Single Cell-Level Functional Proteomics and Genomics exemplified in Cancer and Immunology

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.

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.

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.