You remember a poster in 2003 shilling BIT? Incredible memory.
2003 was a good-ish year. NOFX released the 'War on Errorism' album and Elvis Costello and Diane Krall got married.
Peter Gage was still around in 2003.
Peter William Gage 1937–2005
Written byD. J. Adams and P. H. Barry.
Introduction
Peter William Gage (1937–2005) was recognised nationally and internationally as one of Australia’s leaders in membrane physiology, biophysics and neuroscience. His research on neurotransmission, muscle and the structure–function of ion channels was extraordinarily productive, with over 7, 000 citations. A gifted speaker with a great enthusiasm for research and for the introduction of cutting-edge technology, Peter Gage influenced and encouraged a great many research students, postdoctoral fellows and senior colleagues in their scientific careers.
Peter Gage died peacefully of myeloid leukemia in Canberra Hospital on 13 August 2005 with his partner, Angela Dulhunty, his sister, Janice Ryan, and his adult children around him. Australia had lost one of its foremost investigators in membrane biophysics and neuroscience. As Bertil Hille commented from the USA: ‘For almost 40 years Peter was a leading practitioner and advocate of membrane biophysics in Australia. He had many students. He was imaginative and brave in his range of work. ’ Peter was awarded a DSc from the University of New South Wales (UNSW) in 1976, elected a Fellow of the Australian Academy of Science (AAS) in 1977, awarded an Australian Research Council (ARC) Centre of Excellence in 1982, awarded the Bob Robertson Medal of the Australian Society for Biophysics in 2004 and elected an Honorary Member of the Australian Physiological Society in 2005. His research on neurotransmission, muscle and the structure–function of ion channels was extraordinarily productive, resulting in over 200 publications and more than 7, 000 citations, with nineteen of his papers receiving more than 100 citations each. He had a great enthusiasm for research and for the introduction of cutting-edge technology to Australia. He was a gifted and dynamic lecturer who received innumerable invitations to speak at national and international conferences. All this, together with the quality of his research, attracted many PhD students, postdoctoral fellows and other senior colleagues to his laboratory. He also contributed greatly to the Australian research community by organizing International Union of Physiological Sciences (IUPS) satellite conferences, patch-clamp workshops, numerous Curtin Conferences over many years, and a **A 2000 International Symposium in Cairns. In addition, he was a warm and engaging person with a keen sense of humour whose presence will be greatly missed by his many former students, postdoctoral researchers and colleagues, family members and friends in Australia and around the world.
The authors of this memoir, currently holding professorial positions in their respective Australian universities, first met Peter at different stages in their careers. Peter H. Barry (PHB) as a postdoctoral fellow at UCLA first met Peter in the late 1960s, when Peter encouraged him to contact him when PHB wanted to return to Australia. PHB did this and with Peter’s support came from Cambridge University to work with him at UNSW as a Queen Elizabeth II (QEII) fellow in 1972, continuing to work closely with him there until Peter left to go to the Australian National University (ANU) in 1984. David J. Adams (DJA) first met Peter in 1972, as a science student in Peter’s third-year membrane physiology course, becoming his BSc (Hons) student and subsequently his PhD student until he left to go to the USA as a postdoctoral fellow in 1978.
Peter had a special ability for attracting around him students, colleagues and postdoctoral researchers from a range of different disciplines, and for forming successful collaborations with other scientists both within and outside Australia. This was aided by the fact that 1. Peter was invariably involved in cutting-edge research in areas of membrane physiology; 2. he knew the leading international researchers in the field; and 3. he had an outstanding reputation for his own research in these areas. His attributes included considerable practical expertise in electrophysiological experiments and an enthusiasm for advances in instrumentation—for example, the use of operational amplifiers and computers in electrical recording and data analysis, and techniques such as noise analysis and, later, single channel recording, as the latter was being developed. Peter had a solid background in membrane biophysics, together with a good understanding of the physics and mathematics involved in the modelling of processes like neurotransmission, circuit theory and cable analysis, and that was also required for understanding signal analysis and its relevance to ion channel properties. This gave him the ability either to solve problems himself or to encourage, guide and mentor students and postdoctoral researchers to do this. Where more specialist input was required, Peter had the ability to collaborate effectively with specialized biophysicists, engineers and mathematicians. Furthermore, Peter had a great enthusiasm for basic science and research that he communicated to those in his research group. A high proportion of Peter’s research students and postdoctoral fellows have been successful in their careers, greatly helped by his mentoring and training and the quality of his research group. Peter’s international contacts and research reputation were also of considerable value when recommending his students to other leading international laboratories. In addition, research in the field of biophysical and biomedical research of necessity requires the collaboration with research students, postdoctoral researchers and other research colleagues that Peter was able to provide.
