Edinburgh Human Brain Cluster: Enhancing Investigation of Live Human Brain Slice Models with Deep Patient Phenotyping

The human brain is the most complex organ in the human body, comprising billions of cells of many diverse types, with trillions of connections. Unfortunately, such complexity means that understanding and treating diseases of the nervous system is an enormous challenge, resulting in economic and societal burden. Limitations of existing model systems hamper discovery of new therapies for brain diseases. Cultures of single human cell types, whilst they capture the human genetic landscape, do not include interactions between cells. Conversely, rodent models permit exploration of a living brain structure, but there are significant differences to humans. Only living human brain tissue can fully capture the complexity of human brain diseases. The UKRI Edinburgh Human Brain Cluster (EHBC) will define the rules and limits of working with living human brain tissue for modelling complex diseases. Over the past 5 years, our team has established efficient pipelines to access brain tissue (normally discarded during neurosurgical procedures) from consented adults. Using this tissue, we have gained an internationally-recognised expertise in using living human brain slice cultures (HBSCs) to model brain diseases, but we believe we have only scratched the surface of what this tool is capable of. By collecting detailed data on the patients we receive our tissue from (their medical history, genetics, examination of biological samples), we will observe how variation between people impacts normal brain function, and how their brain tissue responds to experimental disease-mimicking conditions. All model systems have limitations, and HBSCs are no exception to this. To help neurosurgeons and neuroscientists to make human tissue more widely available and accessible, the EHBC will describe a deep clinical and molecular phenotyping that will assist us to determine the impact of underlying disease processes leading to neurosurgery. We will also investigate other sources of biological patient variation, and the impact these have on the complex disease models generated from living human brain tissue. For example, by performing detailed neuropathological assessment of the tissue we will identify latent/intercurrent neurodegenerative brain disease, such as early amyloid plaques, or tau tangles in our samples. This provides a unique opportunity to enhance our experimental models, as well as observe how pre-existing pathology interacts with experimental challenges. Through these investigations, we and other academic and industrial neuroscientists will be able to develop experiments that mitigate, account for, and even benefit from, patient variability, whilst exploiting the ability to study complex, multicellular interactions in living human brain tissue. This reflects a step-change in how we generate human “models” from patient tissue, ultimately improving the robustness and reproducibility of HBSCs as well as enhancing the potential for discoveries. This, alongside our independent aims, will strengthen existing collaborations with research groups across the UK and industrial project partners. In particular, enhanced collaboration with Edinburgh’s UKRI Molecular Medicine cluster will add significant value to both teams. Overall, the EHBC aims to drive uptake of living human brain tissue usage in research, radically refining, reducing, and replacing the use of experimental animals. We will extend our Cluster to collaborating neurosurgical units and research centres across the UK and work closely with our industrial partners to enhance translational potential. We will develop a standardisation of patient and tissue characterisation for research and make experimental data available to the scientific community to inform development of their models.