Professor Doug Brooks

I am the Molecular Medicine Sector Leader for the Sansom Institute in the School of Pharmacy and Medical Science at the University of South Australia. I have over 25 years experience in medical research and am currently an NH&MRC funded Senior Research Fellow and Research Professor in Molecular Medicine. My initial research training was in Immunology with a focus on cancer research, involving the immunochemistry of cell surface antigens. For 24 years I worked in the Lysosomal Diseases Research Unit at the Women’s and Children’s Hospital, on a group of genetic diseases called lysosomal storage disorders. The Lysosomal Diseases Research Unit has been responsible for significant health outcomes for this group of disorders, with the development of strategies for early screening, diagnosis and treatment. This research reflects my strong interest in lysosomal cell biology and a desire to develop practical applications in biochemical medicine that benefit patients and the wider community. The new Molecular Medicine Sector has been developed with a series of research themes involving basic medical research on genetic disease, the early origins of adult health, infection and immunity, autism, and ion channels, together with more applied research on experimental therapeutics and clinical pharmacogenomics. These project areas will be heavily aligned with the national research priorities of Promoting and Maintaining Good Health, A Healthy Start to Life, Aging well and Preventative Health Care. The Molecular Medicine Sectors primary objective is to facilitate technological advances that result in research and health outcomes, which directly benefit all Australians.

• Honours and Doctorate of Philosophy student research programs
• Increasing science literacy and enthusiasm for science in secondary and tertiary students

Bachelor of Science: Flinders University of South Australia, Adelaide, South Australia. 1977.

Honours Bachelor of Science: "Studies of naturally-occurring autoimmune responses in mice." School of Biological Sciences at Flinders University, Adelaide, South Australia. 1978.

Doctorate of Philosophy: "Human B cell differentiation." Department of Clinical Immunology, School of Medicine, Flinders University of South Australia. 1982.

Affiliate Associate Professor: Faculty of Health Sciences, University of Adelaide (Affiliated through the Department of Paediatrics at the Women’s and Children’s Hospital). 2001-2009.

Professor of Molecular Medicine, Sansom Institute, School of Pharmacy and Medical Science, University of South Australia. 2006-2011.

• In terms of research outcomes over the past 6 years, I have made significant contributions to the study of structural modifications of mutant proteins in lysosomal storage patients, the role of protein processing in genetic disease, the study of lysosomal biogenesis and disease, the application of markers for the biogenesis of lysosomes to the development of screening methods for lysosomal storage disorder patients, the development of enzyme replacement therapy for the treatment of lysosomal storage disorder patients and the study of immune response to replacement therapy. This reflects a skill base in the areas of immunochemistry, protein chemistry and cell biology. The intellectual property developed by me in association with the Lysosomal Diseases Research Unit at the Women's and Children's Hospital, has involved three major areas: the characterisation of the lysosomal proteins and the development of procedures to predict clinical severity in patients; the development of enzyme replacement therapy as a strategy for treating patients; and the development of a screening method for patients using lysosomal markers. These developments have impacted on clinical practice/public health through services for genotype phenotype prediction, clinical trials for enzyme replacement therapy in patients and the implementation of screening programs. Using our cell biology studies we are now developing new treatment strategies for genetic disease that address specific mutations. We are also using our knowledge of lysosomal cell biology to study other diseases. Current research projects include:
• 1. Stabilising mutant protein as a therapy for lysosomal storage disorder patients. Lysosomal storage disorders are a group of genetic diseases, which involve an enzyme deficiency in one or more lysosomal enzymes. This deficiency causes the lysosomal accumulation of undegraded substrate. Lysosomal sulphatases have a high degree of structural homology and a common catalytic mechanism. The majority of causative mutations in lysosomal sulphatases are mis-sense point mutations, which alter the folding of the protein, reducing enzyme stability/activity. As a result the mis-folded protein is retained and degraded by the rough endoplasmic reticulum (RER) quality control machinery. In this project, we are investigating if stabilising mutant protein will assist folding and facilitate the exit of this protein from the RER for traffic to the lysosome. To stabilise the protein in vitro, we will: a. use general protein stabilisers (eg. glycerol and trehalose) b. use an ensilico approach to design specific reagents that will bind to the active site of the protein and coordinate the catalytic domain. We will monitor the effect of these protein stabilisers on protein folding and enzyme activity using immune assays in combination with subcellular fractionation and SDS-PAGE.
• 2. Drug-enhanced premature stop codon read-through. Studies in our laboratory have provided evidence that a large number of lysosomal storage disorder patients have a premature stop codon mutation in one or both alleles. As a result, a full-length polypeptide cannot be synthesised and this results in reduced intracellular enzyme activity and the onset of disease. Three different mRNA stop codons are used in mammals; UAA, UAG and UGA, and these differ in their fidelity and natural read-through potential. In this project we are testing reagents in vitro, for their ability to induce premature stop codon read-through and thus, treat the disease.
• 3. Vesicular traffic and neouropathology. We are interested in the regulation of intracellular vesicular traffic by the ubiquitin pathway. The addition of a single ubiquitin molecule to membrane proteins regulates their targeting to the plasma membrane as well as throughout the endosome-lysosome network. The enzymes which add (ligases) or remove (deubiquitylating enzymes) ubiquitin are the major regulatory proteins in these pathways and the subject of our investigations. Dysregulation of vesicular trafficking underpins several pathologies including lysosomal storage disorders, cancers and developmental disorders. This project will study the role of ubiquitylation in lysosomal storage disorder pathogenesis. We are also investigating the impact of lysosomal storage on vesicular traffic in neurons as this may explain the developement of the severe neuropathology suffered by many lysosomal storage disorder patients.
• 4. H. pylori infection of cells Helicobacter pylori (H. pylori) infections are rife in the third world and in indigenous Australians. H. pylori is in fact one of the most successful human pathogens, infecting approximately 50% of the world’s population. H. pylori colonises the gastric epithelium causing severe gastric disease and is an important risk factor for the development of peptic ulcers, gastric adenocarcinoma and MALT lymphoma. Gastric cancers are the second main cause for cancer deaths globally. There is a need to better understand the pathogenicity of H. pylori. In this project the pathogenicity of H. pylori will be investigated in cultured epithelial cells and will focus on the uptake and survival of these bacteria in phagosomes of the endosome–lysosome network.

