Multiplexed Ion Bean Imaging Microscopy to support Digital Pathology in experimental medicine studies

The most common reason why new treatments to not make it during the early phase drug discovery is that they are not safe but rather that they are not very effective. We now know why. Its due to the unsolved problem of how to show that the drug pathways that the drugs are thought to interfere with have been engaged in the tissues of humans treated with the medicines. We propose that this is because we do not have a sufficiently developed understanding of how to link the drugs being tested to the location of cells in tissues. By using a new type of microscopy called MIBI imaging we aim to provide as disruptive an approach to classical histology as the advent of MRI imaging did for plain film X rays in radiology. We call this new type of histology Digital Pathology and if this grant is funded, we will be the first unit in the UK to have access to the MIBI microscope.

Multiplex Ion Beam Imaging (MIBI) uses secondary-ion mass spectroscopy to make a step change in clinical tissue biopsy analysis to GCP-compliant standards. Specifically, this technology permits multiplex imaging (40+ antibodies) simultaneously on both FFPE and frozen sections with very high sensitivity and no probe background allowing detection of very low abundance proteins in the context of spatial biology. Uniquely, it can repeatedly scan tissues, permitting scanning of whole tissue sections at lower resolution, then rescanning areas of interest at sub-cellular interactions. The MIBI images down to 350nm resolution and single molecule imaging capacity in tissue sections, permitting analysis of cell-cell communications at unprecedented resolution and RNA localisation in human pathology samples. In contrast to existing technologies over 100 slides per week, this provides the capacity to incorporate very sensitive multiplex imaging into experimental medicine and early clinical trials, thus generating a unique platform for advanced digital pathology. Specifically in this project we will use the MIBI to develop:
(1) Cell-based readouts for clinical trials and experimental medicine
(2) Precision pathology to develop new treatments for IMIDS
(3) Spatial validation of tissue from the Human Cell Atlas project
(4) Understand tumour microenvironments in difficult to treat tumours
(5) Determine how cellular ecosystems are established as networks, determine their composite members and anatomical location in the tissue and relate this to function.
(6) Examine how the formation of specific cellular ecosystems within the tissue (such as the formation of ectopic lymphoid structures) propagate specific functional states of the tissue in disease (i.e remission versus flare).
(7) Determining the role of microbiome - immune interactions in human IBD
(8) Technologies to integrate spatial MIBIscope images with multiomics datasets