Family background, education and marriage
Peter William Gage was born in Auckland, New Zealand, on 21 October 1937 to John Gage, an accountant, and Kathleen Mary Gage (née Burke). He was the third child with two brothers (John and Michael) and one sister (Janice).
Peter was educated at the Sacred Heart College in Auckland and then studied medicine at the University of Otago, being awarded his MB ChB from the University of New Zealand (the only degree-awarding university in New Zealand from 1870 to1961) in 1960. In the same year, he married Jillian (Jill) Christine Shewan, the daughter of James and Carla Shewan, whom he had met while she was studying physiotherapy and he medicine in Dunedin. They had two daughters, Michelle and Jennifer, and two sons, Peter and David, and have eleven grandchildren. Peter did his internship as a house surgeon at Auckland Hospital in 1961 and was a Research Fellow at Green Lane Hospital, Auckland, in 1962.
PhD at the Australian National University, 1963–1965
In early 1963, he and Jill moved to Canberra with their two daughters, for him to undertake a PhD with Professor John Hub-bard in Sir John Eccles’ department in the John Curtin School of Medical Research (JCSMR) at the ANU in Canberra. This was an exciting time to be at the JCSMR, not only because Eccles was awarded the Nobel Prize that year, but also because it was a very dynamic department. Peter’s PhD research on post-tetanic potentiation, post-tetanic hyperpolarization and neurotransmission was extraordinarily productive and was highly cited. From this period, he produced six papers inNature(3–7, 9), one in theJournal of Pharmacology and Experimental Therapeutics(8) and three in theJournal of Physiology(11–13), with the whole set of papers being cited more than 560 times in other publications. In addition, during this time he had input to two other papers (one inNatureand the other inVision Research) with Ken Brown.
Postdoctoral research at Duke University, North Carolina, 1965–1968
The Gages, now also with a young son Peter, went to the USA in 1965. Peter (senior) commenced work in Paul Horowicz’s department at Duke University on a prestigious National Institutes of Health International Postdoctoral Fellowship in 1965–7. This was followed by an appointment as Assistant Professor in the same department, 1967–8. During this period he worked with a number of leading electrophysiologists including James R. Bloedel, Clay Arm-strong, Robert (Bob) Eisenberg, Rudolpho Llinas, John Moore, David Quastel and Paul Horowicz himself. In addition, Peter worked on neurotransmission at mammalian and amphibian endplates and, with his colleagues, he also investigated the properties of neurotransmitter release and the ionic nature of the underlying postsynaptic current in voltage-clamp experiments on the squid giant synapse. At least seven papers were published from this research, including two inNature(15, 22) and one inScience(27), that have obtained more than 270 citations. Peter’s keenness to introduce new techniques is well illustrated by his secondNaturepaper (22), with Clay Armstrong, in which they recorded synaptic currents at the end plate, and ‘used, then, novel operational amplifiers to build the voltage clamp’, an innovation that paved the way for further developments by Charles F. Stevens and others in their work on understanding synaptic transmission at the endplate [2]. Peter was the first to use these voltage-clamp techniques (22). In addition, Peter published papers in connection with his previous work with David Quastel and Ken Brown.
The impact of all this productive and important research, significant as it was, was, however, somewhat dwarfed by a series of innovative and comprehensive classical experiments. In collaboration with Bob Eisenberg, Peter investigated the role of the transverse tubular system (TTS) in muscle fibres that was then believed (but not yet proven) to be ‘an essential link between the action potential and the activation of the contractile apparatus’ in the fibre (19). In two brief papers inSciencein December 1967, Gage and Eisenberg (18, 19) documented their development of a technique, using a glycerol treatment, to electrically isolate the TTS from the surface membrane of muscle fibres. In their microelectrode experiments, they showed that the glycerol treatment, while it did not affect the production of action potentials in the surface membrane of a muscle fibre, had blocked contraction of the muscle and changed the electrical properties of the fibres, radically reducing their electrical capacitance and eliminating a resistance ‘creep’ phenomenon, as would be predicted if the TTS was disrupted (and hence isolated from the surface membrane of the fibres) (18, 19). They followed this up with three detailed and comprehensive papers in theJournal of General Physiology(24–26), that were published in early 1969, to quantify clearly contributions of the TTS and surface membranes to the conductances and capacitance of whole muscle fibres and to confirm the role of the TTS in excitation–contraction coupling in muscle. This was also a breakthrough in muscle electrophysiology, making it possible to dissect out the individual electrical parameters of underlying muscle fibre components and enabling detailed simulation of currents and ionic diffusion within the muscle fibre and its TTS. The importance of this TTS work is well demonstrated by the fact that these five papers alone have been cited over 770 times, underscoring the fact that Peter Gage’s period at Duke University was highly productive and had a significant impact.