88. Kakavanos R, Lehn P, Callebaut I, Meikle PJ, Parkinson-Lawrence EJ, Hopwood JJ, and Brooks DA. (2006): Common antigenicity for two glycosidases. FEBS Letters. 580: 87-92.

89. Dean CJ, Bockmann MR, Hopwood JJ, Brooks DA, and Meikle PJ. (2006): Detection of mucopolysaccharidosis type II by measurement of iduronate-2-sulfatase in dried blood-spots and plasma samples. Clinical Chemistry. 52: 643-649.

90. Brooks DA, Muller V, and Hopwood JJ. (2006): Stop codon read-through for lysosomal storage disorder patients. Trends in Molecular Medicine, 12: 367-373.

91. Meikle PJ, Grasby DJ, Dean CD, Lang D, Bockmann MR, Whittle AM, Fietz MJ, Simonsen H, Fuller M, Brooks DA, and Hopwood JJ. (2006): Newborn screening for lysosomal storage disorders. Molecular Genetics and Metabolism, 88: 307-314.

92. Parkinson-Lawrence EJ, Fuller M, Hopwood JJ, Meikle PJ, and Brooks DA. (2006): Review: Immunochemistry of lysosomal storage disorders. Clinical Chemistry, 52: 1660-1668.

93. Kakavanos R, Hopwood JJ, Lang D, Meikle PJ, and Brooks DA. (2006): Stabilising normal and mutant Ą-glucosidase. FEBS Letters, 580: 4365-4370.

94. Parkinson-Lawrence EJ, and Brooks DA. (2006): Book Chapter: Lysosomal Biogenesis and Disease. In: Lysosomal Storage Disorders (J. Barranger ed). CRC Press, Boca Raton, Florida USA. Accepted 20th April 2006.

95. Brooks DA, Turner C, Muller V, Hopwood JJ, Meikle PJ (2006): Book Chapter: I-cell disease. In: Lysosomal Storage Disorders (J. Barranger ed). CRC Press, Boca Raton, Florida USA. Accepted 20th April 2006.

96. Parkinson-Lawrence EJ, Muller VJ, Hopwood JJ and Brooks DA. (2007): N-Acetylgalactosamine-6-sulfatase protein detection in MPS IVA patient and normal control samples. Clinica Chimica ACTA, 377: 88-91.

97. Karageorgos L, Brooks DA, Harmatz P, Ketteridge D, Pollard A, Melville EL, Parkinson-Lawrence E, Clements PR, and Hopwood JJ. (2007): Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy. Molecular Genetics and Metabolism, 90: 164-170.

98. Brooks DA. (2007): Getting into the fold. Nature Chemical Biology 3: 84-85.