Richard Callaghan

1. The early-Australian Years
I conducted my undergraduate studies in Science at the University of Melbourne and obtained a BSc (Hons) with a combined major in Biochemistry and Pharmacology in 1986. The following year I began my PhD studies at the Clinical Pharmacology Unit at St Vincent’s Hospital, also a part of the University of Melbourne. My project focussed on the resistance of conjugative drug metabolising systems to acute and chronic liver injury. I obtained my PhD from the University in 1990.

2. The Canadian Adventure
In 1990 I spent a year in the Lipid Biophysics Laboratory at McMaster University in the cold expanses of Hamilton Ontario in Canada. The project focussed on the complex interaction between the multidrug transporter P-glycoprotein and its lipid environment. In 1991 I joined the Cell Biology Laboratory at the University of Toronto. During this period I focussed on the ABC family of transporters. In particular, I explored the pharmacology of P-glycoprotein and the potential for protein therapy with CFTR to restore chloride flux in lung epithelial cells.

3. The English Way
In 1993 I left sunny Canada for England and the dreaming spires of Oxford. I joined the ICRF Laboratories at the Institute of Molecular Medicine at the University of Oxford. My research focus was on the biochemical pharmacology and structure of the drug transporter P-glycoprotein. In 1997 I graduated from post-doctoral work to head my own research group in the Department of Clinical Laboratory Sciences at the University of Oxford. I was also made a Fellow of Merton College Oxford where I taught Medical Biochemistry and Structural Biochemistry. The primary research focus of my group was the contribution of drug transport process to human diseases. 

4. Back to Australia
In February 2012 I returned to Australia to take up a post as Associate Professor at ANU. I hold a cross appointment between the Research School of Biology and the Medical School. My research interests will build on those founded in Oxford; namely understanding transport processes related to human disease. I will teach biochemistry to medical students and run the medical school research project component.

Research interests

Membrane transport is essential for the growth, homeostasis and defence of cells. No better evidence of this fact is the considerable proportion of the genome devoted to membrane bound proteins. However, disruption of membrane transport often contributes to development, or progression, of many disease states. In addition, perturbations in membrane transport processes frequently contribute to the the failure of many therapeutic strategies. Our research interests focus on understanding the contributions of membrane transport processes to disease and overcoming their impact in treating disease. The expertise of our research team is in the biochemical pharmacology of membrane transporters and generating structural information on these proteins. As shown by the diagram opposite, our strategy utilises the triad of structural, functional and pharmacological endeavours. The laboratory has assembled the infrastructure and considerable expertise in enabling us to work within this triad. We have four main streams of research, so click on the appropriate one and see more details on each of the major projects that we deal with:

  1. Contributions of ABC transporters (P-glycoprotein and ABCG2) to chemotherapy resistance in cancer.
  2. Does faulty retinoid transport (by ABCA4)  underpin several visual disorders?
  3. Malarial resistance to chemotherapy and drug translocation.
  4. Adaptive changes to bioenergetic metabolism and nutrient utilisation in solid tumours

 

Recent grants

  • National Health & Medical Research Council (2015-18): “What is the role of ABCA4 in the visual process” Value $312,077
  • National Health & Medical Research Council (2013-16): “Modelling drug interactions with P-glycoprotein” Value $30,000 of $274,724
  • Association for International Cancer Research (2012-2015): “How do drugs bind to the multidrug resistance P-glycoprotein” Value £156,634
  • Wellcome Trust Project (2012-13): “The molecular process underlying multidrug efflux by P-glycoprotein” Value £114,743
  • Medical Research Council Departmental PhD Studentship (2010-2013): “Solid Tumour Metabolism” Value £72,000
  • Wellcome Trust Project (2010-2013): “The interaction between ABCG2 and the Pim-1 kinase” Value £168,220
  • Medical Research Council Project (2009-2012): “The role of pfCRT in drug resistance by malaria” Value £129,343
  • Wellcome Trust Project (2009-2010): “Providing a dynamic molecular mechanism of the drug efflux pump P-gp” Value £80,000
  • Medical Research Council Project (2005-2008): “Structural analysis of the multidrug resistance P-gp” Value £236,256
  • EC Framework 6 Research Training Network (2005-2008): “Regulation of transbilayer lipid dynamics by membrane proteins” Value £164,000
  • Cancer Research UK Project (2005-2009): “High resolution 3-D structure of human P-gp” Value £222,355
  • Cancer Research UK PhD Studentship (2005-2009): “Localisation of the drug binding region of P-gp” Value £61,500

 