Academic positions at the University of New South Wales, 1968–1984
In addition to research, Peter was a committed educator. He had organized and taught a unit on cellular neurophysiology at Duke University, and also held a teaching position during the latter part of his time there. Then, in 1968, he returned to Australia to take up a Senior Lectureship in the School of Physiology and Pharmacology in the Faculty of Medicine at UNSW. He enthusiastically undertook the heavier teaching loads typical of Australian universities compared with those of major US universities. Throughout Peter’s time at UNSW, Walter (Darty) Glover was Head of School (HOS; 1969–85), except when Peter arrived in 1968 when Robert Holland was Acting HOS. During his time in the School, Peter taught both medical and science students. He was very concerned that medical students should be given a strong grounding in basic science and he taught them the biophysics of excitable cells, on topics such as membrane potentials, action potentials (Hodgkin & Huxley equations), muscle and neurotransmission. He also set up a unit in Biophysics for Physiology II for the third-year science students, which provided an excellent background for students wanting to do a BSc (Hons) year in membrane biophysics. On the home front, about two years after the Gage family returned to Australia, Peter’s youngest son, David, was born.
Soon after he arrived at UNSW, Peter was able to establish an active research group and obtain support from the Australian Research Grants Committee (ARGC; the forerunner of the ARC) and the National Health and Medical Research Council (NHMRC). The early members of Peter’s research group included PhD students Angela Dulhunty, Ron Balnave and Robert (Bob) McBurney, a chemical engineer— Dirk Van Helden—and an MSc student, Susan Andrews. Research over the next few years included: 1. measuring the electrical properties of single isolated skeletal muscle fibres and investigating the mechanism of glycerol treatment for disrupting the TTS in those fibres (with Dulhunty: 38, 41, 42); 2. investigating the properties of transmitter release at the toad neuromuscular junction, the temperature dependence of facilitation on release and the inhibitory effect of manganese on release (both with Balnave: 29, 35, 44) and the stimulation of acetylcholine (ACh) release by lithium (with a staff member, John Carmody: 34); and 3. exploring the mechanism of action of blue-ringed octopus toxin to block neuromuscular transmission by blocking presynaptic action potentials (with Dulhunty: 30) and that of miniature endplate currents and potentials, including their simulation, generated by quanta of acetylcholine in toad muscle fibres without transverse tubules (with McBurney: 33, 37, 45).
It should be noted that, early on, Peter had attracted funding to obtain a ‘large’ 4K (word; 8K byte) Digital Equipment Corporation (DEC) PDP8I computer, which was used for data acquisition, theoretical calculations and simulation studies. It was the first computer in the School. An 8K PDP8e was added shortly after for the same cost as an extra 4K of memory for the PDP8I.
Peter was promoted to Associate Professor in 1971. In 1972, Peter Barry (PHB; see Introduction) a QEII Fellow, also arrived to join the group, remaining a collaborator with Peter at UNSW for the rest of Peter’s time there.
In keeping with Peter’s enthusiasm for new technologies and new research projects, he wanted to develop a marine laboratory, similar to the laboratories at Woods Hole in the USA and Plymouth in the UK, in order to work on the giant axon of the squid. To work on squid required setting up a laboratory close to where the squid were caught, so in the early 1970s Peter obtained research funding and set up a small preliminary laboratory in a caravan on a farming property near Shell Harbour, south of Wollongong. The laboratory was established with Dirk Van Helden but, while the idea was excellent, there proved to be logistical problems in doing research so far from Sydney and unfortunately it never quite took off.
As mentioned earlier, Peter’s PhD students generally gained prestigious fellowships and positions in leading international laboratories, in no small measure a reflection of Peter’s international reputation, his international links and the excellent research training imparted to his students. Dulhunty, with her PhD completed in 1973, was awarded a Muscular Dystrophy Association Fellowship at the University of Rochester (USA), to work with Paul Horowicz and Clara Franzini-Armstrong; McBurney, with his PhD also completed in 1973, received a Florey Fellowship to work with Andrew Crawford at the University of Cambridge; Van Helden, with his PhD completed in 1975, was awarded a Ramaciotti Fellowship at UNSW in 1976–7, followed by a Nuffield Travelling Fellowship to work with Bernhard Frankenhaeuser at the Karolinska Institute in Stockholm and with Richard Keynes at the University of Cambridge.
