work together to advance this new technology. SCRC is strongly linked with national CRUK collaborators and has UK Regenerative Medicine Platform hubs partnerships. We will share SCRC advances with regional colleagues in the Mercia Stem Cell Alliance (http://www.msca.ls.manchester.ac.uk/). Internationally, we will extend existing worldwide collaborations in cancer and regenerative medicine.
Patients
SCRC will allow characterisation of rare circulating tumour cells that give rise to drug-resistant populations, for directed early therapy to block relapse and metastasis, and the selection, expansion and characterisation of stem/progenitor cells to underpin repair and regeneration of muscle, joints, skin and vasculature.
Realising the benefits: Within its first 3-5 years, these cellular signatures will lead to targeted cell-based precision therapies.
Biopharma
Single cell research is urgently needed to inform the design and delivery of cell-based biologics. This need is highlighted by the many industrial partnerships we have established for SCRC. As an example, Zeiss is committing £428K to SCRC in order to work together in partnership to innovate in single cell imaging, and in microfluidics of single cells, on top of ~£1m for our Systems Microscopy Centre. Our SCRC capabilities will also be integrated with N8 which has >240 industrial partners.
Realising the benefits: University of Manchester Intellectual Property (UMIP) and the CRUK Manchester Institute's Drug Discovery Unit will support commercialisation of our single cell advances towards therapies targeting cells that give rise to drug-resistant cancers and stem cells for tissue regeneration. We will work towards a spin-out to market single cell discoveries.
Graduates
Graduate training of future UK leaders is a priority of the University of Manchester. Our EPSRC & MRC Centre for Doctoral Training in Regenerative Medicine (>30 industrial partners) will be linked to SCRC to ensure training in single cell technologies. Other PhD programmes that will greatly benefit from SCRC include CRUK, BBSRC DTP and Wellcome Trust and BHF 4-year programmes.
Realising the benefits: Major impact will arise by graduate training in the latest technologies to analyse and exploit cell heterogeneity.
General Public
Public engagement is a top University priority. .
Realising the benefits: SCRC will be a powerful platform to inform the public about our translational research, through NowGen and Faculty activities (see also Communications)
Publications
Kitchen GB
(2020)
The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia.
in Proceedings of the National Academy of Sciences of the United States of America
Kitchen GB
(2021)
The histone methyltransferase Ezh2 restrains macrophage inflammatory responses.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Lane JM
(2016)
Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank.
in Nature communications
Lloyd K
(2020)
Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease
in Disease Models & Mechanisms
Louise Hunter A
(2020)
Adipocyte REVERBa dictates adipose tissue expansion during obesity
Manning CS
(2019)
Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis.
in Nature communications
Martin K
(2016)
PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis.
in Nature communications
Martín-Sánchez F
(2016)
Inflammasome-dependent IL-1ß release depends upon membrane permeabilisation.
in Cell death and differentiation
Matthews LC
(2015)
Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy.
in Proceedings of the National Academy of Sciences of the United States of America
McCaffrey JC
(2017)
Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1.
in Scientific reports
McDonnell SJ
(2019)
ER stress-linked autophagy stabilizes apoptosis effector PERP and triggers its co-localization with SERCA2b at ER-plasma membrane junctions.
in Cell death discovery
McNamara AV
(2016)
Role of Estrogen Response Element in the Human Prolactin Gene: Transcriptional Response and Timing.
in Molecular endocrinology (Baltimore, Md.)
Mesquita B
(2017)
Molecular analysis of single circulating tumour cells following long-term storage of clinical samples.
in Molecular oncology
Minas G
(2020)
Multiplexing information flow through dynamic signalling systems.
in PLoS computational biology
Minshawi F
(2019)
Human TNF-Luc reporter mouse: A new model to quantify inflammatory responses.
in Scientific reports
Mohamed TMA
(2016)
The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy.
in Nature communications
Mohan S
(2020)
Profiling of Circulating Free DNA Using Targeted and Genome-wide Sequencing in Patients with SCLC.
in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Momiji H
(2019)
Disentangling juxtacrine from paracrine signalling in dynamic tissue.
in PLoS computational biology
Morgan DJ
(2016)
Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production.
in Scientific reports
Movahedi M
(2016)
Risk of Incident Diabetes Mellitus Associated With the Dosage and Duration of Oral Glucocorticoid Therapy in Patients With Rheumatoid Arthritis.
in Arthritis & rheumatology (Hoboken, N.J.)
