The nostril: a window to the brain

By Pierce Goldsmith

A new research method developed by Australian scientist Alan Mackay-Sim and his team has the potential to shed light on the biological underpinnings of mental illnesses.

By using this non-invasive procedure, it is hoped that researchers will be able to better understand the causes of mental illness such as Parkinson’s disease and schizophrenia.

Mental illness affects 45 per cent of all Australians aged 16-85 years at some point in their life, according to the Australian Bureau of Statistics. The direct cost to the Australian economy is estimated by the Australian Institute of Health and Wellfare to be $4.1 billion per year.

Currently, the precise biological interactions that coalesce to form a brain disorder are poorly understood. While scientists are often able to identify a few contributing factors, understanding the complexity of these diseases remains elusive.

However, recent work conducted by Dr Alan Mackay-Sim may help to provide a more concrete understanding of the development of mental illness.

Mental disorders such as Parkinson’s disease and schizophrenia are puzzling because the disorders arise from complex gene-environment interactions. In order to come up with better treatments for mental disorders, it is important for scientists to uncover the precise mechanisms that cause these problems to materialise.

One way of investigating these mechanisms is to look for differences in the cells of individuals with mental illness compared to those without.

Cells such as skin fibroblasts and transformed lymphocytes have previously been used to investigate cellular differences associated with Parkinson’s disease and schizophrenia, but they are non-neural, so their utility is limited in investigating brain disorders.

These cells do not replicate the genetic, epigenetic, biochemical or cellular dysregulations responsible for brain disease, explains Mackay-Sim, Director of the National Adult Stem Cell Research Centre and the Eskitis Institute for Cell and Molecular Therapies, and a Professor at the Griffith School of Biomolecular and Physical Sciences.

The alternative, being explored by his team are neurosphere-derived cells from tissue involved in the detection of odor: the olfactory mucosa.

Unlike previously used cell types, these multipotent stem cells from the organ of smell have the benefit of being easy to obtain from adults with complex genetic diseases, and are simple to handle since they do not require genetic reprogramming.

According to Mackay-Sim, these cells “have the potential to be informative about neurological diseases because they are neurological tissue that can reflect cellular properties of other neural tissue and hence has the potential to model cellular pathologies in the brain.”

Collecting these cells to search for disease-dependent alterations in cell biology is a simple procedure done under local anaesthetic, and since olfactory sensory neurons are replaced by neurogenesis that continues throughout adult life, the procedure has no effect on the sense of smell.

By using a cell derived model for a brain disorder, scientists are able to tease out disease specific differences between individuals with brain disorders and controls. At this point, their research has yielded significant results for schizophrenia and Parkinson’s disease.

By comparing 42 patient and control cell lines, differences in gene expression, protein expression and cell function were discovered. Specifically, dysregulated neurodevelopmental pathways were discovered in schizophrenia and problems with oxidative stress and xenobiotic metabolism in Parkinson’s, which are both consistent with current understanding of the disorders.

The most exciting prospect of having a new patient-cell-based model is its use in finding specific genes and cell pathways for future studies.

“Growing the stem cells in vitro has the advantages of being able to be banked and experiments replicated and expanded without continually getting new biopsies,” said Mckay-Sim.

This method of storing standardised cultures for future experimentation will make subsequent research in the field of brain disorders significantly more rapid and easily accessible.

Given this ease of conducting future experiments, scientists hope that patient-derived cells will act as a discovery platform for finding new causes and mechanisms of disease. This cell-model may also result in therapeutic advancement such as new drug targets and assays for screening for drug lead compounds.