David Adams (DJA; see Introduction) joined Peter’s research group as a BSc (Hons) student in 1973, before starting a PhD in 1974. He worked with Peter on the electrophysiology ofAplysianeurons, investigating various monovalent and divalent ionic currents, conductance changes, gating currents, and the effects of depressant drugs, obtaining his PhD in 1978 (52, 54, 57, 59, 63, 72–74, 81, 91; including two papers inNature, one inScienceand four in theJournal of Physiology). He received a Muscular Dystrophy Association Fellowship to work with Bertil Hille at the University of Washington in Seattle and a Beit Memorial Fellowship at University College, London. Dirk Van Helden, under Peter, developed computer programs to use the technique of noise analysis to determine indirectly the conductance and lifetime of single ionic channels in biological membranes. At this time, Owen Hamill had arrived in Sydney with a BSc from Monash University to do a PhD with Peter. He worked on synaptic transmission investigating the effects of general anaesthetics and ethanol (e. g. 49, 54, 59). Van Helden, with some early input from Hamill, used the noise analysis technique to investigate the effect of permeant cations and some anaesthetics on the lifetime and conductances of ACh endplate channels in muscle fibres (e.g. 60, 64, 67, 69–71, 75, 76, 79). In 1978, Van Helden left for the Karolinska Institute, returning in 1980 on a QEII Fellowship. Hamill completed his PhD in 1977 and after working as a Postdoctoral Fellow with Peter at UNSW (1978–9), obtained a Von Humboldt Fellowship to work at the Max-Planck-Institut für biophysikalische Chemie in Göttingen, Germany, with Erwin Neher and Bert Sakmann on the patch-clamp technique (for which Neher and Sakmann were awarded the Nobel Prize in 1991).
In 1976, following an invitation to write a major review on ‘Generation of end-plate potentials’ forPhysiological Reviews(55; to date cited 164 times), Peter was awarded a DSc from the UNSW and was promoted to a personal chair in the School of Physiology and Pharmacology. The following year, 1977, he was elected a Fellow of the AAS.
In the late 1970s, Peter stimulated the interest of the physical chemist Ray Golding in physiological problems, and they co-supervised a physical chemistry student, Tatsanee Mallanoo, in a PhD project on a physico-chemical analysis of synaptic transmission (1978). Peter also supervised the anaesthetist Thomas Torda’s MD project to investigate the effects of some anaesthetic drugs on neurotransmission at the mammalian neuromuscular junction (1978) (53, 62, 78). In the early 1980s, a PhD student from Canada, Ken Takeda, came to work with Peter and subsequently, together with PHB, investigated the effects of nitrate ions, divalent ions and external sodium concentration on the properties of endplate ACh channels (80, 90, 93). Takeda obtained a postdoctoral position in the Centre National de la Recherche Scientifique (CNRS) at Gif-sur-Yvette, France, and subsequently a permanent academic position with the CNRS at Strasbourg. Around this time, Peter also supervised the PhD project of an electrical engineer, Nick Datyner, on the control of acetylcholine secretion at mammalian motor nerve terminals (1981) (83, 94). Over this period, Peter had also been particularly interested in setting up the new technique of patch-clamping that was being developed in Germany by Neher and Sakmann. This directly measured the current in pA (10-12 A) passing through a single protein channel, and was thus able to determine the conductance and open duration of these channels directly, rather than inferring them indirectly by noise analysis. Through his international connections Peter was able to obtain the electronic circuits, generously supplied by Erwin Neher, to build the appropriate amplifier. A new PhD student, Nino Quartararo, jointly supervised by PHB and Peter Gage in PHB’s laboratory, then successfully built a patch-clamp amplifier and electrophysiology set-up, thus initiating patch-clamp measurements in Australia.
By this time, Peter had built up a large research facility that also included PHB’s laboratory. It comprised a PDP 11/34 computer for data analysis and theoretical studies, eight fully equipped electrophysiological laboratories with three PDP 11/03 computers for online data acquisition and analysis, and the older PDP8e and PDP8I computers. In this period Peter also attracted a number of international visitors who spent their study leave in his laboratory, such as Nancy Lane-Perham (1972) (40) from the University of Cambridge, James McLarnon (1978), Peter Vaughan (1979) from the University of British Columbia, John Mac-Donald (1980) from the University of Auckland, Alan Harvey (1979–80) (85) from the University of Strathclyde and Paul Adams (1981–2) from the State University of New York, Stony Brook. There were also two postdoctoral fellows, Dirk Van Helden who had returned as a QEII Fellow, and a Muscular Dystrophy Association Fellow, Ruth Wachtel from Duke University, as well as four PhD students, an MD student, an MSc student and a BSc (Hons) student, an electrical engineer as an NHMRC Research Associate, a senior Technical Officer, Rodney Malbon, an ARGC Student Assistant and some other support staff.
