Single Cell-Level Functional Proteomics and Genomics exemplified in Cancer and Immunology
Lead Research Organisation:
King's College London
Department Name: Immunology Infection and Inflam Diseases
Abstract
We propose to create a state-of-the-art facility for studying the function and nature of single human cells involved in disease processes, combining the latest developments in cell isolation and analysis of genes and proteins. The system will be developed in collaboration with industrial partners, and exemplified via cohesive research programmes in immune-mediated disease, regenerative medicine and cancer. These provide distinct challenges but have significant cross-talk, making them ideal for exploring the full potential of the facility. For example, cancer growth and spread are characterised by variants of cells from "self" developing ways of evading the immune system; whilst autoimmune and inflammatory disease (diabetes, arthritis) arises because the immune system targets self. Moreover, in transplantation and regenerative medicine, responses to self and neo-self cells are a major barrier to graft acceptance. Through the synergistic development of new technology platforms that analyse complex cellular processes in cancer, inflammation, autoimmunity and transplantation on a single site that houses all of the relevant expertise and related infrastructure already, we aim to resolve complex disease processes at the single cell level. The expertise and methodologies brought together by the consortium create an opportunity to share technological benefits in an overlapping set of systems. Our goal is that the Single Cell-Level Functional Proteomics and Genomics system, once developed, will accelerate clinically important discoveries about disease processes, their treatment and monitoring, and act as a model for the establishment of similar facilities in centres of excellence across a range of clinical arenas.
Technical Summary
We propose to create a state-of-the-art facility for single cell functional analysis, combining the latest developments in cell sorting with microfluidics-based cellomics, optical proteomics and single cell expression and genomics analysis. The expertise and methodologies brought together by the consortium create an opportunity to share technological benefits in an overlapping set of systems. The approach is innovative in being highly enabling for research across multiple clinical arenas; we will be operative in relation to multiple source materials (tissue, blood, culture) and levels of abundance. We will exploit the power of mass cytometry (CyTOF already in place) to maximize pre-sort capability, with the bonus of higher purity and data focusing. The modular design presents a challenge in terms of ensuring that platforms can be linked; but offers the considerable advantage of not being locked into a single commercial technology platform that runs the risk of scientific and budgetary constraint. The strategy thus increases our research possibilities whilst reducing the overall risk. The system will be developed in collaboration with industry, and exemplified via cohesive research programmes in immune-mediated and infectious disease, regenerative medicine and cancer. These provide distinct challenges but have significant cross-talk, making them ideal for exploring the full potential of the facility. For example, cancer growth and dissemination are characterised by immune evasion and tolerance to self/neo-antigens, whereas autoimmunity is distinguished by failure of self-antigenic tolerance, and the transfer of heterologous and autologous cells in regenerative medicine can engender responses that oppose tolerance induction. Through the synergistic development of new technology platforms that analyse complex cellular processes in cancer, inflammation, autoimmunity and alloimmunity on one site, we aim to resolve complex disease processes at the single cell level.
Planned Impact
Potential beneficiaries, beyond the academic, include clinicians managing complex diseases and their patients; policy makers at national and international level; commercial entities.
Clinicians managing complex diseases and their patients, are expected to benefit from our discovery science, which offers the opportunity for new disease insights, biomarkers and therapeutic avenues.
Policy makers and commercial entities will benefit from the success of our platform, should single cell analyses provide superior mechanistic, diagnostic and monitoring insights over conventional approaches, leading to shifts in technology development and deployment.
Acceleration of UK-based technology platforms such as these offers a competitive edge, leading to high-profile publications and international recognition, development of unique expertise, and knock-on effects on 3rd sector technologists based in the UK.
We would expect to see some or all of the above benefits emerging in a 3-7 year time-frame post-award.
Clinicians managing complex diseases and their patients, are expected to benefit from our discovery science, which offers the opportunity for new disease insights, biomarkers and therapeutic avenues.
Policy makers and commercial entities will benefit from the success of our platform, should single cell analyses provide superior mechanistic, diagnostic and monitoring insights over conventional approaches, leading to shifts in technology development and deployment.
Acceleration of UK-based technology platforms such as these offers a competitive edge, leading to high-profile publications and international recognition, development of unique expertise, and knock-on effects on 3rd sector technologists based in the UK.
We would expect to see some or all of the above benefits emerging in a 3-7 year time-frame post-award.
