Head of the Discipline of Microbiology, in the Department of Physiology, Anatomy and Microbiology (2015 -).
I study neurodegenerative disease, mitochondrial biology and the roles of mitochondria in disease. I use 2 model systems to understand the cytopathological pathways involved:
1. The eukaryotic microbe Dictyostelium - one of 10 model organisms recognized by the NIH for their value in biomedical research. Dictyostelium provides a tractable, molecular genetic model for mitochondrial disease and neurodegenerative diseases and I am a world leader in this research. Using the Dictyostelium model I specifically manipulate (separately and together) known disease genes and genes encoding proteins hypothesized to be involved in the associated cytopathological pathways. I then use biochemical, molecular and cell biological assays to determine the cellular consequences of disturbances in these pathways. The results support pathological roles for cellular stress signalling pathways in mitochondrial and neurodegenerative diseases.
2. Immortalized, cultured lymphocytes (lymphoblasts) from human disease patients and healthy control individuals. In our growing collection, we currently have a total of ca. 240 different primary lymphoblast cell lines from healthy individuals and patients with Parkinsons, FXTAS or ME/CFS. The aim is to study the roles of mitochondria and cellular stress signalling pathways in these diseases and determine the applicability to them of our findings in the Dictyostelium model.
This research requires my advanced expertise in mitochondrial & molecular biology, biochemistry and cell physiology, including the complete array of modern molecular techniques as well as in the diverse statistical methods in the data analysis.
My research career began with an Honours degree in Microbiology at the University of Queensland in 1975 (H1 and 1st in cohort), after which I completed an MSc in the same area, microbial molecular genetics. I published the first molecular genetic investigation of herbicide (2,4-D) degradation in the environment (in Nature and J Bacteriol, the top microbiology journal of the time). During this time I became interested in microbial models for studying fundamental molecular mechanisms in biology. Nonmammalian model organisms have made enormous contributions to science, featuring in about half of the Nobel Prizes in Chemistry and in Physiology or Medicine. Recognizing their importance, I decided to move in 1978 to the ANU for PhD studies on the established nonmammalian model, Dictyostelium. My first contribution was publication in Cell of the discovery of an extracellular chemical signal controlling photosensory behaviour in Dictyostelium. My interest in this continued with my move in 1980 to the Max Planck Institute for Biochemistry in Munich, where I also worked on nonmuscle cell motility and chemotaxis, for which Dictyostelium provides the best understood system and “model of first choice”. Here I developed the first chemotaxis chamber that provides truly stable, linear chemical gradients, wrote the first cell tracking software to automate data collection and proposed the now accepted model of coupled, global inhibition and local activation signals controlling pseudopod extension (published in J. Cell Biol. and Semin. Cell Biol.).
On returning to a lecturing position at La Trobe in 1985, I continued my research on photosensory signal transduction in Dictyostelium, becoming the leading authority on this and one of the world’s top researchers on microbial phototaxis. In the 1990s I developed the first accurate, sensitive technique for measuring cytosolic Ca2+ levels in Dictyostelium in real time. Based on recombinant aequorin and my own software, this led to seminal contributions to understanding Ca2+ signalling in response to morphogens and attractants, the first publications being in EMBO J. and J. Cell Sci. As leader of the only laboratory able to conduct such measurements, I still receive requests for collaboration, most recently on the dysregulation of Ca2+ signalling elicited by Alzheimer’s Disease-causing mutations in Dictyostelium presenilin genes. During the 1990s I also developed the first method for nontargeted gene disruption in Dictyostelium so that we could identify genes important for photosensory signalling. The first we found was the mitochondrial large subunit rRNA gene, which we had knocked out in a subset of the cell’s mitochondrial genomes. The phenotypes in this first mitochondrial disease model led me to be the first to realize that intracellular signalling is dysregulated by defects in oxidative phosphorylation that are not severe enough to cause cell death. We revealed the nature of this dysregulation by showing that chronic hyperactivity of the energy-sensing protein kinase AMPK is responsible for diverse cytopathologies in mitochondrially diseased cells (published in Mol. Biol. Cell and Disease Models and Mechanisms).
Since mitochondrial abnormalities feature in most neurodegenerative diseases, even if the genetic cause is not overtly mitochondrial, our work predicted that AMPK activities would be chronically elevated in these diseases and contribute to the underlying cytopathology. This has been confirmed by others for Alzheimer’s, Huntington’s and Motor Neuron Diseases. In our most recent work, both with Dictyostelium and with cultured cells from human patients, we discovered unexpectedly that mitochondria in Parkinson’s disease cells are functionally normal but hyperactive. The post-mortem defects in brain mitochondria are likely a secondary result not a primary cause of disease pathology.