Figure 1. Shortly after the award of the
Nerve–Muscle Research Centre in 1982;
Peter (centre) with Peter H. Barry and Angela
Dulhunty. [© UNSW; UNSW Archives CN1127/4;
reproduced with permission from UNSW
publication
Uniken, no. 142(1), 19 February 1982]
In 1982, Peter was awarded one of the first ARC Centres of Excellence, the ‘Nerve Muscle Research Centre’, to investigate the normal and abnormal function of nerve and muscle and the signal transmission between them. The staff included three full-time permanent academic research staff (Peter as Director, PHB as Assistant Director and Angela Dulhunty, seconded from the University of Sydney; Fig. 1). New postdoctoral fellows over the next couple of years included Graham Collingridge (on leave from the University of Bristol) and Graham Lamb from the University of Melbourne; new PhD students included Brian Robertson from the UK, W. Roland Taylor, David McKinnon, Pankaj Sah, Chris French and Gavin Schneider, together with BSc Hons and BMedSci students and a number of other support staff including a computer programmer, two electrical engineers and an administrative assistant. The new facilities included a faster and more powerful PDP 11/44 computer to enable development of programs and data analysis to cope with twelve active research projects.
Some of Peter’s collaborative research highlights at the Centre included the following:
- Single channel currents were successfully recorded and analysed by Nino Quartararo, and later by David McKinnon, in intact denervated single muscle fibres (e.g. see fig. 7 in 104, 106, 121), for what was arguably the first time in Australia. The laboratories subsequently helped to train researchers in other Australian universities in this technique.
- Collingridge and Robertson began using acute brain slices for electrophysiology, a technique that was then practised in only a few laboratories worldwide, and successfully recorded spontaneous inhibitory postsynaptic currents in neurons in hippocampal slices using a single electrode voltage-clamp system (98, 101) and demonstrated that some general anaesthetics prolong the inhibitory currents (107). Peter’s group was the first to record such currents and use them to examine the effects of general anaesthetics on **Aergic synaptic transmission.
- Schneider started to record some very large chloride currents in cultured pulmonary alveolar cells, which would later lead to the observation of equally spaced current sublevels and a demonstration of ‘co-channel’ behaviour (116, 163).
- Chris French observed an interesting slow inward current in rat hippocampal neurons, which was blocked by tetrodotoxin. It was subsequently shown to be a persistent sodium current (108, 132) that plays a role in hypoxia (166).
- Peter and colleagues set up a three-microelectrode end-of-fibre voltage-clamp system and were the first to record asymmetrical charge movement in mammalian muscle fibres. There were some highly cited papers by Dulhunty and Peter Gage (e.g. 96, 105) on measurements showing a close link between asymmetrical charge movement across muscle membranes and activation of contraction in muscle in normal and paraplegic rats, and an interesting ultrastructural observation by them of internal cysternae of muscle fibres in normal and paraplegic rats (97, 102) that were later identified with crucial elements in the link between depolarization of the muscle tubular system and release of calcium from the sarcoplasmic reticulum that directly enables muscle contraction.
In 1984, after his productive tenure at UNSW, Peter was appointed as Professor and Head of Physiology in the JCSMR at the ANU, with an arrangement worked through with the Director of the JCSMR, Professor Bob Porter. Under the arrangement, Peter brought with him a support staff member and a number of his students, and the ANU provided some postdoctoral fellowships and a senior academic position. Peter was also able to take a significant amount of his equipment, including the PDP 11/44 computer and many of the electrophysiological set-ups, to the ANU.
Peter took with him the laboratory administrator, Rodney Malbon, six PhD students—Robertson, Sah, Taylor, McKinnon, French and Schneider—and a postdoctoral fellow, Graham Lamb (funded initially by UNSW and then on an ANU fellowship). Peter was joined in Canberra by other new ANU postdoctoral fellows—Alasdair Gibb from the UK, Mauri Krouse from the USA and Kevin Buckett from the UK. In addition, Dulhunty was the successful academic applicant for the position at the JCSMR. PHB’s laboratory remained at UNSW with the PDP 11/34 computer and some additional equipment. Nino Quartararo completed his PhD on ion channel measurements and continued for a few years with postdoctoral research in that laboratory as it subsequently expanded independently. It is clear that while Peter’s move from UNSW meant that the Nerve-Muscle Research Centre now ceased to exist as a funded unit, the core of its personnel had moved to the JCSMR and the research that had been stimulated and expanded during its lifetime continued not only with the large group at the ANU but also in PHB’s laboratory at UNSW, with good collaboration between the two groups.