Naseeb S
(2016)
Widespread Impact of Chromosomal Inversions on Gene Expression Uncovers Robustness via Phenotypic Buffering.
in Molecular biology and evolution
Ninova M
(2016)
MicroRNA evolution, expression, and function during short germband development in Tribolium castaneum.
in Genome research
Pariollaud M
(2018)
Circadian clock component REV-ERBa controls homeostatic regulation of pulmonary inflammation.
in The Journal of clinical investigation
Pelzer D
(2021)
Foxm1 regulates neural progenitor fate during spinal cord regeneration.
in EMBO reports
Phillips NE
(2017)
Identifying stochastic oscillations in single-cell live imaging time series using Gaussian processes.
in PLoS computational biology
Poolman TM
(2019)
Rheumatoid arthritis reprograms circadian output pathways.
in Arthritis research & therapy
Ptushkina M
(2017)
A non-transcriptional role for the glucocorticoid receptor in mediating the cell stress response.
in Scientific reports
Ray D
(2016)
Endocrinology: Adult and Pediatric
Reynolds JA
(2016)
Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus.
in Scientific reports
Rutkowski D
(2015)
An abnormality in glucocorticoid receptor expression differentiates steroid responders from nonresponders in keloid disease.
in The British journal of dermatology
Smyllie NJ
(2016)
Visualizing and Quantifying Intracellular Behavior and Abundance of the Core Circadian Clock Protein PERIOD2.
in Current biology : CB
Strehl C
(2016)
Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force.
in Annals of the rheumatic diseases
Taylor KM
(2018)
The tobacco carcinogen NNK drives accumulation of DNMT1 at the GR promoter thereby reducing GR expression in untransformed lung fibroblasts.
in Scientific reports
Wang H
(2019)
Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.
in Nature communications
West AC
(2017)
Misalignment with the external light environment drives metabolic and cardiac dysfunction.
in Nature communications
Yang N
(2020)
Hypoxia regulates GR function through multiple mechanisms involving microRNAs 103 and 107.
in Molecular and cellular endocrinology
Yang SH
(2019)
ZIC3 Controls the Transition from Naive to Primed Pluripotency.
in Cell reports
Zhang Z
(2019)
Genome-wide effect of pulmonary airway epithelial cell-specific Bmal1 deletion.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Zhuang X
(2019)
The circadian clock components BMAL1 and REV-ERBa regulate flavivirus replication.
in Nature communications
| Description | BBSRC EPSRC COVID rapid response grants expert reviewer |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Reviewing rapid response grants intended to make a difference in UK COVID response within 18 months |
| Description | Babraham Institute Scientific Advisory Committee |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| URL | http://www.babraham.ac.uk/about-us/governance-and-funding |
| Description | Contribution to the Manchester BRC award 2017 |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Impact | The single cell facility provides training, supervision, and access to equipment for the new Manchester BRC. The core is an essential part of the BRC allowing investigators to apply appropriate technology to human samples. |
| Description | Member and deputy chair of UKRI Future Leaders Fellowship panel involvement in 3 sift and 2 interview committees from 2018 - 2021) |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Award of Fellowships for training of future leaders |
| URL | https://www.ukri.org/funding/funding-opportunities/future-leaders-fellowships/ |
| Description | Member of BBSRC critical friends group in Bioimaging |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | Member of MRC Discovery Awards Committee |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | Member of MRC Human Cell Atlas Panel |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| URL | https://mrc.ukri.org/funding/browse/hca/human-cell-atlas/ |
| Description | Member of MRC Methodology Panel |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| URL | https://mrc.ukri.org/about/our-structure/research-boards-panels/methodology-research-programme-panel... |
| Description | Member of MRC Sjills Fellowship Panel |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Appointment of MRC skills dellowships and award of institutional skills dellowships grants to develop the careers and training of early career researchers to March 2020 |
| URL | https://mrc.ukri.org/skills-careers/fellowships/skills-development-fellowships/ |
| Description | Member of joint research council tecnology touching life advisory group |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| URL | https://www.ukri.org/research/themes-and-programmes/technology-touching-life/ |
| Description | NERC COVID and environment network |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | Roving panel member for EPSRC CDT interviews |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| URL | https://epsrc.ukri.org/skills/students/centres/2018-cdt-exercise/ |