Positions held

  • 2012 - Co-Chair of the FEBS ABC Transporter Meeting
  • 2011 - Distinguished Visiting Fellow at the University of Technology Sydney
  • 2010 - Co-Chair of the Gordon Research Conference on "Multidrug Efflux Systems"
  • 2008 - Voted to the Scientific Advisory Board of the FEBS Conference on ABC Transporters

 

Collaborators

Major international collaborators

  1. Associate Professor Ian Kerr, University of Nottingham, UK
  2. Professor Robert Ford, University of Manchester, UK
  3. Dr Marcus Allen, Brighton University, UK
  4. Dr Fraser MacMillan, University of East Anglia, UK
  5. Dr Alice Rothnie, Aston University, UK
  6. Professor Susan PC Cole, Queen's University, Kingston, Canada

Australian collaborators

  1. Dr Ingrid Gelissen, University of Sydney
  2. Prof Peter Scammells, MIPS, Monash University, Melbourne
  3. Assoc Professor Tony George, University of Technology, Sydney
  4. Dr Megan O'Mara, Australian National University
  5. Assoc Professor Mary Bebawy, University of Technology, Sydney
  6. Dr David De Souza, Bio21 Institute, University of Melbourne

Selected publications

Selected research articles (last 10 years only)

1    Skrzypek, R. & Callaghan, R. The "pushmi-pullyu" of resistance to chloroquine in malaria. Essays Biochem 61, 167-175 (2017).

2    Mittra, R. et al. Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein. Biochem Pharmacol 123, 19-28 (2017).

3    Board, M. et al. Acetoacetate is a more efficient energy-yielding substrate for human mesenchymal stem cells than glucose and generates fewer reactive oxygen species. Int J Biochem Cell Biol 88, 75-83, (2017).

4    Smith, H. et al. The Effects of Severe Hypoxia on Glycolytic Flux and Enzyme Activity in a Model of Solid Tumors. J Cell Biochem 117, 1890-1901,  (2016).

5    Mittra, R., Coyle, E. & Callaghan, R. in ABC Transporters - 40 Years on   (ed Anthony M. George) Ch. 8, 153-194 (Springer International Publishing, 2016).

6    Darby, R. A., Unsworth, A., Knapp, S., Kerr, I. D. & Callaghan, R. Overcoming ABCG2-mediated drug resistance with imidazo-[1,2-b]-pyridazine-based Pim1 kinase inhibitors. Cancer Chemother Pharmacol 76, 853-864,  (2015).

7    Callaghan, R. Providing a molecular mechanism for P-glycoprotein; why would I bother? Biochem Soc Trans 43, 995-1002, (2015).

8    van Wonderen, J. H. et al. The central cavity of ABCB1 undergoes alternating access during ATP hydrolysis. FEBS J 281, 2190-2201,(2014).

9    Pollock, N. L. et al. Improving the stability and function of purified ABCB1 and ABCA4: The influence of membrane lipids. Biochim Biophys Acta 1838, 134-147,  (2014).

10    Debono, A. J. et al. The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. ChemMedChem 9, 399-410,  (2014).

11    Callaghan, R., Luk, F. & Bebawy, M. Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy? Drug Metab Dispos 42, 623-631,  (2014).

12    Bloch, K. et al. Metabolic alterations during the growth of tumour spheroids. Cell Biochem Biophys 68, 615-628,  (2014).

13    Pluchino, K. M., Hall, M. D., Goldsborough, A. S., Callaghan, R. & Gottesman, M. M. Collateral sensitivity as a strategy against cancer multidrug resistance. Drug Resist Updat 15, 98-105,  (2012).

14    Espinosa, M. et al. Survivin isoform Delta Ex3 regulates tumor spheroid formation. Cancer Lett 318, 61-67,  (2012).

15    Callaghan, R., George, A. M. & Kerr, I. D. in Comprehensive Biophysics   (ed H. Egelman Editor-in-Chief: Edward)  145-173 (Elsevier, 2012).

16    Pollock, N. L., Niesten, P. & Callaghan, R. in Membrane Asymmetry & Transmembrane Motion of Lipids   (eds A. Herrman & P. F. Devaux) Ch. 11, 225-249 (John Wiley & Sons, 2011).

17    Pollock, N. L. & Callaghan, R. The lipid translocase, ABCA4: seeing is believing. FEBS J 278, 3204-3214,  (2011).

18    Mellor, H. R. & Callaghan, R. Accumulation and distribution of doxorubicin in tumour spheroids: the influence of acidity and expression of P-glycoprotein. Cancer Chemother Pharmacol 68, 1179-1190 (2011).