On the personal side, Peter and Jill separated in the early 1980s, some years before his move to the ANU (the marriage being officially dissolved in 1991), and from that time on until the end of his life, his partner was Angela Dulhunty, his research colleague.
Australian National University, 1984–2005
Peter’s period at the ANU was marked by major academic achievements. He had been appointed to the John Eccles Chair of Physiology and Head of the Department of Physiology. The Physiology Department was dissolved in 1988 and replaced by the Division of Neuroscience. Peter remained in that Division for several years and then transferred to the Division of Biochemistry and Molecular Biology in 1999 and was a part of the Membrane Biology Program at the ANU. Peter’s science continued to flourish at the ANU and he made a major contribution to Australian physiology and biophysics, holding two very successful Patch Clamp Workshops at the JCSMR between 1986 and 1989 and then a series of Curtin Conferences at Canberra Grammar School from 1995 to 2003. These conferences were re-established in 2009 by the Ion Channels and Transporters community in his honour.
Peter’s work between 1984 and 1990 was in part a continuation of a number of projects begun at UNSW, with PhD student and postdoctoral fellows who transferred to the ANU with him. This work included an extensive study of post synaptic currents in the hippocampus, with important work on anaesthetic effects on these currents, with C. French, Robertson, Sah, Gibb and Frances Edwards (107, 108, 110, 123, 125, 127, 128). Fran Edwards (123) started as a PhD student with Peter for a couple of years before she transferred her ANU scholarship to Germany for personal reasons, to complete her PhD with the subsequent Nobel prize winner, Bert Sakmann.
Peter continued the first single-channel work to be performed in Australia, which started at UNSW, with an analysis of anion channels in pulmonary epithelia with Schneider and Krouse in a strong collaboration with John Young and David Cook from the University of Sydney. This research included some ground-breaking observations and analysis of multiple conductance levels in the channels (111) and led to a publication inNature(113). The novel and productive studies of gating charge movement and excitation–contraction coupling in mammalian muscle continued with Dulhunty, Lamb, Bruce Wakefield and a collaboration with Ian Neering and Martin Fryer at UNSW (115, 118, 122, 126, 129, 130). The long-term collaboration with PHB and Quartararo on ion permeation also continued into this period (121). A stream of visitors to the ANU during this time included Florian Dreyer (Germany), David Leaver (Australia) (124), John Macdonald (NZ), Bob Martin (USA), Sue Pockett (NZ), Bob French (Canada), Joe McArdle (USA) (133) and Pei-Hong Zhu (China), together with a collaboration with David Hirst (151) from the University of Melbourne.
Peter began an extensive collaboration with the physical chemist/theoretical biophysicist Shin-Ho Chung and the mathematician John Moore at the ANU, which led to the development of the Hidden Markov Model (HMM) for high-powered analysis of single-channel currents and definition of the probability of small subconductance levels that were difficult to distinguish from background noise (136). Other collaborators in this work included Louis Premkumar and Derek Laver (134, 136, 141, 146, 163, 169). HMM was also used to illustrate a novel phenomenon of coupled gating between channels in hippocampal neurons (137). This important, innovative model has been used by numerous investigators in Australia and overseas and was developed commercially. The model was applied to choride channels in the sarcoplasmic reticulum of skeletal muscle in a collaboration with Dulhunty and Laver (153).
Another discovery by Peter’s laboratory during the 1980s was the persistent sodium current that underlies the massive increase in intracellular calcium during ischaemia in cardiac myocytes and neurons. This collaborative work included an extensive characterization of the current and its sensitivity to the redox environment started with Lamb and Wakefield (130). It remained a mainstream interest in the laboratory over the following fifteen years with collaborative contributions from Buckett, French and Sah (132), David Saint and Yue-Kun Ju (135, 140, 147, 151, 156, 158) and Anna Hammarström (166, 173, 179, 184, 185, 192).