| Description | A "Molecular Imaging (FLIM/FCS) toolbox" to investigate molecular interactions and activation in super-resolution and widefield mode |
| Amount | £255,000 (GBP) |
| Funding ID | 202923/Z/16/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 11/2016 |
| End | 10/2020 |
| Description | An upright confocal microscope for multidisciplinary research |
| Amount | £282,781 (GBP) |
| Funding ID | BB/R014361/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2018 |
| End | 04/2019 |
| Description | MRC project grant |
| Amount | £675,328 (GBP) |
| Funding ID | MR/P011853/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 02/2020 |
| Description | NIHR Biomedical research centre |
| Amount | £25,000,000 (GBP) |
| Funding ID | Manchester BRC 2017-2022 |
| Organisation | National Institute for Health Research |
| Department | NIHR Biomedical Research Centre |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 03/2022 |
| Description | Quantification of protein dynamics driving the circadian clock |
| Amount | £610,426 (GBP) |
| Funding ID | BB/P017347/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 12/2017 |
| End | 11/2020 |
| Description | Temporal manipulation of genetic circuits in single cells |
| Amount | £122,019 (GBP) |
| Funding ID | BB/P027040/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 09/2018 |
| Description | Wellcome Trust 4-year PhD Programme in Quantitative and Biophysical Biology |
| Amount | £2,555,000 (GBP) |
| Funding ID | 108867/B/15/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2017 |
| End | 01/2023 |
| Description | clinical research fellowship |
| Amount | £269,390 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2016 |
| End | 07/2019 |
| Description | programme grant |
| Amount | £2,000,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 08/2022 |
| Description | research grant |
| Amount | £844,160 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 02/2020 |
| Title | Data from: Dynamic NF-?B and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation |
| Description | |
| Type Of Material | Database/Collection of data |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Title | algorithm for single cell genomics |
| Description | The primary focus of computational (including use of the MRC fundedcomputation and storage hardware) and bioinformatics (MRC funded Post Doc) aspects of this grant has been the development of novel analysis pipelines that reduce NGS based error and make single cell analysis more reliable. As a first step in this process we have repurposed techniques from transcript assembly to exploit the redundancy that result from sequencing multiple PCR products from each initial starting DNA fragment. This allows us to identify and correct both PCR and imaging errors in Illumina deep sequencing data. Our algorithm reduces background noise in the normal control samples and eliminates false positives from the tumour samples. Together these lead to significant improvement in mutation calling accuracy. The code is highly parallelised and makes use of a MapReduce framework to run efficiently on HPC hardware, such as that provided through the SCRC. The first manuscript from this research is in final stages of drafting. |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | We intend to extend these approaches to allow us to align and assemble data from all the CTCs from a patient simultaneously, alongside patient matched normal controls. This exploits the evolutionary hierarchy resulting from all cells in the dataset being ultimately derived from the same ancestor cell. In this way, the algorithm can, for each CTC, 'borrow' information from the other CTCs in the set, improving the overall signal to noise ratio. We expect this to improve mutation-calling accuracy and to be substantially faster than other techniques. When used in a clinical setting, reducing processing time is particularly beneficial. |
| Description | Carl Zeiss |
| Organisation | Carl Zeiss AG |
| Country | Germany |
| Sector | Private |
| PI Contribution | We have advised Zeiss on trends in bioimaging since 1996. We have provided new data and tested prototype equipment. We have spoken at Zeiss organised meetings. We have given them an opportunity to display Zeiss equipment at our training courses. We have organised symposia that have been supported by Zeiss. We have held expert discussion meetings to review microscopy trends that have involved senior Zeiss staff |