People |
ORCID iD |
Mark Peakman (Principal Investigator) |
Publications
Alhadj Ali M
(2017)
Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.
in Science translational medicine
Aluko J
(2018)
Semi-autonomous real-time programmable fluorescence lifetime segmentation with a digital micromirror device.
in Optics express
Levitt JA
(2020)
Quantitative real-time imaging of intracellular FRET biosensor dynamics using rapid multi-beam confocal FLIM.
in Scientific reports
Mason G
(2015)
Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry
in The Journal of Immunology
Poland SP
(2016)
New high-speed centre of mass method incorporating background subtraction for accurate determination of fluorescence lifetime.
in Optics express
Rocca FM
(2016)
Real-time fluorescence lifetime actuation for cell sorting using a CMOS SPAD silicon photomultiplier.
in Optics letters
Zhao Y
(2018)
Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue
in Nature Communications
Description | Cancer Research UK Multidisciplinary Project Award |
Amount | £500,000 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2016 |
End | 09/2019 |
Title | Development of new advanced microscopy tools |
Description | Development of new advanced microscopy tools. Significant improvement in imaging throughput of fluorescence lifetime imaging and novel methods development. Key papers are in preparation. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Development of new advanced microscopy tools. Significant improvement in imaging throughput of fluorescence lifetime imaging and novel methods development. Key papers are in preparation. |
Title | Multiplex single cell Gene expression for T lymphocytes |
Description | Multiplex single cell Gene expression for T lymphocytes |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | none yet |
Description | Development of electronic sensors for fluorescence lifetime imaging (application to Quantic and on-going research). |
Organisation | Photon Force Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Development of electronic sensors for fluorescence lifetime imaging (application to Quantic and on-going research). Visiting Research Fellow (Jakub Nedbal), a full time Photon Force employee is based in the Ameer-Beg research group ~20% FTE. |
Collaborator Contribution | Development of electronic sensors for fluorescence lifetime imaging (application to Quantic and on-going research). Visiting Research Fellow (Jakub Nedbal), a full time Photon Force employee is based in the Ameer-Beg research group ~20% FTE. |
Impact | Development of electronic sensors for fluorescence lifetime imaging (application to Quantic and on-going research). Visiting Research Fellow (Jakub Nedbal), a full time Photon Force employee is based in the Ameer-Beg research group ~20% FTE. |
Start Year | 2016 |
Description | Development of microfluidic sensors for liquid biopsy |
Organisation | Optofluidics Inc. |
Country | United States |
Sector | Private |
PI Contribution | Development of microfluidic sensors for liquid biopsy. |
Collaborator Contribution | Development of microfluidic sensors for liquid biopsy. |
Impact | Development of microfluidic sensors for liquid biopsy. |
Start Year | 2015 |
Description | INNODIA Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes H2020 EC - Innovative Medicines Initiative |
Organisation | INNODIA |
Country | Global |
Sector | Public |
PI Contribution | one PhD student one Research assistant |
Collaborator Contribution | Laboratory studies on biomarkers for T1D |
Impact | none yet |
Start Year | 2015 |
Title | Therapeutic Intervention - Drug - Beta call multiple peptide immunotherapy Early clinical assessment |
Description | peptide immunotherapy for T1D. Commercial collaboration with UCB Funding from Wellcome trust |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2017 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | none |
URL | http://www.multipeptide.co.uk/about-multipept1de/ |
Description | Colloquia, University of Dundee |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | 6/11/2015 Ameer-Beg, S. M. (PI), "Advanced microscopy solutions for protein-protein interaction monitoring in live cells and organisms", Invited Colloquia, University of Dundee, Division of Imaging and Technology in the School of Medicine. |
Year(s) Of Engagement Activity | 2016 |
Description | Frontiers in Bioimaging |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | 14/7/2016 Ameer-Beg, S. M. (PI), "Imaging strategies for protein interaction monitoring in live cells", Invited Speaker, Frontiers in Bioimaging 2016, London. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.imaging-git.com/events/frontiers-bioimaging-2016 |
Description | Neuroscience Symposium, Kyoto, Japan |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 16/3/2017 - Ameer-Beg, S. M. (PI), "Protein-protein interactions at the interface: Biophotonics approaches to live-cell dynamic FRET measurements", Invited Speaker, UK-Japan Spring Neuroscience Symposium, Kyoto, Japan. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.neuroscience2016.jnss.org/en/program.html |