The late 1980s to early 1990s also resulted in the beginning of a long-term project with **A-induced currents and **AAreceptors. This work included Peter’s collaborations with research assistant John Curmi, and PhD students and postdoctoral fellows including L. Premkumar, Chung, Saint, Bryndis Birnir, Louise Tierney, Julie Dalziel, Andrea Everitt, Michelle Lim and Mansoureh Eghbali (134, 135, 143, 144, 148, 149, 161, 162, 175, 176, 178, 182, 187, 188, 201). To pursue these studies in greater detail and to take advantage of the rapidly evolving application of molecular biology techniques to ion channels in the 1990s, Peter began a rewarding and fruitful collaboration with Graeme Cox, a biochemist and molecular biologist at the JCSMR. They expressed **AAreceptors, investigated the role of various subunits in determining the characteristics of **AAreceptor channels and undertook extensive mutation analysis to understand the conductance and gating of these channels and the molecular determinants of their drug responses, including anaesthetic actions. This work is continuing at the JCSMR under the direction of Louise Tierney. The first publication in this extensive work was in 1992 (142) and the most recent publication was in 2008 (202), with numerous communications in between, including a paper inNature. The work has been in collaboration with numerous PhD students and postdoctoral fellows, including Tierney, Birnir, Lim, Eghbali, Susan Howitt, Brett Cromer and Tien (Cindy) Luu (152, 159, 162, 164, 167, 168, 171, 174, 177, 190, 196, 198). This novel research led to a paradigm shift in understanding ion channel conductance by showing that single channel conductance could vary with ligand and drug application. This resulted in Peter developing the concept that channels could associate and synchronously gate together to produce variable conductance units, and predicting that the increased conductance of such resultant ‘channels’ under certain circumstances may be due to the direct interactions between the individual channels. This hypothesis has subsequently been supported by experiments indicating that proteins like **ARAP, which facilitate channel clustering, also lead to high conductance state ‘channels’ (198).
The early 1990s produced the unprecedented discovery of viral ion channels, which also formed a major research area for Peter’s group over the following fifteen years and led to two patents. This research was also with Graeme Cox, together with Gary Ewart, Anita Premkumar, Sabine Piller, David Jans, Patricia Jans, Julian Melton, Lauren Wilson, Philip Board and Eric Gowans, a virologist from the Burnet Institute in Melbourne (154, 155, 157, 165, 170, 172, 183, 185, 186, 188, 191, 194, 197, 199). The viral ion channel research formed the impetus for setting up the biotechnology company Biotron. Drugs developed by the company and based on the ANU research have been shown to block viral ion channels and prevent viral replication. These drugs are currently in phase Ib/IIa clinical trials for the hepatitis C virus.
Finally, another area of research for Peter opened up in the early 2000s with the remarkable discovery that glutathione transferases and CLIC proteins are novel modulators of ryanodine receptor ion channels and form one of the few endogenous inhibitors of the cardiac ryanodine receptor. This work, which began in collaboration with Dulhunty and Board, and with Pierre Pouliquin and Yasser Abdelatiff (181, 193, 195, 200), is continuing at the ANU. Other research collaborators with Peter not mentioned elsewhere over this recent period at the ANU included postdoctoral fellows Nesrin Oszarac, N. P. Pillai (152, 159, 160) and Weiping Wu, PhD students Steven Weiss, Rolla Khorie and Victoria Seymour, and research assistant Terry Sutherland (157).
Figure 2. Peter, a founder, shareholder and Director of the biotechnology company Biotron Pty Ltd, in his office at the time Biotron began trading on the Australian Stock Exchange on 22 January 2001. Peter was elated, as this was the culmination of three years of intense work and negotiation. [© Newspix/photographer: John Feder; reproduced with permission]
During the period 1998–2005, Peter was instrumental in developing the biotechnology company Biotron. Figure 2 shows Peter’s elation when Biotron started to trade on the Australian Stock Exchange. He was passionate in his belief that research should be developed commercially. The company was originally developed in collaboration with a business partner, Peter Scott, and included JCSMR researchers Chris Parish, Board, Dulhunty and Cox. The company was eventually listed on the Australian Stock Exchange and Peter remained a Board member until his death in 2005.
