Establishment of a cutting-edge imaging modality to enable multi-parameter analyses within tissues

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The development of technologies that allow the study of cells in extreme detail, measuring many different molecules simultaneously (called multi-parameter analysis), has revolutionised research within the biomedical field. These technologies have demonstrated the complexity and extreme cellular heterogeneity (variation) that exists within and underpins biological processes, spanning tissue and organismal development and physiology, through to maintenance of tissue homeostasis, aging or generation of an immune response. As a consequence, in many different research areas it now requires examination of more than 10 different molecules (in this context referred to as parameters) to simply identify a cell of interest. For example, it can require studying up to 15 different parameters to identify different immune cell subsets. Moreover, it can require 5-10 parameters to accurately define the activity or status of a cell of interest. Whilst these multi-parameter technologies (which include techniques called flow cytometry, CyTOF and single cell RNA-sequencing), have been extremely powerful, the problem with them is that they all require that the tissue under examination is processed into single cell suspensions for analysis, and all context regarding where in the tissue the cell came from is lost. The more we reveal regarding various biological processes, the more obvious it becomes that most biological events (whether tissue homeostasis, generation of an immune response, response to injury or disease), are multi-factorial, involving the interaction of different cell types within the tissue. Moreover, the location of the cells within the tissue / organ frequently plays a major role in influencing the outcome of the response. Consequently, it has become clear that to truly understand how a particular cell population contributes to a biological process, or how a biological process develops and is regulated during health, or how it is modified during disease, it is critical to complement investigations such as flow cytometry, CyTOF and single cell transcriptomics, with multi-parameter investigations within the tissue (i.e. studying cells and biological processes within the physiological tissue structure). Historically this has not been possible as traditional imaging approaches for examining tissues have only allowed the study of up to 5 different molecules at a time, which means researchers have not even been able to identify their cell of interest within the tissue environment, let alone investigate how the cell interacts with other cells or define where it is located within the tissue structure. To support multi parameter biological examinations within a physiological tissue environment, Fluidigm has recently developed the Hyperion Imaging mass cytometer system that allows the concurrent imaging of up to 37 parameters within an individual tissue section. Thus, the Hyperion system fundamentally changes, by approximately 10 fold, the power of multi-parameter histological investigations that are possible within biological research. In this application we request funds to purchase a Hyperion imaging system. The purchase of the Hyperion system will provide a step change in the ability of our consortium (outlined in the case for support), as well as other researchers at Manchester, and within the North West of England, to perform multi-parameter imaging investigations within physiological tissue environments. This will provide fundamental new insights into many different biological processes integral within different BBSRC strategy areas, particularly within the "understanding the rules of life" and the "bioscience for an integrated understanding of health" themes.