Martin Lewis

Project #1. Precision medicine for mental health.

Approximately half of every population have natural gene variations that affect many of the medicines we use.  Identifying the genetic variations for an individual can guide the dose or type of medicines prescribed.  Matching of pharmaceuticals to particular genotypes is known as pharmacogenomics.  It is estimated ~50% of patients do not respond to the first antidepressant they are prescribed.  Access to accurate genetic testing, interpretation and translation into precision medicine is required to increase successful treatment responses.

A number of genetic analysis platforms are used to identify gene variations including microarrays, high resolution melt analysis, sanger-, second- and third- generation sequencing.  The suitability of each analysis platform is dependent on the gene(s) of interest.  Our laboratory is interested in long-read third generation sequencing technologies to better detect variations in genes with high homology to other genes. Variants are read from the sequence data, converted into allele types, genotypes and functional phenotypes.

We aim to improve genotyping for precision medicine in mental health services.  This project offers individuals genetic testing to recommend precision medicine to guide clinical pharmacologists and prescribing physicians. Personalised prescriptions are particularly important for antidepressants and antipsychotics to decrease the length of time to optimise treatments.  Our research team includes a neuroscientist and geneticist, psychiatric clinician, clinical pharmacologist and psychiatrists.

Project #2. Epigenetics and Major Depression.

Chronic psychological stress often manifests itself as Major Depressive Disorder (MDD).  Sustained stress can alter corticotrophin releasing hormone, adrenocorticotropic hormone and cortisol.  The homeostasis of the hypothalamic–pituitary–adrenal (HPA) axis can become dysregulated by a number of maladaptive changes when this neuroendocrine system is kept under pressure.

Stressors in our environment have an impact on gene expression through epigenetic modifications to our chromosomes. One type of epigenetic change is the modification of histone proteins that pack our DNA into chromosomes. A regulator of gene expression PHF21B is associated with major depression. PHF21B belongs to a class of proteins that read epigenetic modifications on histones and respond by facilitating specific changes to gene expression. Our aim is to understand what cell signals regulate PHF21B and determine the set of gene expression changes mediated by this epigenetic reader.

Project # 3.  Discovery of MECFS Biomarkers.

Myalgic encephalomyelitis chronic fatigue syndrome (MECFS) often develops following a viral infection and can disrupt usual life activities and sleep. Suffers of this long-term illness can develop depression in time, although MECFS is distinctly different from depression.  While exercise may exacerbate fatigue in MECSF suffers, those with depression often report exercise can improved mood. Similarly, antidepressants are not likely to give symptom relief for those with MECSF.

In collaboration with Dr Michael Musker our research investigates potential genetic and inflammatory biomarkers in MECFS suffers. South Australian study participants include those with MECFS and a reference group without MECFS. Our preliminary study examined circadian expression levels of selected cytokines in peripheral blood in conjunction with medical biochemistry, and a range of other measures. Participants are currently being recruited for the next two phases of the study.