Scientific achievements in biophysics and neuroscience
Throughout his research career, Peter’s work on neurotransmission, skeletal muscle and the structure and function of ion channels was highly productive. Some particularly noteworthy areas of his collaborative research include:
- with Bob Eisenberg (24–26), the use of glycerol treatment to isolate and investigate the electrical properties and role of the TTS in muscle, continued with Angela Dulhunty (41, 42), and extended to the generation of end-plate potentials in muscle (33, 37, 55)
- showing that general anaesthetics prolong inhibitory postsynaptic currents in hippocampal neurons (107)
- with Dulhunty, being the first to measure asymmetric charge movement in mammalian muscle, which showed a fibre-type dependence (96), and elucidating the role of the dihydropyridine receptor in skeletal muscle excitation–contraction coupling (126)
- suggesting that activation of ion channels in pulmonary alveolar cells was coupled (163)
- with Peter Barry describing cation permeability through acetylcholine receptors (68, 71, 76, 80, 90, 93, 104)
- investigating asymmetrical charge movements in neurons with David Adams (52, 63, 74)
- with Chris French characterizing the persistent sodium channel (108, 132), later showing it to be increased in hypoxia, and reversed by reducing agents
- showing that a series of virus proteins also formed ion channels in lipid bilayers (154, 155, 157) and that some of them could also form channels in neurons, depolarizing and killing them (165, 170)
- uncovering spontaneously opening **AAchannels in neurons that could be modulated by drugs (e.g. 158, 159, 175, 176, 178, 182)
- showing that members of the glutathione transferase structural family modulate ryanodine receptor Ca2+ channels (181)
- showing, in a collaborative project with plant biologists, that a wheat protein that has anti-bacterial and anti-fungal activity, forms ion channels (180).
Overall, Peter’s research resulted in more than 200 publications, the majority in high-impact journals (including sixteen inNatureand three inScience), that included a large number of invited reviews and invited book chapters. His work was cited well over 7,000 times, with nineteen publications receiving over 100 citations each. He also held numerous research grants, mainly from the NHMRC and ARC.
Service to Australian science
Peter introduced many cutting-edge electrophysiological techniques to Australia. He established his laboratory as a central resource for training other researchers, and his organization of annual Curtin Conferences in Canberra on ion channels from 1995, various Patch Clamp Workshops and the **A 2000 International Symposium reinforced this role. The new techniques included: voltage-clamping with operational amplifiers; the three-electrode voltage clamp for measuring asymmetric charge movement in muscle (with Dulhunty); the patch-clamp technique for directly studying ion channels (with PHB and Nino Quartararo); and (with members of his group at the ANU) the hippocampal slice technique to study synaptic currents.
Peter had more than thirty successful PhD students, many of whom went on to establish international reputations, and at least twenty-two postdoctoral fellows. He also attracted numerous distinguished senior scientists from around the world who visited and collaborated with his group at both UNSW and the JCSMR. Peter was an excellent speaker with innumerable invitations to speak at national and international conferences. His founding role in Biotron, and on its Board, together with two patents of his own, will be of continuing value in encouraging the commercialization of basic research discoveries in Australia.
Awards and affiliations
- In 1977, Peter was elected a Fellow of the Australian Academy of Science. He served on the Council (1983–6) and was Vice-President in 1985–6.
- In 1976, he was awarded a DSc from the UNSW.
- In 1982, he was awarded one of the first ARC Research Centres of Excellence, the Nerve–Muscle Research Centre at UNSW.
Figure 3. Peter’s award of the Bob Robertson Medal in 2004. Peter (centre) with the then President of the Australian Society for Biophysics and Judith Whitworth, then director of the John Curtin School of Medical Research.
- In 2004, he was awarded the Bob Robertson Medal of the Australian Society for Biophysics, named in honour of Sir Rutherford (Bob) Robertson, in recognition of Peter’s outstanding contributions to the field of biophysics in Australia, his contributions to the Society— of which he had been a member for many years—and to Australian science in general. Because he was too ill at the last moment to have it presented at the Society’s meeting, it was awarded a few months later by the Society’s then President, Peter Barry, at a special presentation in the JCSMR with Judith Whitworth, the Director (Fig. 3).
- In 2005, Peter was elected an Honorary Member of the Australian Physiological Society (AuPS), formerly the Australian Physiological and Pharmacological Society (APPS), of which he had been a member since 1964, Treasurer in 1973–5 and President in 2000–4.
- He was also a member of the International Brain Research Organisation and the Australian Society for Biochemistry and Molecular Biology.
Some personal comments
Peter was a very engaging person with a keen sense of humour, who was always very supportive of research colleagues and staff. He was especially proud of his children— Michelle, a general practitioner, Jennifer, a lawyer, Peter, an aerospace engineer and David, a successful business man—and of his grandchildren. He was also keenly interested in music, in native vegetation regeneration on his hobby farm, and in activities such as tennis, skiing, horse riding and camping. He is survived by his former wife, Jill, their four children and eleven grandchildren, and his subsequent partner, Angela.
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