Professor Milton T W Hearn

FTS, FRACI, FAID BSc (Hons), 1965; PhD, 1970; DSc, 1983 (University of Adelaide)

Telephone: +61 - 3 9905 3720 Facsimile: +61 - 3 9905 5882 Email: Milton.Hearn@med.monash.edu.au

Current Research Interest:

Structure and Function Relationships of Cystine Knot Superfamily of Growth Factors and Glycoprotein Hormones.

The cystine knot superfamily comprises many important homodimeric and heterodimeric proteins, which are involved in reproductive function, embryogenic differentiation, tissue repair and remodelling, and the function of the specialised organs such as the liver, pituitary and gonads. Included in this superfamilty are the transforming growth factor-ßs, the activins, inhibins, the gonadotropic hormones, follitropin and lutropin, platelet-derived growth factor and a variety of key developmental and cytodifferentiational proteins required for brain, bone and organ development. Several of these proteins have been implicated in the formation of tumours. In our research programme with these proteins, we are studying their structure and function at the detailed molecular level with the objective to develop potent agonists and antagonists for use as therapeutic agents. A panel of techniques ranging from conformational studies, peptide and peptidomimetic design and synthesis, site directed mutagenesis, receptor binding behaviour and in vitro and in vivo bioassays are being employed as part of these studies.

Gomme, P.T., Thompson, P.T., Whisstock, J., Stanton, P.G. and Hearn, M.T.W. (1999) Identification of functional regions of the thyrotropin b-subunit recognised by two monoclonal antibodies which block receptor recognition: A chimeric peptide approach. J. Peptide Res., 54, 218-229.

Hearn, M.T.W. and Gomme, P.T. (2000) Molecular architecture and biorecognition processes of the cystine knot proteins: Part I. The glycoprotein hormones. J. Mol. Recogn., 13, 164-218.

Fairlie, W.D., Stanton, P.G. and Hearn, M.T.W. (1996). Contribution of specific disulphide bonds to two epitopes of thyroid-stimulating hormone b-subunit associated with receptor recognition. Eur. J. Biochem., 240, 622-627.

Interaction of Heparin Binding Growth Factors in Reproduction and Tumorigenesis

The objectives of these investigations are to delineate the synergistic effects of several members of the heparin binding family of growth factors, including fibroblast growth factor-2 (FGF-2) in conjunction with various cystine knot proteins such as activin and their binding proteins, e.g. follitropin. In particular, pathways of gene induction, and intracellular regulation are being explored. These proteins have been intimately implicated with the growth of blood vessels in solid tumours and in the control of cell differentiation. Our studies, based in part on advanced proteomic methods, are providing a detailed molecular description of the processes associated with cell differentiation in highly vascularised tissues associated with normal as well as transformed, i.e. tumour, cells.

Li, S.K.B and Hearn, M.T.W. (2000) Isolation of thecal cells: An assessment of their purity and steroidogenic potential. J. Biochem. Biophys. Meths., 45, 125-134.

Schmitt, J.F., Susil, B, J. and Hearn, M.T.W. (1996). Aberrant FGF-2, FGF-3, FGF-4 and c erb B2 gene copy number in human ovarian, breast and endometrial tumors.Growth Factors, 13, 19-35.

Katsahambas, S. and Hearn, M.T.W. (1996). Localisation of basic fibroblast growth factor mRNA (FGF-2 mRNA) in the uterus of mated and unmated gilts. J. Histochem. Cytochem., 44,1289-1301.

Molecular Mechanisms of Action of Bioactive Peptides as Therapeutic Targets in Reproduction, Diabetes and Infection

This project addresses the design, synthesis and biological evaluation of novel bioactive peptides involved in sperm function, regulation of mammalian reproduction, control of blood glucose levels as anti-diabetes peptide analogues, and a synthetic vaccines, using procedures based in part on synthetic combinatorial libraries with novel amino acid structures for the identification of new lead compounds. As part of these investigations, the application of molecular modelling procedures and the definition of tissue specific processing and signalling pathways form an integral component.

Hearn, M.T.W., O'Donoghue, M., Robson, J., Ng, F. and Rae, I. (1999) Peptides with hypoglycemic action. US Patent 6,048,840.

Keah, H.H., O'Bryan, M., de Kretser, D. and Hearn, M.T.W. (2000) Synthesis of peptides related to the sperm tail protein tpx-1, a member of the CRISP superfamily of proteins. J. Pept. Res., in press.

Higgins, K., Thompson, P.E. and Hearn, M.T.W. (1996). Conformational analysis of human growth hormone [6-13] peptide analogues. Int. J Peptide Protein Res., 48, 1-11.

