Advancing translational research in neurological disorders

Professor Mill’s lab specialises in understanding the epigenetic regulation of gene expression in the developing and aging brain, and how this can impact upon the development of dementia, autism and schizophrenia. His team has made major advances in understanding how genes are activated across the life course, and identifying molecular changes in specific neural cell-types involved in disease.

His team is using novel sequencing approaches to explore the transcriptional complexity of genes in the central nervous system, identifying thousands of novel RNA molecules – or isoforms - which in turn can produce thousands of different proteins. His team have identified new isoforms linked to Alzheimer’s disease, schizophrenia and autism. “We’re only at the tip of the iceberg in understanding how these novel isoforms are involved in the onset of diseases in the brain,” he said. “It’s a very exciting time. In Exeter, we have the latest and best technologies to perform long-read sequencing via Exeter’s Sequencing Facility and real strengths in data science and informatics. We’re learning far more than ever before about the transcriptional changes in specific cell types associated with brain disease, which is uncovering novel pathways to pathology and the opportunity to identify new treatments.”

Professor Mill’s work lays the foundations for his colleagues in Exeter to explore in detail the molecular mechanisms underpinning brain disease. Genomic samples gathered from skin cells from study participants often go to the lab of Dr Akshay Bhinge at the University of Exeter’s Living Systems Institute.

Dr Bhinge can extract stem cells, which can then be evolved into neurons for study. He said: “We can coax stem cells into becoming the same kind of nerve cells as are affected in disease.

“We can understand what goes wrong using genetics. We then create models using human cells and high-tech tissue culture, and methods such as microfluidics, which help us understand whether targeting a specific gene function really improves the outcome for the cell, and our mathematicians help us interpret what we’re seeing. We also use high content imaging and powerful high resolution microscopes to understand how to fix what goes wrong.

“Exeter has all the overlapping technologies we need for this complex and interconnected journey of discovery. We have all the expertise to give a really holistic view of understanding.”

A key part of the infrastructure is Exeter’s Mireille Gillings Neuroimaging Centre. Dr Heather Wilson is part of Exeter’s Neurodegeneration Imaging Group, which uses the facility’s high-tech scanners to look at pictures of the brain on a molecular level. The group uses neuroimaging technologies to examine changes in the brain at different disease stages, and to compare with healthy individuals, to understand how disease related changes occurs over time and to test new treatments across neurodegenerative diseases.

Dr Wilson said: “Our modern scanners are dedicated to research, which means we can use them for a wide variety of studies. Genetic analysis means we can identify people who are carriers of specific genetic mutations and may not yet have clinical symptoms. We are using neuroimaging techniques to understand molecular disease related changes early in the disease course, and related to specific genetic mutations. “

To progress fundamental findings, we need animal studies to test how genetic discoveries translate in a living organism. Working with experts at the University’s Aquatic Resources Centre Professor Soojin Ryu has created a unique model in zebrafish, studying high levels of stress in early life can affect later life, and the onset of psychiatric disorders.

Professor Ryu said: “We use zebrafish to understand how exposure to stress changes susceptibility, and we’re looking at molecules that you can target to develop new therapies. Genetically modified Zebrafish model – can manipulate the stress level. We’re finding molecules that are affected by early life stress exposure which have a striking overlap with the molecules in human psychiatric disease. Our research will help developing biomarkers that can help identify high risk groups for psychiatric disorders arising from stress exposure. Then look for key targets that could be used to search for new drugs.

“To drive my research I need two things that Exeter provides: I need a great strength in cellular and molecular biology, otherwise you can’t understand mechanistic processes. I also need a very strong medical school and people who are working with genetics in patients. We’re extremely strong in both areas, and importantly they interact together very well. That’s the ethos and community we need to translate my findings into clinical benefits as swiftly as possible.”