| Collaborator Contribution | Zeiss have made a cash contribution to training courses (received) of £16,250. Zeiss estimate of total value of in-kind staff time for collaboration, training courses and other meetings (including visits of teams from Germany) ?25,000. In addition, Zeiss have also committed over £30,000 in cash and ~£80000 in in kind staff for future training meetings and collaborative visits. Zeiss helped to design the new Systems Microscopy Centre in Manchester and made a 45% discount (value ?350k) for the purchase of equipment in 2011. Zeiss are a formal MICA partner on both Liverpool and Manchester awards from the MRC/BBSRC New Microscopy Initiative. In the award to Manchester they have made a contribution of £614,314 in staff time, development costs and equipment contribution. This involves FCS (developed during this project), luminescence fluorescence imaging, light sheet microscopy and SOFI super-resolution imaging. More recently Zeiss have made a further contribution to our new clinical single cell centre. This includes over £400k in equipment discounts and £25k in cash contribution to training and symposia. Over the years the Zeiss contributions have included them helping us with public understanding of science exhibitions where they loaned equipment, provided support for professional poster preparation and used their delivery services to transport our exhibit materials and equipment to the exhibition venues. This included an exhibition in Buckingham Palace in 2006. Zeiss have sponsored 2-3 meetings per year in Manchester. In 2016 this included a session on light sheet imaging and a session on new confocal imaging technologies. In 2017 they have sponsored an image analysis daya and will sponsor a single cell biology workshop. IN 2021-22 they provided support for the traing of tw PhD students including firect training, access to microscopy facilities and funds to attend an external course (delayed by Covid to September 2022) |
| Impact | Annual training courses MICA collaborative MRC grant MICA collaboration on new single cell centre The relationship with Zeiss has been two way. We have been given the opportunity to be early adopters f new technology and to feedback idease for improvement. We receive very favourable deals on microscope purchases and maintenance contracts. Specific areas of successful collaboration lie in improvements to higher throughput live cell imaging using the confocal microscopes; optimisation of truly dark microscopes for quantitative luminescence imaging and the development of FCS. Multiple workshops organised (2-3 per yeat) |
| Description | andrew mc donald |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | andrew is developing high resolution analysis of lung immune cells. in human asthma. |
| Collaborator Contribution | he is using the new kit. |
| Impact | none yet |
| Start Year | 2016 |
| Description | daniel davis |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | daniel is working on The nanoscale organisation of naïve and regulatory T cell surfaces in juvenile idiopathic arthritis patients with wellcome support |
| Collaborator Contribution | he is using single cell sequencing approaches. |
| Impact | none yet |
| Start Year | 2016 |
| Description | elaine bignell |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | elaine is working on Antifungal potency of the airway epithelium in health and disease: a single cell approach with wellcome support |
| Collaborator Contribution | she is using the kit with wellcome funding the project. |
| Impact | none yet |
| Start Year | 2016 |
| Description | hannah durrington |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Hannah is working on Applying single cell technology to Steroid Resistant Asthma: identifying the role of circadian mechanisms in Th17 cells. with wellcome support |
| Collaborator Contribution | she is using FACS and single cell genomics |
| Impact | none yet |
| Start Year | 2017 |
| Description | john blaikley |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | John is working on Does single cell biological noise conceal circadian timing information? with MRC and wellcome support |
| Collaborator Contribution | he is using the kit, with wellcome and MRC salary support. |
| Impact | none yet |
| Start Year | 2016 |
| Description | sebastian viatte |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Seb is working on Monocyte heterogeneity in health and inflammatory disease with wellcome support |
| Collaborator Contribution | he is using the kit, with funding from wellcome |
| Impact | none yet |
| Start Year | 2016 |
| Description | School Visit, Altrincham Girls School |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Dean Jackson - Advice and practice interviews for students |
| Year(s) Of Engagement Activity | 2016 |
| Description | School visit (Liverpool Life Sciences, University Technical College) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Liverpool Life Sciences UTC is the first school in the UK specialising in Science and Health Care for 14 to 19 year olds. Talk at Liverpool Life Sciences UTC conference on "How Organisms Age" |
| Year(s) Of Engagement Activity | 2016 |
| Description | School visit, (Manchester Grammar School) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Dean Jackson Feb 2017, Science Fair judge for student projects |
| Year(s) Of Engagement Activity | 2017 |
| Description | school visit (Xaverian College) |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Dean Jackson - STEM ambassador |
| Year(s) Of Engagement Activity | 2016 |