19    Darby, R. A. J., Callaghan, R. & McMahon, R. M. P-glycoprotein Inhibition: The Past, the Present and the Future. Current Drug Metabolism 12, 722-731 (2011).

20    Jeyabalan, J. et al. SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1. PLoS One 5, e10646, doi:10.1371/journal.pone.0010646 (2010).

21    Crowley, E., O'Mara, M. L., Kerr, I. D. & Callaghan, R. Transmembrane helix 12 plays a pivotal role in coupling energy provision and drug binding in ABCB1. FEBS J 277, 3974-3985,  (2010).

22    Crowley, E., McDevitt, C. A. & Callaghan, R. Generating inhibitors of P-glycoprotein: where to, now? Methods Mol Biol 596, 405-432,  (2010).

23    Crowley, E. & Callaghan, R. Multidrug efflux pumps: drug binding - gates or cavity? FEBS Journal 277, 530-539,  (2010).

24    Callaghan, R. Multidrug efflux pumps: the big issues. FEBS J 277, 529,  (2010).

25    McDevitt, C. A., Collins, R., Kerr, I. D. & Callaghan, R. Purification and structural analyses of ABCG2. Adv Drug Deliv Rev 61, 57-65,  (2009).

26    Heikal, A. et al. The stabilisation of purified, reconstituted P-glycoprotein by freeze drying with disaccharides. Cryobiology 58, 37-44,  (2009).

27    Ford, R. C., Kamis, A. B., Kerr, I. D. & Callaghan, R. in Transporters as drug carriers   (eds G.F. Ecker & P. Chiba)  (Wiley-VCH, 2009).

28    Crowley, E. et al. Transmembrane helix 12 modulates progression of the ATP catalytic cycle in ABCB1. Biochemistry 48, 6249-6258, (2009).

29    Storm, J. et al. Cytosolic region of TM6 in P-glycoprotein: topographical analysis and functional perturbation by site directed labeling. Biochemistry 47, 3615-3624,  (2008).

30    Rivers, F., O'Brien, T. J. & Callaghan, R. Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations. Eur J Pharmacol 598, 1-8,  (2008).

31    Mellor, H. R. & Callaghan, R. Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology 81, 275-300,  (2008).

32    McHugh, K. & Callaghan, R. in Multidrug Resistance: Biological and Pharmaceutical Advances in Antitumour Treatment   (ed N.A. Colabufo) Ch. 7, 321-353 (Research Signpost, 2008).

33    McDevitt, C. A. et al. Structural insights into P-glycoprotein (ABCB1) by small angle X-ray scattering and electron crystallography. FEBS Lett 582, 2950-2956, (2008).

34    McDevitt, C. A. et al. Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2? FEBS J 275, 4354-4362,  (2008).

35    Carrier, D. J. et al. The binding of auxin to the Arabidopsis auxin influx transporter AUX1. Plant Physiol 148, 529-535,  (2008).

36    Callaghan, R., Crowley, E., Potter, S. & Kerr, I. D. P-glycloprotein: So many ways to turn it on. Journal of Clinical Pharmacology 48, 365-378,  (2008).

37    Callaghan, R. & Crowley, E. in Horizons in Medicine Vol. 20  (ed P. Mathieson)  197-207 (Royal College of Physicians, 2008).

38    Storm, J. et al. Residue G346 in transmembrane segment six is involved in inter-domain communication in P-glycoprotein. Biochemistry 46, 9899-9910, (2007).

39    Modok, S. et al. Transport kinetics of four- and six-coordinate platinum compounds in the multicell layer tumour model. Br J Cancer 97, 194-200,  (2007).

40    McDevitt, C. A. & Callaghan, R. How can we best use structural information on P-glycoprotein to design inhibitors? Pharmacol Ther 113, 429-441, (2007).

41    Hall, M. D., Mellor, H. R., Callaghan, R. & Hambley, T. W. Basis for design and development of platinum(IV) anticancer complexes. J Med Chem 50, 3403-3411, (2007).

42    Alderden, R. A. et al. Elemental tomography of cancer-cell spheroids reveals incomplete uptake of both platinum(II) and platinum(IV) complexes. J Am Chem Soc 129, 13400-13401, (2007).

 

All publications

  • Lecturer & Discipline Leader in Medical Biochemistry to Year 1 MChD students
  • Chair of the MChD Research Projects Committee
  • Lecturer in BIOL2171 - energy metabolism and biomembranes
  • Lecturer in BIOL2174 - active transport mechanisms
  • Lecturer in BIOL3108 - cancer chemotherapy and resistance