Analytical Biotechnology, Biorecognition and BioSeparation Sciences

These investigations involve a major international collaborative research programme into the molecular basis of biorecognition phenomena manifested between peptides or proteins and naturally occurring ligands, as well as different types of biological and chemical surfaces. We are currently involved in the development of new bioanalytical techniques to study and characterise the biophysical relationships involved in protein - ligand and protein - receptor interactions. Central to these developments have been our investigations on new classes of chemical ligands, which when immobilised, permit enhancement of resolution and separation capabilities either in chromatographic or electrophoretic modes. These procedures permit new approaches to probe and map the surfaces of biomacromolecules in terms of their hydrophobic, ionic and dipolar characteristics. Potential application of these technologies include the development of novel isolation, purification and characterisation methods with wild-type of genetically engineered proteins, as well as various industrial applications in analytical and process biotechnology associated with downstream purification and scale-up of well characterised therapeutic proteins.

Hearn, M.T.W. (2000). Physicochemical factors in polypeptide and protein purification and analysis by high performance chromatographic techniques: Current status and challenges for the future, in Handbook of Bioseparation, (ed. S. Ahuja) Academic Press, San Diego, 72-235.

Zachariou, M. and Hearn, M.T.W., (2000) Selectivity characteristics and fractionation of several human serum proteins with immobilised hard Lewis metal ion-chelate sorbents. J. Chromatogr., in press.

Hearn, M.T.W., Keah, H.H., Boysen, R.I., Cassiano, L., Messana, I., Rossetti, D. and Castagnola, M. (2000) Determination of dissociation constants and other biophysical parameters of polypeptide retromers in solution. Anal. Chem., 72, 1964 -1972.

Hearn, M.T.W. and Zhao, G.L. (1999) Thermodynamic behaviour of polypeptides in hydrophobic environments. Anal. Chem., 71, 4874-4885.

Boysen, R.I., Wang, Y., Keah, H.H. and Hearn, M.T.W. (1999) Observations on the origin of the non-linear van’t Hoff behaviour of polypeptides in hydrophobic environments. J. Biophys. Chem., 77, 79-97.

Career Synopsis and Research Profile:

Milton T W Hearn graduated from the University of Adelaide in 1965, where he was awarded his B.Sc (Hons). He subsequently completed his Ph.D. (1970) and D.Sc. (1983) degrees from the same University. From 1979-1975, Professor Hearn held positions as N.R.C. Postdoctoral Teaching Fellow and George Murray Travelling Fellow at the Department of Chemistry, University of British Columbia; and I.C.I. Research Fellow, College Lecturer in Organic Chemistry (Christ Church) and Junior Research Fellow at Wolfson College at Oxford University. From 1975 to 1980 he held a Medical Research Council of New Zealand Senior Research Fellowship at the University of Otago Medical School. From 1981 to 1983, he was a National Health and Medical Research Council of Australia Senior Research Fellow and McGauran Fellow at St. Vincent’s Institute of Medical Research, and was appointed Principal Research Fellow from 1983-1986. He has been Distinguished Visiting Professor at Yale University (1984), University of Paris (1992) and Johannes Gutenberg University (1995). He is currently Professor of Biochemistry, and Director, Centre for Bioprocess Technology. He has received various awards including the H.J. Smith Medal of the RACI, the Senior Organon Award of the Endocrine Society of Australia, the Japan Society for the Advancement of Science Award and the Alexander von Humboldt Forschungspreis.

His research interests have focused on the development and application of new methods for biochemical analysis and separation in biomedical research and biotechnology, as well as the characterisation of protein hormones and growth factors in normal and disease states. Professor Hearn has been the senior author of 405 original scientific publications and several books, and is the inventor/co-inventor of several issued patents in protein purification technology, affinity chromatography and other "downstream" aspects of biotechnology, as well as the development of biopharmaceutical compounds.

Professor Hearn is a Fellow of the Royal Australian Chemical Institute (elected 21 May, 1985), a Fellow, Australian Institute of Directors (elected 12 October, 1987), and a Fellow, Australian Academy of Technological Sciences and Engineering (elected 20 October, 1990). Professor Hearn currently serves as Regional/Associate Editor on the Editorial Boards of the following international Journals specialising in the field of protein chemistry and bioseparation sciences: Journal of Molecular Recognition; Journal of Chromatography, Journal of Molecular Pharmacology; Isolation and Purification, Biochemical and Biophysical Research Methods, International Journal of Biochromatography, and LC/GC. Since their inception in 1981, Professor Hearn has been Co-chairman of the highly successful annual International Symposia on HPLC of Proteins, Peptides and Polynucleotides (ISPPP), and is currently Chair, Australian Peptide Association, Chair, International Commission on Biotechnology, Councillor, Australian Academy of Technological sciences and Engineering, and a member of various national and international Governmental Committees. Professor Hearn is currently a member of the Therapeutic Goods Committee of the Federal Government Department of Social Services.