Mini-brains in a dish and exploring treatments for childhood disease

11 January 2018
Becker team growing neurons to study the cerebellum and its disorders
Dr Nayler is continuing his research at Oxford University, following a breakthrough in understanding a rare genetic disease at the University of Queensland. By growing brain organoids in a dish, he and his team are exploring treatment strategies for this disease. 

Dr Sam Nayler is very intrigued about the cerebellum. Rightly so, as the cerebellum is the primary centre for not only motor coordination but language and learning in the central nervous system. The cerebellum is receiving increasing attention as having a role in cognitive function including emotional processing, reward expectation and executive functioning. 

The cerebellum, which accounts for only 10% of the total brain volume, and has more neurons than the remainder of the central nervous system, is an incredibly complex part of the brain, and the underlying molecular processes more so; scientists understand surprisingly little about these processes and what happens when they are disrupted. The cerebellum is implicated in a range of disorders including including motor diseases (ataxia, dystonia) and non-motor diseases (Autism Spectrum Disorder, dyslexia, fetal alcohol syndrome). Abnormal formation of the cerebellum contributes to a number of disorders including medulloblastoma, the most common form of paediatric or childhood cancer. 

Dr Nayler is interested in a genetically and clinically diverse group of neurological conditions that primarily affect the cerebellum. These are called cerebellar ataxias. One disease, Ataxia-telangiectasia (A-T), also known as Louis-Bar syndrome, is the focus of his research. This research has taken him from University of Queensland to Oxford University, funded by the Oxford Nuffield Medical Fellowship, a highly competitive Fellowship that supports research programmes of major importance for one Australian, one New Zealander and one South African fellow per year. In trying to understand A-T, Dr Nayler and the team at Oxford University, led by Professor Esther Becker are making significant headway into demystifying the cerebellum through the use of stem cells.

A-T is a debilitating disease caused by mutations in the ataxia-telangiectasia (ATM) gene – a gene involved in repairing damage to DNA. Studying this disease is incredibly difficult, as animal models cannot clearly mimic the neurological aspects of this disease. In a previous study, Dr Nayler created model tissues from stem cells taken from patient samples. The Wolvetang Group at University of Queensland, of which Dr Nayler was a member, took samples of skin from patients and reprogramed them to become induced pluripotent stem cells (iPSCs), which have the potential to grow into virtually any cell type, given the right conditions. In this case the technology was used to produce immature cerebellar neurons, the cell type affected in A-T.

Sam and his team are now using organoid technologies, which make use of 3D, self-organizing stem cell groups or aggregates to produce neurons that are more physiologically mature and therefore more relevant when studying the cerebellum and its disorders. 

As well as working on growing healthy neurons from iPS cells, Dr Nayler is focussing on producing the cell type affected in A-T, which are called Purkinje neurons. The hope is that one day, Purkinje neurons may be used as drug-screening models to inform treatment of this disease. Dr Sam Nayler will continue to collaborate with the Wolvetang group at University of Queensland, who have been working on generating genetically modified or corrected iPSCs from A-T patients using CRISPR. 

Furthermore, the team aim to undertake single cell sequencing on the neurons they are growing. This detailed analysis will let them examine each cell more carefully, enabling the team a better picture of the disease and how it might manifest and be treated. 

Dr Sam Nayler (third from right) and team at Oxford University